title: Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Randomized double-blind placebo-controlled trial of thalidomide in combination with gemcitabine and Carboplatin in advanced non-small-cell lung cancer. Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial Rociletinib in EGFR-mutated non-small-cell lung cancer. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. A Randomized Phase 3 Trial Comparing Pemetrexed/Carboplatin and Docetaxel/Carboplatin as First-Line Treatment for Advanced, Nonsquamous Non-small Cell Lung Cancer Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. The role of pemetrexed as maintenance treatment in advanced NSCLC: a Phase III randomized trial Influence of comorbidity on survival, toxicity and health-related quality of life in patients with advanced non-small-cell lung cancer receiving platinum-doublet chemotherapy. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial First-line crizotinib versus chemotherapy in ALK-positive lung cancer. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Docetaxel vs. vinorelbine in elderly patients with advanced non--small-cell lung cancer: a hellenic oncology research group randomized phase III study. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the Project ENABLE II randomized controlled trial. Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group (HeCOG). American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. A randomized study of gemcitabine plus cisplatin and vinorelbine plus cisplatin in patients with advanced non-small-cell lung cancer. Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL) Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. Symptom and Quality of Life Benefit of Afatinib in Advanced Non–Small-Cell Lung Cancer Patients Previously Treated with Erlotinib or Gefitinib: Results of a Randomized Phase IIb/III Trial (LUX-Lung 1) Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. The PARAMOUNT trial: a phase III randomized study of maintenance pemetrexed versus placebo immediately following induction first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. The IASLC Lung Cancer Staging Project: The New Database to Inform the Eighth Edition of the TNM Classification of Lung Cancer Safety and efficacy of weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in elderly patients with advanced non-small-cell lung cancer. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. Gefitinib versus pemetrexed as second‐line treatment in patients with nonsmall cell lung cancer previously treated with platinum‐based chemotherapy (KCSG‐LU08‐01) Docetaxel versus docetaxel plus gemcitabine as front-line treatment of patients with advanced non-small cell lung cancer: a randomized, multicenter phase III trial. Safety, Resource Use, and Quality of Life in Paramount: A Phase III Study of Maintenance Pemetrexed Versus Placebo after Induction Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03). Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Increased satisfaction with care and lower costs: results of a randomized trial of in-home palliative care. Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. Looking Beyond Surveillance, Epidemiology, and End Results: Patterns of Chemotherapy Administration for Advanced Non-small Cell Lung Cancer in a Contemporary, Diverse Population Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. Quality of Life Analysis of TORCH, a Randomized Trial Testing First-Line Erlotinib Followed by Second-Line Cisplatin/Gemcitabine Chemotherapy in Advanced Non–Small-Cell Lung Cancer Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). Developing a service model that integrates palliative care throughout cancer care: the time is now. Phase III trial comparing vinflunine with docetaxel in second-line advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy. Health-Related Quality-of-Life in a Randomized Phase III First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients from Asia with Advanced NSCLC (IPASS) Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer Pemetrexed versus erlotinib in pretreated patients with advanced non–small cell lung cancer: A Hellenic Oncology Research Group (HORG) randomized phase 3 study Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Impact of an inpatient palliative care team: a randomized control trial. Quality of life and disease-related symptoms in previously treated Japanese patients with non-small-cell lung cancer: results of a randomized phase III study (V-15-32) of gefitinib versus docetaxel. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer.
abstract: BACKGROUND Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits lig and binding . We aim ed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated , stage IV , non-squamous non-small-cell lung cancer ( NSCLC ) . METHODS We did this r and omised , open-label , controlled phase 3 study at 103 sites in 20 countries . Patients aged 18 years or older , with an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 - 2 and adequate organ function , were r and omly assigned 1:1 to treatment with a block r and omisation scheme ( block size of four ) via a telephone-based interactive voice-response system or interactive web-response system . Patients received either cisplatin 75 mg/m(2 ) and pemetrexed 500 mg/m(2 ) on day 1 of a 3-week cycle for a maximum of six cycles alone , or with necitumumab 800 mg on days 1 and 8 . Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects . R and omisation was stratified by smoking history , ECOG performance status , disease histology , and geographical region . Patients and study investigators were not masked to group assignment . The primary endpoint was overall survival . Efficacy analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00982111 . FINDINGS Between Nov 11 , 2009 , and Feb 2 , 2011 , we r and omly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin ( n=315 ) or pemetrexed and cisplatin alone ( n=318 ) . Enrolment was stopped on Feb 2 , 2011 , after a recommendation from the independent data monitoring committee . There was no significant difference in overall survival between treatment groups , with a median overall survival of 11·3 months ( 95 % CI 9·5 - 13·4 ) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months ( 10·1 - 13·1 ) in the pemetrexed and cisplatin group ( hazard ratio 1·01 [ 95 % CI 0·84 - 1·21 ] ; p=0·96 ) . The incidence of grade 3 or worse adverse events , including deaths , was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group ; in particular , deaths regarded as related to study drug were reported in 15 ( 5 % ) of 304 patients in the necitumumab group versus nine ( 3 % ) of 312 patients in the pemetrexed and cisplatin group . Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group ( 155 [ 51 % ] of 304 vs 127 [ 41 % ] of 312 patients ) . Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3 - 4 rash ( 45 [ 15 % ] of 304 vs one [ < 1 % ] of 312 patients in the pemetrexed and cisplatin alone group ) , hypomagnesaemia ( 23 [ 8 % ] vs seven [ 2 % ] patients ) , and grade 3 or higher venous thromboembolic events ( 23 [ 8 % ] vs 11 [ 4 % ] patients ) than did those in the pemetrexed and cisplatin alone group . INTERPRETATION Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC . Unless future studies identify potentially useful predictive biomarkers , necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin . FUNDING Eli Lilly and Company BACKGROUND The study compared the efficacy of a first-line treatment with day 1 i.v . vinorelbine ( NVBiv ) and day 8 oral vinorelbine ( NVBo ) versus docetaxel ( DCT ) in a cisplatin-based combination in advanced non-small-cell lung cancer , in terms of time to treatment failure ( TTF ) , overall response , progression-free survival ( PFS ) , overall survival ( OS ) , tolerance and quality of life ( QoL ) . METHODS Patients were r and omly assigned to receive cisplatin 80 mg/m2 with NVBiv 30 mg/m2 on day 1 and NVBo 80 mg/m2 on day 8 every 3 weeks , after a first cycle of NVBiv 25 mg/m2 on day 1 and NVBo 60 mg/m2 on day 8 ( arm A ) or cisplatin 75 mg/m2 and DCT 75 mg/m2 on day 1 every 3 weeks ( arm B ) , for a maximum of six cycles in both arms . RESULTS From 2 February 2004 to 1 January 2006 , 390 patients were entered in a r and omised study and 381 were treated . The patient characteristics are as follows ( arms A/B ) : metastatic ( % ) 80.5/84.8 ; patients with three or more organs involved  ( % ) 45.3/40.8 ; median age 59.4/62.1 years ; male 139/146 ; squamous ( % ) 34.2/33.5 ; adenocarcinoma ( % ) 41.6/39.3 ; median TTF ( arms A/B in months ) [ 95 % confidence interval ( CI ) ] : 3.2 ( 3.0 - 4.2 ) , 4.1 ( 3.4 - 4.5 ) ( P = 0.19 ) ; overall response ( arms A/B ) ( 95 % CI ) : 27.4 % ( 21.2 % to 34.2 % ) , 27.2 % ( 21.0 % to 34.2 % ) ; median PFS ( arms A/B in months ) ( 95 % CI ) : 4.9 ( 4.4 - 5.9 ) , 5.1 ( 4.3 - 6.1 ) ( P = 0.99 ) and median OS ( arms A/B in months ) ( 95 % CI ) : 9.9 ( 8.4 - 11.6 ) , 9.8 ( 8.8 - 11.5 ) ( P = 0.58 ) . The median survival for squamous histology was 8.87/9.82 months and for adenocarcinoma 11.73/11.60 months for arms A and B , respectively . Main haematological toxicity was grade 3 - 4 neutropenia : 24.4 % ( arm A ) and 28.8 % ( arm B ) . QoL as measured by the Lung Cancer Symptom Scale was similar in both arms . CONCLUSIONS Both arms provided similar efficacy in terms of response , time-related parameters and QoL , with an acceptable tolerance profile . In the current Global Lung Oncology Branch trial 3 , NVBo was shown to be effective as a substitute for the i.v . formulation . This can relieve the burden of the i.v . injection on day 8 and can optimise the hospital 's re sources and improve patient convenience BACKGROUND Necitumumab is a second-generation , recombinant , human immunoglobulin G1 EGFR antibody . In this study , we aim ed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer . METHODS We did this open-label , r and omised phase 3 study at 184 investigative sites in 26 countries . Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer , with an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 - 2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion . Enrolled patients were r and omly assigned central ly 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block r and omisation scheme ( block size of four ) by a telephone-based interactive voice response system or interactive web response system . Chemotherapy was gemcitabine 1250 mg/m(2 ) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2 ) administered intravenously over 120 min on day 1 of a 3-week cycle . Necitumumab 800 mg , administered intravenously over a minimum of 50 min on days 1 and 8 , was continued after the end of chemotherapy until  disease progression or intolerable toxic side-effects occurred . R and omisation was stratified by ECOG performance status and geographical region . Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash -- a class effect of EGFR antibodies -- that would have unmasked most patients and investigators to treatment . The primary endpoint was overall survival , analysed by intention to treat . We report the final clinical analysis . This study is registered with Clinical Trials.gov , number NCT00981058 . FINDINGS Between Jan 7 , 2010 , and Feb 22 , 2012 , we enrolled 1093 patients and r and omly assigned them to receive necitumumab plus gemcitabine and cisplatin ( n=545 ) or gemcitabine and cisplatin ( n=548 ) . Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group ( median 11·5 months [ 95 % CI 10·4 - 12·6 ] ) vs 9·9 months [ 8·9 - 11·1 ] ; stratified hazard ratio 0·84 [ 95 % CI 0·74 - 0·96 ; p=0·01 ] ) . In the necitumumab plus gemcitabine and cisplatin group , the number of patients with at least one grade 3 or worse adverse event was higher ( 388 [ 72 % ] of 538 patients ) than in the gemcitabine and cisplatin group ( 333 [ 62 % ] of 541 ) , as was the incidence of serious adverse events ( 257 [ 48 % ] of 538 patients vs 203 [ 38 % ] of 541 ) . More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3 - 4 hypomagnesaemia ( 47 [ 9 % ] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [ 1 % ] of 541 in the gemcitabine and cisplatin group ) and grade 3 rash ( 20 [ 4 % ] vs one [ < 1 % ] ) . Including events related to disease progression , adverse events with an outcome of death were reported for 66 ( 12 % ) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 ( 11 % ) of 541 patients in the gemcitabine and cisplatin group ; these were deemed to be related to study drugs in 15 ( 3 % ) and ten ( 2 % ) patients , respectively . Overall , we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations . INTERPRETATION Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease . FUNDING Eli Lilly and Company PURPOSE Cancers rely on angiogenesis for their growth and dissemination . We hypothesized that thalidomide , an oral antiangiogenic agent , when combined with chemotherapy , and as maintenance treatment , would improve survival in patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Seven hundred twenty-two patients were r and omly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years . All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles . End points were overall survival ( OS ) , progression-free survival ( PFS ) , response rate , grade 3/4 toxicity , and quality of life ( QoL ) . RESULTS The median OS rates were 8.9 months ( placebo ) and 8.5 months ( thalidomide ) . The hazard ratio ( HR ) was 1.13 ( 95 % CI , 0.97 to 1.32 ; P = .12 ) . The 2-year survival rate was 16 % and 12 % in the placebo and thalidomide arms , respectively . The PFS results were consistent with those for OS . The risk of having a thrombotic event was increased by 74 % in the thalidomide group : HR of 1.74 ( 95 % CI , 1.20 to 2.52 ; P = .003 ) . There were no differences in hematologic toxicities , but a slight excess of rash and neuropathy in the thalidomide group . QoL scores were similar but thalidomide was associated with less insomnia , and more constipation and peripheral neuropathy . In a retrospective analysis , patients with nonsquamous histology in the thalidomide group had a poorer survival : 2-year risk difference of 10 % ( 95 % CI , 4 % to 16 % ; P < .001 ) . CONCLUSION In this large trial of patients with NSCLC , thalidomide in combination with chemotherapy did not improve survival overall , but increased the risk of thrombotic events . Unexpectedly , survival was significantly worse in patients with nonsquamous histology Purpose Liposomal cisplatin was developed to reduce the systemic toxicity of cisplatin , particularly the nephrotoxicity , and it has been used in combination with other agents in pancreatic and head and neck cancers and non-small-cell lung cancer ( NSCLC ) . Our objective was to compare the effectiveness of lipoplatin combined with paclitaxel versus cisplatin with paclitaxel in advanced non-squamous NSCLC . Methods During 2007–2010 , 202 patients with non-squamous NSCLC ( stage IIIB and IV ) were recruited from the two participating institutions and divided into two arms : Arm A was treated with liposomal cisplatin 200 mg/m2 combined with paclitaxel 135 mg/m2 and Arm B with cisplatin 75 mg/m2 in combination with paclitaxel 135 mg/m2 , repeated every 2 weeks . The number of cycles administered was 632 ( Arm A ) and 640 ( Arm B ) , totaling 1,272 . Results A partial response was achieved by 59.22 % of Arm A patients versus 42.42 % of Arm B , and the difference was statistically significant ( P 0.036 ) . The median survival time in months was 10 for Arm A and 8 for Arm B ( P 0.1551 ) . After 18 months , the number of surviving patients was double for Arm A versus Arm B. Conclusion Liposomal cisplatin in combination with paclitaxel produces a statistically significantly higher response rate than cisplatin combined with paclitaxel in non-squamous NSCLC BACKGROUND The OPTIMAL study found that erlotinib improved progression-free survival ( PFS ) versus st and ard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) . This report describes the quality of life ( QoL ) and up date d PFS analyses from this study . PATIENTS AND METHODS Chinese patients ≥ 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received erlotinib ( 150 mg/day ; n = 82 ) or gemcitabine-carboplatin ( n = 72 ) . The primary efficacy end point was PFS ; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung ( FACT-L ) question naire , Trial Outcome Index ( TOI ) and Lung Cancer Subscale ( LCS ) . RESULTS Patients receiving erlotinib experienced clinical ly relevant improvements in QoL compared with the chemotherapy group in total FACT-L , TOI and LCS ( P < 0.0001 for all scales ) . Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 ( non-significant ) . In the up date d analysis , PFS was significantly longer for erlotinib than chemotherapy ( median PFS 13.7 versus 4.6 months ; HR = 0.164 , 95 % CI = 0.105 - 0.256 ; P < 0.0001 ) , which was similar to the previously reported primary analysis . CONCLUSION Erlotinib  improves QoL compared with st and ard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC BACKGROUND Previous , uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer . METHODS In this phase 3 , open-label study , we r and omly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib ( 250 mg per day ) ( 609 patients ) or carboplatin ( at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute ) plus paclitaxel ( 200 mg per square meter of body-surface area ) ( 608 patients ) . The primary end point was progression-free survival . RESULTS The 12-month rates of progression-free survival were 24.9 % with gefitinib and 6.7 % with carboplatin-paclitaxel . The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority , as compared with carboplatin-paclitaxel , with respect to progression-free survival in the intention-to-treat population ( hazard ratio for progression or death , 0.74 ; 95 % confidence interval [ CI ] , 0.65 to 0.85 ; P<0.001 ) . In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene ( EGFR ) mutation , progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel ( hazard ratio for progression or death , 0.48 ; 95 % CI , 0.36 to 0.64 ; P<0.001 ) , whereas in the subgroup of 176 patients who were negative for the mutation , progression-free survival was significantly longer among those who received carboplatin-paclitaxel ( hazard ratio for progression or death with gefitinib , 2.85 ; 95 % CI , 2.05 to 3.98 ; P<0.001 ) . The most common adverse events were rash or acne ( in 66.2 % of patients ) and diarrhea ( 46.6 % ) in the gefitinib group and neurotoxic effects ( 69.9 % ) , neutropenia ( 67.1 % ) , and alopecia ( 58.4 % ) in the carboplatin-paclitaxel group . CONCLUSIONS Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia . The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib . ( Clinical Trials.gov number , NCT00322452 . BACKGROUND Activating BRAF(V600E ) ( Val600Glu ) mutations are found in about 1 - 2 % of lung adenocarcinomas , which might provide an opportunity for targeted treatment in these patients . Dabrafenib is an oral selective inhibitor of BRAF kinase . We did a trial to assess the clinical activity of dabrafenib in patients with advanced non-small-cell lung cancer ( NSCLC ) positive for the BRAF(V600E ) mutation . METHODS In this phase 2 , multicentre , non-r and omised , open-label study , we enrolled previously treated and untreated patients with stage IV metastatic BRAF(V600E)-positive NSCLC . Patients received oral dabrafenib 150 mg twice daily . The primary endpoint was investigator-assessed overall response , which was assessed in patients who had received at least one dose of dabrafenib ; safety was also assessed in this population . The study is ongoing but not enrolling patients in this cohort . This trial is registered with Clinical Trials.gov , number NCT01336634 . FINDINGS Between Aug 3 , 2011 , and Feb 25 , 2014 , 84 patients were enrolled , six of whom had not previously received systemic treatment for NSCLC . 26 of the 78 previously treated patients achieved an investigator-assessed overall response ( 33 % [ 95 % CI 23 - 45 ] ) . Four of the six previously untreated patients had an objective response . One patient died from an intracranial haemorrhage that was judged by the investigator to be due to the study drug . Serious adverse events were reported in 35 ( 42 % ) of 84 patients . The most frequent grade 3 or worse adverse events were cutaneous squamous-cell carcinoma in ten ( 12 % ) , asthenia in four ( 5 % ) , and basal-cell carcinoma in four ( 5 % ) . INTERPRETATION Dabrafenib showed clinical activity in BRAF(V600E)-positive NSCLC . Our findings suggest that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options . FUNDING GlaxoSmithKline BACKGROUND Anaplastic lymphoma kinase ( ALK ) gene rearrangements are oncogenic drivers of non-small-cell lung cancer ( NSCLC ) . Brigatinib ( AP26113 ) is an investigational ALK inhibitor with potent pre clinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors . We aim ed to assess brigatinib in patients with advanced malignancies , particularly ALK-rearranged NSCLC . METHODS In this ongoing , single-arm , open-label , phase 1/2 trial , we recruited patients from nine academic hospitals or cancer centres in the USA and Spain . Eligible patients were at least 18 years of age and had advanced malignancies , including ALK-rearranged NSCLC , and disease that was refractory to available therapies or for which no curative treatments existed . In the initial dose-escalation phase 1 stage of the trial , patients received oral brigatinib at total daily doses of 30 - 300 mg ( according to a st and ard 3 + 3 design ) . The phase 1 primary endpoint was establishment of the recommended phase 2 dose . In the phase 2 expansion stage , we assessed three oral once-daily regimens : 90 mg , 180 mg , and 180 mg with a 7 day lead-in at 90 mg ; one patient received 90 mg twice daily . We enrolled patients in phase 2 into five cohorts : ALK inhibitor-naive ALK-rearranged NSCLC ( cohort 1 ) , crizotinib-treated ALK-rearranged NSCLC ( cohort 2 ) , EGFRT790M-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor ( cohort 3 ) , other cancers with abnormalities in brigatinib targets ( cohort 4 ) , and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active , measurable , intracranial CNS metastases ( cohort 5 ) . The phase 2 primary endpoint was the proportion of patients with an objective response . Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment . This trial is registered with Clinical Trials.gov , number NCT01449461 . FINDINGS Between Sept 20 , 2011 , and July 8 , 2014 , we enrolled 137 patients ( 79 [ 58 % ] with ALK-rearranged NSCLC ) , all of whom were treated .  Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase ( 240 mg daily ) and grade 4 dyspnoea ( 300 mg daily ) . We initially chose a dose of 180 mg once daily as the recommended phase 2 dose ; however , we also assessed two additional regimens ( 90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg ) in the phase 2 stage . four ( 100 % [ 95 % CI 40 - 100 ] ) of four patients in cohort 1 had an objective response , 31 ( 74 % [ 58 - 86 ] ) of 42 did in cohort 2 , none ( of one ) did in cohort 3 , three ( 17 % [ 4 - 41 ] ) of 18 did in cohort 4 , and five ( 83 % [ 36 - 100 ] ) of six did in cohort 5 . 51 ( 72 % [ 60 - 82 ] ) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response ( 44 [ 62 % ( 50 - 73 ) ] had a confirmed objective response ) . All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response ( 100 % [ 63 - 100 ] ) . Three ( 50 % [ 95 % CI 12 - 88 ] ) of six patients in cohort 5 had an intracranial response . The most common grade 3 - 4 treatment-emergent adverse events across all doses were increased lipase concentration ( 12 [ 9 % ] of 137 ) , dyspnoea ( eight [ 6 % ] ) , and hypertension ( seven [ 5 % ] ) . Serious treatment-emergent adverse events ( excluding neoplasm progression ) reported in at least 5 % of all patients were dyspnoea ( ten [ 7 % ] ) , pneumonia ( nine [ 7 % ] ) , and hypoxia ( seven [ 5 % ] ) . 16 ( 12 % ) patients died during treatment or within 31 days of the last dose of brigatinib , including eight patients who died from neoplasm progression . INTERPRETATION Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC . These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC . A r and omised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospect ively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial ( 90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg ) . FUNDING ARIAD Pharmaceuticals BACKGROUND Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer ( NSCLC ) setting . The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy . We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC . METHODS In this r and omised , open-label , phase 2 cohort of a multicohort study ( KEYNOTE-021 ) , patients were enrolled at 26 medical centres in the USA and Taiwan . Patients with chemotherapy-naive , stage IIIB or IV , non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were r and omly assigned ( 1:1 ) in blocks of four stratified by PD-L1 tumour proportion score ( < 1 % vs ≥1 % ) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy . The primary endpoint was the proportion of patients who achieved an objective response , defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked , independent central review , in the intention-to-treat population , defined as all patients who were allocated to study treatment . Significance threshold was p<0·025 ( one sided ) . Safety was assessed in the as-treated population , defined as all patients who received at least one dose of the assigned study treatment . This trial , which is closed for enrolment but continuing for follow-up , is registered with Clinical Trials.gov , number NCT02039674 . FINDINGS Between Nov 25 , 2014 , and Jan 25 , 2016 , 123 patients were enrolled ; 60 were r and omly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group . 33 ( 55 % ; 95 % CI 42 - 68 ) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 ( 29 % ; 18 - 41 ) of 63 patients in the chemotherapy alone group ( estimated treatment difference 26 % [ 95 % CI 9 - 42 % ] ; p=0·0016 ) . The incidence of grade 3 or worse treatment-related adverse events was similar between groups ( 23 [ 39 % ] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [ 26 % ] of 62 in the chemotherapy alone group ) . The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia ( seven [ 12 % ] of 59 ) and decreased neutrophil count ( three [ 5 % ] ) ; an additional six events each occurred in two ( 3 % ) for acute kidney injury , decreased lymphocyte count , fatigue , neutropenia , and sepsis , and thrombocytopenia . In the chemotherapy alone group , the most common grade 3 or worse events were anaemia ( nine [ 15 % ] of 62 ) and decreased neutrophil count , pancytopenia , and thrombocytopenia ( two [ 3 % ] each ) . One ( 2 % ) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two ( 3 % ) of 62 patients in the chemotherapy group : one because of sepsis and one because of pancytopenia . INTERPRETATION Combination of pembrolizumab , carboplatin , and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC . This finding is being further explored in an ongoing international , r and omised , double-blind , phase 3 study . FUNDING Merck & BACKGROUND Atezolizumab is a humanised antiprogrammed death-lig and 1 ( PD-L1 ) monoclonal antibody that inhibits PD-L1 and programmed death-1 ( PD-1 ) and PD-L1 and B7 - 1 interactions , reinvigorating anticancer immunity . We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer . METHODS We did a r and omised , open-label , phase 3 trial ( OAK ) in 194 academic or community oncology centres in 31 countries . We enrolled patients who had squamous or non-squamous non-small-cell lung cancer , were 18 years or older , had measurable disease per Response Evaluation Criteria in Solid Tumors , and had an Eastern Cooperative Oncology Group performance status of 0 or 1 . Patients had received one to two previous cytotoxic chemotherapy regimens ( one or more platinum based combination therapies ) for stage IIIB or IV non-small-cell lung cancer . Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel , CD137 agonists , anti-CTLA4 , or therapies targeting the PD-L1 and PD-1 pathway were excluded . Patients were r and omly assigned ( 1:1 ) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block r and omisation ( block size of eight ) via an interactive voice or web response system . Co primary endpoints were overall survival in the intention-to-treat ( ITT ) and PD-L1-expression population TC1/2/3 or IC1/2/3 ( ≥1 % PD-L1 on tumour cells or tumour-infiltrating immune cells ) . The primary efficacy analysis was done in the first 850 of 1225 enrolled patients . This study is registered with Clinical Trials.gov , number NCT02008227 . FINDINGS Between March 11 , 2014 , and April 29 , 2015 , 1225 patients were recruited . In the primary population , 425 patients were r and omly assigned to receive atezolizumab and 425 patients were assigned to  receive  docetaxel  .  Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression population s. In the ITT population , overall survival was improved with atezolizumab compared with docetaxel ( median overall survival was 13·8 months [ 95 % CI 11·8 - 15·7 ] vs 9·6 months [ 8·6 - 11·2 ] ; hazard ratio [ HR ] 0·73 [ 95 % CI 0·62 - 0·87 ] , p=0·0003 ) . Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab ( n=241 ) compared with docetaxel ( n=222 ; median overall survival was 15·7 months [ 95 % CI 12·6 - 18·0 ] with atezolizumab vs 10·3 months [ 8·8 - 12·0 ] with docetaxel ; HR 0·74 [ 95 % CI 0·58 - 0·93 ] ; p=0·0102 ) . Patients in the PD-L1 low or undetectable subgroup ( TC0 and IC0 ) also had improved survival with atezolizumab ( median overall survival 12·6 months vs 8·9 months ; HR 0·75 [ 95 % CI 0·59 - 0·96 ] ) . Overall survival improvement was similar in patients with squamous ( HR 0·73 [ 95 % CI 0·54 - 0·98 ] ; n=112 in the atezolizumab group and n=110 in the docetaxel group ) or non-squamous ( 0·73 [ 0·60 - 0·89 ] ; n=313 and n=315 ) histology . Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab ( 90 [ 15 % ] of 609 patients ) versus docetaxel ( 247 [ 43 % ] of 578 patients ) . One treatment-related death from a respiratory tract infection was reported in the docetaxel group . INTERPRETATION To our knowledge , OAK is the first r and omised phase 3 study to report results of a PD-L1-targeted therapy , with atezolizumab treatment result ing in a clinical ly relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer , regardless of PD-L1 expression or histology , with a favourable safety profile . FUNDING F. Hoffmann-La Roche Ltd , Genentech , BACKGROUND Non-small-cell lung cancer ( NSCLC ) with a mutation in the gene encoding epidermal growth factor receptor ( EGFR ) is sensitive to approved EGFR inhibitors , but resistance develops , mediated by the T790 M EGFR mutation in most cases . Rociletinib ( CO-1686 ) is an EGFR inhibitor active in pre clinical models of EGFR-mutated NSCLC with or without T790 M . METHODS In this phase 1 - 2 study , we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor . In the expansion ( phase 2 ) part of the study , patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily , 625 mg twice daily , or 750 mg twice daily . Key objectives were assessment of safety , side-effect profile , pharmacokinetics , and preliminary antitumor activity of rociletinib  . Tumor biopsies to identify T790 M were performed during screening . Treatment was administered in continuous 21-day cycles . RESULTS A total of 130 patients were enrolled . The first 57 patients to be enrolled received the free-base form of rociletinib ( 150 mg once daily to 900 mg twice daily ) . The remaining patients received the hydrogen bromide salt ( HBr ) form ( 500 mg twice daily to 1000 mg twice daily ) . A maximum tolerated dose ( the highest dose associated with a rate of dose-limiting toxic effects of less than 33 % ) was not identified . The only common dose-limiting adverse event was hyperglycemia . In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose , the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59 % ( 95 % confidence interval [ CI ] , 45 to 73 ) , and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29 % ( 95 % CI , 8 to 51 ) . CONCLUSIONS Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790 M resistance mutation . ( Funded by Clovis Oncology ; Clinical Trials.gov number , NCT01526928 . ) BACKGROUND Nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , disrupts PD-1-mediated signaling and may restore antitumor immunity . METHODS In this r and omized , open-label , international phase 3 study , we assigned patients with nonsquamous non-small-cell lung cancer ( NSCLC ) that had progressed during or after platinum-based doublet chemotherapy  to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS Overall survival was longer with nivolumab than with docetaxel .  The median overall survival was 12.2 months ( 95 % confidence interval [ CI ] , 9.7 to 15.0 ) among 292 patients in the  nivolumab group and 9.4 months ( 95 % CI , 8.1 to 10.7 ) among 290 patients in the docetaxel group ( hazard ratio for death , 0.73 ; 96 % CI , 0.59 to 0.89 ; P=0.002 ) . At 1 year , the overall survival rate was 51 % ( 95 % CI , 45 to 56 ) with nivolumab versus 39 % ( 95 % CI , 33 to 45 ) with docetaxel . With additional follow-up , the overall survival rate at 18 months was 39 % ( 95 % CI , 34 to 45 ) with nivolumab versus 23 % ( 95 % CI , 19 to 28 ) with docetaxel . The response rate was 19 % with nivolumab versus 12 % with docetaxel ( P=0.02 ) . Although progression-free survival did not favor nivolumab over docetaxel ( median , 2.3 months and 4.2 months , respectively ) , the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel ( 19 % and 8 % , respectively ) . Nivolumab was associated with even greater efficacy  than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression ( ≥1 % , ≥5 % , and ≥10 % ) of the PD-1 lig and . Treatment-related adverse events of grade 3 or 4 were reported in 10 % of the patients in the nivolumab group , as compared with 54 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy  , overall survival was longer with nivolumab than with docetaxel . ( Funded by Bristol-Myers Squibb ; CheckMate 057 Clinical Trials.gov number , NCT01673867 . ) BACKGROUND Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2 . We aim ed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer ( NSCLC ) after platinum-based therapy . METHODS In this multicentre , double-blind , r and omised phase 3 trial ( REVEL ) , we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen . Patients were r and omly allocated ( 1:1 ) with a central ised , interactive voice-response system ( stratified by sex , region , performance status , and previous maintenance therapy [ yes vs no ] ) to receive docetaxel 75 mg/m(2 ) and either ramucirumab ( 10 mg/kg ) or placebo on day 1 of a 21 day cycle until disease progression , unacceptable toxicity , withdrawal , or death . The primary endpoint was overall survival in all patients allocated to treatment . We assessed adverse events according to treatment received . This study is registered with Clinical Trials.gov , number NCT01168973 . FINDINGS Between Dec 3 , 2010 , and Jan 24 , 2013 , we screened 1825 patients , of whom 1253 patients were r and omly allocated to treatment . Median overall survival was 10·5 months ( IQR 5·1 - 21·2 ) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months ( 4·2 - 18·0 ) for 625 patients who received placebo plus docetaxel ( hazard ratio 0·86 , 95 % CI 0·75 - 0·98 ; p=0·023 ) . Median progression-free survival was 4·5 months ( IQR 2·3 - 8·3 ) for the ramucirumab group compared with 3·0 months ( 1·4 - 6·9 ) for the control group ( 0·76 , 0·68 - 0·86 ; p<0·0001 ) . We noted treatment-emergent adverse events in 613 ( 98 % ) of 627 patients in the ramucirumab safety population and 594 ( 95 % ) of 618 patients in the control safety population . The most common grade 3 or worse adverse events were neutropenia ( 306 patients [ 49 % ] in the ramucirumab group vs 246 [ 40 % ] in the control group ) , febrile neutropenia ( 100 [ 16 % ] vs 62 [ 10 % ] ) , fatigue ( 88 [ 14 % ] vs 65 [ 10 % ] ) , leucopenia ( 86 [ 14 % ] vs 77 [ 12 % ] ) , and hypertension ( 35 [ 6 % ] vs 13 [ 2 % ] ) . The numbers of deaths from adverse events ( 31 [ 5 % ] vs 35 [ 6 % ] ) and grade 3 or worse pulmonary haemorrhage ( eight [ 1 % ] vs eight [ 1 % ] ) did not differ between groups . Toxicities were manageable with appropriate dose reductions and supportive care . INTERPRETATION Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC . FUNDING Eli Lilly BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer ( NSCLC ) who have disease progression during or after first-line chemotherapy have limited treatment options . This r and omized , open-label , international , phase 3 study evaluated the efficacy and safety of nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , as compared with docetaxel in this patient population . METHODS We r and omly assigned 272 patients to receive nivolumab , at a dose of 3 mg per kilogram of body weight every 2 weeks , or docetaxel , at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS The median overall survival was 9.2 months ( 95 % confidence interval [ CI ] , 7.3 to 13.3 ) with nivolumab versus 6.0 months ( 95 % CI , 5.1 to 7.3 ) with docetaxel . The risk of death was 41 % lower with nivolumab than with docetaxel ( hazard ratio , 0.59 ; 95 % CI , 0.44 to 0.79 ; P<0.001 ) . At 1 year , the overall survival rate was 42 % ( 95 % CI , 34 to 50 ) with nivolumab versus 24 % ( 95 % CI , 17 to 31 ) with docetaxel . The response rate was 20 % with nivolumab versus 9 % with docetaxel ( P=0.008 ) . The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel ( hazard ratio for death or disease progression , 0.62 ; 95 % CI , 0.47 to 0.81 ; P<0.001 ) . The expression of the PD-1 lig and ( PD-L1 ) was neither prognostic nor predictive of benefit . Treatment-related adverse events of grade 3 or 4 were reported in 7 % of the patients in the nivolumab group as compared with 55 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced , previously treated squamous-cell NSCLC , overall survival , response rate , and progression-free survival were significantly better with nivolumab than with docetaxel , regardless of PD-L1 expression level . ( Funded by Bristol-Myers Squibb ; CheckMate 017 Clinical Trials.gov number , NCT01642004 . ) Introduction : This study compared survival without toxicity in patients with advanced , nonsquamous non-small cell lung cancer who were treated with first-line pemetrexed/carboplatin or docetaxel/carboplatin .  Methods : This multicenter , open-label , parallel-group , phase 3 trial comprised patients r and omized ( 1:1 ) to pemetrexed/carboplatin ( n = 128 ) or docetaxel/carboplatin ( n = 132 ) . Patients received treatment on day 1 of each 21-day cycle ( maximum of six cycles ) . Treatment included carboplatin ( area under the curve = 5 mg/ml × min ) and pemetrexed ( 500 mg/m2 ) or docetaxel ( 75 mg/m2 ) . The primary outcome measure , survival without treatment-emergent grade 3/4 toxicity , was defined as the time from r and omization to the first treatment-emergent grade 3/4 adverse event or death and was analyzed using a log-rank test . The analysis population included 106 patients in the pemetrexed/carboplatin ( Pem/Carb ) group and 105 patients in the docetaxel/carboplatin ( Doc/Carb ) group . Results : Survival without treatment-emergent grade 3/4 toxicity was significantly longer in the Pem/Carb versus the Doc/Carb group ( log-rank p < 0.001 ; median survival without treatment-emergent grade 3/4 toxicity : 3.2 versus 0.7 months ; adjusted hazard ratio = 0.45 [ 95 % confidence interval : 0.34–0.61 ] ) . Overall survival was similar in the Pem/Carb versus the Doc/Carb group ( log-rank p = 0.934 ; median survival : 14.9 versus 14.7 months ; adjusted hazard ratio = 0.93 [ 95 % confidence interval : 0.66–1.32 ] ) . Compared with the Doc/Carb group , fewer patients in the Pem/Carb group experienced grade 3/4 drug-related , treatment-emergent neutropenia , leukopenia , or febrile neutropenia , and more patients experienced anemia and thrombocytopenia . There were three study drug-related deaths during treatment in each group . Conclusions : The favorable benefit-to-risk profile of pemetrexed/carboplatin suggests that pemetrexed/carboplatin is an appropriate first-line treatment option for chemonaïve patients with advanced , nonsquamous non-small cell lung cancer PURPOSE Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer ( NSCLC ) , but progression invariably occurs . We investigated the efficacy and safety of alectinib , a potent and selective ALK inhibitor with excellent CNS penetration , in patients with crizotinib-refractory ALK-positive NSCLC . PATIENTS AND METHODS Alectinib 600 mg was administered orally twice daily . The primary end point was objective response rate ( ORR ) by central independent review committee ( IRC ) . RESULTS Of the 138 patients treated , 84 patients ( 61 % ) had CNS metastases at baseline , and 122 were response evaluable ( RE ) by IRC .  ORR by IRC was 50 % ( 95 % CI , 41 % to 59 % ) , and the median duration of response ( DOR ) was 11.2 months ( 95 % CI , 9.6 months to not reached ) . In 96 patients ( 79 % ) previously treated with chemotherapy , the ORR was 45 % ( 95 % CI , 35 % to 55 % ) . Median IRC-assessed progression-free survival for all 138 patients was 8.9 months ( 95 % CI , 5.6 to 11.3 months ) . CNS disease control rate was 83 % ( 95 % CI , 74 % to 91 % ) , and the median CNS DOR was 10.3 months ( 95 % CI , 7.6 to 11.2 months ) . CNS ORR in 35 patients with baseline measurable CNS lesions was 57 % ( 95 % CI , 39 % to 74 % ) . Of the 23 patients with baseline CNS metastases ( measurable or nonmeasurable ) and no prior radiation , 10 ( 43 % ) had a complete CNS response . At 12 months , the cumulative CNS progression rate ( 24.8 % ) was lower than the cumulative non-CNS progression rate ( 33.2 % ) for all patients . Common adverse events were constipation ( 33 % ) , fatigue ( 26 % ) , and peripheral edema ( 25 % ) ; most were grade 1 to 2 . CONCLUSION Alectinib is highly active and well tolerated in patients with advanced , crizotinib-refractory ALK-positive NSCLC , including those with CNS metastases A r and omized Phase III trial tested the efficacy of pemetrexed as maintenance treatment in patients with advanced non-small-cell lung cancer ( NSCLC ) who were without progression after completing four cycles of first-line platinum-based chemotherapy .  The primary endpoint of the trial was progression-free survival ( PFS ) .  Pemetrexed was significantly better than placebo both in terms of PFS and overall survival . The study was not design ed as a direct comparison between ‘ early ’ and ‘ delayed ’ administration of pemetrexed because there was no m and atory cross-over in the control arm , in which less than 20 % of patients actually received pemetrexed as second-line . However , a relevant proportion of patients with advanced NSCLC , due to early death or clinical deterioration , will never be able to receive a second-line treatment after disease progression . At the end of first-line treatment , the immediate administration of a drug that has not been received before ( instead of adopting the ‘ wait and watch ’ approach based on stopping treatment until disease progression ) could be a positive strategy , allowing patients to receive early one more potentially active drug without an unacceptable increase in toxicity . This strategy should be discussed with patients . Prespecified analysis of efficacy by tumor histology showed a significant interaction between treatment and histology , with pemetrexed producing significant and clinical ly meaningful benefit compared to placebo in the non-squamous group , without efficacy in patients with squamous tumors AIM OF THE STUDY To investigate whether patients with severe comorbidity receiving platinum-based chemotherapy for advanced non-small-cell lung cancer ( NSCLC ) have a shorter overall survival , experience more toxicity or more deterioration of health-related quality of life ( HRQoL ) than other patients during treatment . PATIENTS AND METHODS Patients enrolled onto a phase III trial comparing pemetrexed/carboplatin with gemcitabine/carboplatin as first-line therapy of stage IIIB/IV NSCLC were analysed . Eligible patients had performance status 0 - 2 and adequate kidney/liver/bone-marrow function .  Comorbidity was assessed from hospital medical records using the Cumulative Illness Rating Scale for Geriatrics ( CIRS-G ) . Toxicity was grade d using the CTCAE v3.0 and the patients reported HRQoL on the European Organisation for Research and Treatment of Cancer ( EORTC ) Quality of Life Question naire (QLQ)-C30/LC13 . RESULTS Data from 402 of the 436 of the patients enrolled onto the phase III trial were analysed . The patients with severe comorbidity had similar survival as other patients ( 6.9 versus 8.1months ; p=.34 ) , similar frequency of neutropenia ( 48 % versus 42 % ; p=.16 ) , but experienced more neutropenic fevers ( 12 % versus 5 % ; p=.012 ) and deaths from neutropenic infections ( 3 % versus 0 % ; p=.027 ) . They had more thrombocytopenia ( 46 % versus 36 % ; p=.03 ) , but not more thrombocytopenic bleedings ( 3 % versus 4 % ; p=.65 ) . In general , the patients with severe comorbidity reported poorer HRQoL , but not significantly more deterioration of HRQoL. CONCLUSIONS The results from our study suggest that patients with advanced NSCLC who have severe co-existing disorders benefit from and tolerate platinum-doublet chemotherapy as well as other patients . They do , however , appear to have a higher risk of acquiring infections when neutropenic The objective of this study was to develop a prospect ively applicable method for classifying comorbid conditions which might alter the risk of mortality for use in longitudinal studies . A weighted index that takes into account the number and the seriousness of comorbid disease was developed in a cohort of 559 medical patients . The 1-yr mortality rates for the different scores were : " 0 " , 12 % ( 181 ) ; " 1 - 2 " , 26 % ( 225 ) ; " 3 - 4 " , 52 % ( 71 ) ; and " greater than or equal to 5 " , 85 % ( 82 ) . The index was tested for its ability to predict risk of death from comorbid disease in the second cohort of 685 patients during a 10-yr follow-up . The percent of patients who died of comorbid disease for the different scores were : " 0 " , 8 % ( 588 ) ; " 1 " , 25 % ( 54 ) ; " 2 " , 48 % ( 25 ) ; " greater than or equal to 3 " , 59 % ( 18 ) . With each increased level of the comorbidity index , there were stepwise increases in the cumulative mortality attributable to comorbid disease ( log rank chi 2 = 165 ; p less than 0.0001 ) . In this longer follow-up , age was also a predictor of mortality ( p less than 0.001 ) . The new index performed similarly to a previous system devised by Kaplan and Feinstein . The method of classifying comorbidity provides a simple , readily applicable and valid method of estimating risk of death from comorbid disease for use in longitudinal studies . Further work in larger population s is still required to refine the approach because the number of patients with any given condition in this study was relatively small BACKGROUND Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles . On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer ( NSCLC ) , we aim ed to assess efficacy and safety of this combination in a phase 3 trial . METHODS In our double-blind , placebo-controlled , r and omised phase 3 trial ( BeTa ) , we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment . Patients were r and omly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab ( bevacizumab group ) or erlotinib plus placebo ( control group ) according to a computer-generated r and omisation sequence by use of an interactive voice response system . The primary endpoint was overall survival in all enrolled patients . Patients , study staff , and investigators were masked to treatment assignment . We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses . This trial is registered with Clinical Trials.gov , number NCT00130728 . FINDINGS Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group ( hazard ratio [ HR ] 0·97 , 95 % CI 0·80 - 1·18 , p=0·7583 ) . Median overall survival was 9·3 months ( IQR 4·1 - 21·6 ) for patients in the bevacizumab group compared with 9·2 months ( 3·8 - 20·2 ) for controls . Progression-free survival seemed to be longer in the bevacizumab group ( 3·4 months [ 1·4 - 8·4 ] ) than in the control group ( 1·7 months [ 1·3 - 4·1 ] ; HR 0·62 , 95 % CI 0·52 - 0·75 ) and objective response rate suggested some clinical activity of bevacizumab and erlotinib . However , these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done , to control type I error rate . In the bevacizumab group , 130 ( 42 % ) of 313 patients with safety  data had a serious adverse event , compared with 114 ( 36 % ) controls . There were 20 ( 6 % ) grade 5 adverse events , including two arterial thromboembolic events , in the bevacizumab group , and 14 ( 4 % ) in the control group . INTERPRETATION Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC . FUNDING Genentech BACKGROUND For non-small cell lung cancer ( NSCLC ) patients with epidermal growth factor receptor ( EGFR ) mutations , first-line gefitinib produced a longer progression-free survival interval than first-line carboplatin plus paclitaxel but did not show any survival advantage in the North East Japan 002 study . This report describes the quality of life ( QoL ) analysis of that study . METHODS  Chemotherapy-naïve patients with sensitive EGFR-mutated , advanced NSCLC were r and omized to receive gefitinib or chemotherapy ( carboplatin and paclitaxel ) .  Patient QoL was assessed weekly using the Care Notebook , and the primary endpoint of the QoL analysis was time to deterioration from baseline on each of the physical , mental , and life well-being QoL scales . Kaplan-Meier probability curves and log-rank tests were employed to clarify differences . RESULTS QoL data from 148 patients ( 72 in the gefitinib arm and 76 in the carboplatin plus paclitaxel arm ) were analyzed . Time to defined deterioration in physical and life well-being significantly favored gefitinib over chemotherapy ( hazard ratio [ HR ] of time to deterioration , 0.34 ; 95 % confidence interval [ CI ] , 0.23 - 0.50 ; p < .0001 and HR , 0.43 ; 95 % CI , 0.28 - 0.65 ; p < .0001 , respectively ) . CONCLUSION QoL was maintained much longer in patients treated with gefitinib than in patients treated with st and ard chemotherapy , indicating that gefitinib should be considered as the st and ard first-line therapy for advanced EGFR-mutated NSCLC in spite of no survival advantage PURPOSE PointBreak ( A Study of Pemetrexed , Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer ) compared the efficacy and safety of pemetrexed ( Pem ) plus carboplatin ( C ) plus bevacizumab ( Bev ) followed by pemetrexed plus bevacizumab ( PemCBev ) with paclitaxel ( Pac ) plus carboplatin ( C ) plus bevacizumab ( Bev ) followed by bevacizumab ( PacCBev ) in patients with advanced nonsquamous non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were r and omly assigned to receive pemetrexed 500 mg/m(2 ) or paclitaxel 200 mg/m(2 ) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles . Eligible patients received maintenance until disease progression : pemetrexed plus bevacizumab ( for the PemCBev group ) or bevacizumab ( for the PacCBev group ) . The primary end point of this superiority study was overall survival ( OS ) . RESULTS Patients were r and omly assigned to PemCBev ( n = 472 ) or PacCBev ( n = 467 ) . For PemCBev versus PacCBev , OS hazard ratio ( HR ) was 1.00 ( median OS , 12.6 v 13.4 months ; P = .949 ) ; progression-free survival ( PFS ) HR was 0.83 ( median PFS , 6.0 v 5.6 months ; P = .012 ) ; overall response rate was 34.1 % versus 33.0 % ; and disease control rate was 65.9 % versus 69.8 % . Significantly more study drug-related grade 3 or 4 anemia ( 14.5 % v 2.7 % ) , thrombocytopenia ( 23.3 % v 5.6 % ) , and fatigue ( 10.9 % v 5.0 % ) occurred with PemCBev ; significantly more grade 3 or 4 neutropenia ( 40.6 % v 25.8 % ) , febrile neutropenia ( 4.1 % v 1.4 % ) , sensory neuropathy ( 4.1 % v 0 % ) , and alopecia ( grade 1 or 2 ; 36.8 % v 6.6 % ) occurred with PacCBev . CONCLUSION OS did not improve with the PemCBev regimen compared with the PacCBev regimen , although PFS was significantly improved with PemCBev . Toxicity profiles differed ; both regimens demonstrated tolerability BACKGROUND Pembrolizumab is a humanized monoclonal antibody against programmed death 1 ( PD-1 ) that has antitumor activity in advanced non-small-cell lung cancer ( NSCLC ) , with increased activity in tumors that express programmed death lig and 1 ( PD-L1 ) . METHODS In this open-label , phase 3 trial , we r and omly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50 % of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab ( at a fixed dose of 200 mg every 3 weeks ) or the investigator 's choice of platinum-based chemotherapy .  Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression . The primary end point , progression-free survival , was assessed by means of blinded , independent , central radiologic review . Secondary end points were overall survival , objective response rate , and safety . RESULTS Median progression-free survival was 10.3 months ( 95 % confidence interval [ CI ] , 6.7 to not reached ) in the pembrolizumab group versus 6.0 months ( 95 % CI , 4.2 to 6.2 ) in the chemotherapy group ( hazard ratio for disease progression or death , 0.50 ; 95 % CI , 0.37 to 0.68 ; P<0.001 ) . The estimated rate of overall survival at 6 months was 80.2 % in the pembrolizumab group versus 72.4 % in the chemotherapy group ( hazard ratio for death , 0.60 ; 95 % CI , 0.41 to 0.89 ; P=0.005 ) . The response rate was higher in the pembrolizumab group than in the chemotherapy group ( 44.8 % vs. 27.8 % ) , the median duration of response was longer ( not reached [ range , 1.9 + to 14.5 + months ] vs. 6.3 months [ range , 2.1 + to 12.6 + ] ) , and treatment-related adverse events of any grade were less frequent ( occurring in 73.4 % vs. 90.0 % of patients ) , as were grade 3 , 4 , or 5 treatment-related adverse events ( 26.6 % vs. 53.3 % ) . CONCLUSIONS In patients with advanced NSCLC and PD-L1 expression on at least 50 % of tumor cells , pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy . ( Funded by Merck ; KEYNOTE-024 Clinical Trials.gov number , NCT02142738 . ) BACKGROUND NEJ002 study , comparing gefitinib with carboplatin ( CBDCA ) and paclitaxel ( PTX ; Taxol ) as the first-line treatment for advanced non-small cell lung cancer ( NSCLC ) harboring an epidermal growth factor receptor ( EGFR ) mutation , previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival ( PFS ) . Subsequent analysis was carried out mainly regarding overall survival ( OS ) . MATERIAL S AND METHODS For all 228 patients in NEJ002 , survival data were up date d in December , 2010 . Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated . RESULTS The median survival time ( MST ) was 27.7 months for the gefitinib group , and was 26.6 months for the CBDCA/PTX group ( HR , 0.887 ; P=0.483 ) . The OS of patients who received platinum throughout their treatment ( n=186 ) was not statistically different from that of patients who never received platinum ( n=40 ) . The MST of patients treated with gefitinib , platinum , and pemetrexed ( PEM ) or docetaxel ( DOC , Taxotere ; n=76 ) was around 3 years . CONCLUSIONS No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study , probably due to a high crossover use of gefitinib in the CBDCA/PTX group . Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC , the first-line gefitinib is strongly recommended Background : Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues . The primary objectives were to determine nephrotoxicity , gastrointestinal side-effects , peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate , time to tumor progression ( TTP ) and survival . Patients and methods : Two hundred and thirty-six chemotherapy-naive patients with inoperable non-small-cell lung cancer were r and omly allocated to receive either 200 mg/m2 of liposomal cisplatin and 135 mg/m2 paclitaxel ( arm A ) or 75 mg/m2 cisplatin and 135 mg/m2 paclitaxel ( arm B ) , once every 2 weeks on an outpatient basis . Two hundred and twenty-nine patients were assessable for toxicity , response rate and survival . Nine treatment cycles were planned . Results : Arm A patients showed statistically significant lower nephrotoxicity , grade 3 and 4 leucopenia , grade 2 and 3 neuropathy , nausea , vomiting and fatigue . There was no significant difference in median and overall survival and TTP between the two arms ; median survival was 9 and 10 months in arms A and B , respectively , and TTP was 6.5 and 6 months in arms A and B , respectively . Conclusions : Liposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel .  Nephrotoxicity in particular was negligible after liposomal cisplatin administration . TTP and survival were similar in both treatment arms BACKGROUND Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer ( NSCLC ) in fit , non-elderly adults , but monotherapy is recommended for patients older than 70 years . We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC . METHODS In this multicentre , open-label , phase 3 , r and omised trial we recruited patients aged 70 - 89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0 - 2 . Patients received either four cycles ( 3 weeks on treatment , 1 week off treatment ) of carboplatin ( on day 1 ) plus paclitaxel ( on days 1 , 8 , and 15 ) or five cycles ( 2 weeks on treatment , 1 week off treatment ) of vinorelbine or gemcitabine monotherapy . R and omisation was done central ly with the minimisation method . The primary endpoint was overall survival , and analysis was done by intention to treat . This trial is registered , number NCT00298415 . FINDINGS 451 patients were enrolled . 226 were r and omly assigned  monotherapy  and 225  doublet chemotherapy .  Median age was 77 years and median follow-up was 30.3 months ( range 8.6 - 45.2 ) . Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy ( hazard ratio 0.64 , 95 % CI 0.52 - 0.78 ; p<0.0001 ) ; 1-year survival was 44.5 % ( 95 % CI 37.9 - 50.9 ) and 25.4 % ( 19.9 - 31.3 ) , respectively . Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group ( most frequent , decreased neutrophil count ( 108 [ 48.4 % ] vs 28 [ 12.4 % ] ; asthenia 23 [ 10.3 % ] vs 13 [ 5.8 % ] ) . INTERPRETATION Despite increased toxic effects , platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC . We feel that the current treatment paradigm for these patients should be reconsidered . FUNDING Intergroupe Francophone de Cancérologie Thoracique , Institut National du Cancer BACKGROUND The efficacy of the ALK inhibitor crizotinib as compared with st and ard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer ( NSCLC ) is unknown . METHODS We conducted an open-label , phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease . Patients were r and omly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy ( pemetrexed , 500 mg per square meter of body-surface area , plus either cisplatin , 75 mg per square meter , or carboplatin , target area under the curve of 5 to 6 mg per milliliter per minute ) every 3 weeks for up to six cycles . Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy . The primary end point was progression-free survival as assessed by independent radiologic review . RESULTS Progression-free survival was significantly longer with crizotinib than with chemotherapy ( median , 10.9 months vs. 7.0 months ; hazard ratio for progression or death with crizotinib , 0.45 ; 95 % confidence interval [ CI ] , 0.35 to 0.60 ; P<0.001 ) . Objective response rates were 74 % and 45 % , respectively ( P<0.001 ) . Median overall survival was not reached in either group ( hazard ratio for death with crizotinib , 0.82 ; 95 % CI , 0.54 to 1.26 ; P=0.36 ) ; the probability of 1-year survival was 84 % with crizotinib and 79 % with chemotherapy . The most common adverse events with crizotinib were vision disorders , diarrhea , nausea , and edema , and the most common events with chemotherapy were nausea , fatigue , vomiting , and decreased appetite . As compared with chemotherapy , crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life . CONCLUSIONS Crizotinib was superior to st and ard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC . ( Funded by Pfizer ; PROFILE 1014 Clinical Trials.gov number , NCT01154140 . ) BACKGROUND Platinum-containing two-drug combinations improve survival and cancer-related symptoms in patients with advanced non-small-cell lung cancer ( NSCLC ) . However , survival benefit is modest and platinum-containing regimens cause substantial toxic effects . We did a prospect i ve r and omised open-label phase III study to compare an experimental platinum-free , triplet , sequential regimen of vinorelbine plus gemcitabine followed by docetaxel with the st and ard platinum-containing , doublet regimen paclitaxel plus carboplatin in patients with advanced NSCLC . METHODS Between March , 2001 , and April , 2005 , patients with stage IIIB ( positive pleural effusion ) or IV NSCLC , performance status 0 to 1 , and adequate organ function , were r and omly assigned to experimental treatment or to st and ard treatment . R and omisation was done central ly by use of a dynamic balancing algorithm . Patients were stratified by weight loss , lactate dehydrogenase concentration , and disease stage . Patients in the experimental group were scheduled to receive intravenous vinorelbine ( 25 mg/m(2 ) ) plus gemcitabine ( 1000 mg/m(2 ) ) on days 1 and 8 every 21 days for three cycles , followed by intravenous docetaxel ( 60 mg/m(2 ) ) on day 1 every 21 days for three cycles . Patients in the st and ard group were scheduled to receive intravenous paclitaxel ( 225 mg/m(2 ) ) plus carboplatin ( area under the curve=6 ) for 3 h on day 1 , every 21 days for six cycles . The primary endpoint was overall survival , and secondary endpoints were progression-free survival , response , and toxic effects . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00079287 . FINDINGS Of the 401 patients enrolled and r and omised in the trial , five patients in the experimental group and three in the st and ard group were ineligible for analysis ; thus 196 patients in the experimental group and 197 in the st and ard group were included in analyses . Patient characteristics were well-balanced between the two groups with regard to major prognostic factors . Median overall survival was 13.6 months ( range 12.0 - 16.4 ) in the experimental group versus 14.1 months ( 11.9 - 17.5 ) in the st and ard group ( p=0.97 ) . 49 of 196 patients ( 25 % ) in the experimental group had a partial response compared with 73 of 197 patients ( 37 % ) in the st and ard group ( p=0.012 ) . There were no complete responses . Median progression-free survival was 5.5 months ( 95 % CI 4.9 - 6.3 ) in the experimental group compared with 5.8 months ( 5.3 - 6.1 ) in the st and ard group ( p=0.74 ) . The incidence of grade 3 and 4 neutropenia , neuropathy , arthralgia , and myalgia was lower in the experimental group than in the st and ard group , although the incidence of pulmonary toxic effects was higher . INTERPRETATION Although platinum-containing regimens remain the st and ard treatment for advanced NSCLC , non-platinum regimens could provide equivalent efficacy with a different toxicity profile BACKGROUND Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor ( TKI ) therapy in non-small-cell lung cancer ( NSCLC ) . The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus st and ard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC . METHODS We undertook an open-label , r and omised , phase 3 trial at 22 centres in China . Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received either oral erlotinib ( 150 mg/day ) until disease progression or unacceptable toxic effects , or up to four cycles of gemcitabine plus carboplatin . Patients were r and omly assigned ( 1:1 ) with a minimisation procedure and were stratified according to EGFR mutation type , histological subtype ( adenocarcinoma vs non-adenocarcinoma ) , and smoking status . The primary outcome was progression-free survival , analysed in patients with confirmed disease who received at least one dose of study treatment . The trial is registered at Clinical Trials.gov , number NCT00874419 , and has completed enrolment ; patients are still in follow-up . FINDINGS 83 patients were r and omly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin ; 82 in the erlotinib  group and 72 in the  chemotherapy group were included in analysis of the primary endpoint . Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy ( 13.1 [ 95 % CI 10.58 - 16.53 ] vs 4.6 [ 4.21 - 5.42 ] months ; hazard ratio 0.16 , 95 % CI 0.10 - 0.26 ; p<0.0001 ) . Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib ( including neutropenia in 30 [ 42 % ] of 72 patients and thrombocytopenia in 29 [ 40 % ] patients on chemotherapy vs no patients with either event on erlotinib ) ; the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations ( three [ 4 % ] of 83 patients ) and skin rash ( two [ 2 % ] patients ) . Chemotherapy was also associated with increased treatment-related serious adverse events ( ten [ 14 % ] of 72 patients [ decreased platelet count , n=8 ; decreased neutrophil count , n=1 ; hepatic dysfunction , n=1 ] vs two [ 2 % ] of 83 patients [ both hepatic dysfunction ] ) . INTERPRETATION Compared with st and ard chemotherapy , erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability . These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC . FUNDING F Hoffmann-La Roche Ltd ( China ) ; Science and Technology Commission of Shanghai Municipality BACKGROUND / PURPOSE This study compared front-line treatment with docetaxel or vinorelbine in elderly patients with advanced/metastatic non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Chemotherapy-naive patients with inoperable stage IIIB and stage IV NSCLC who were > 65 years of age with performance status ( PS ) of 0 - 2 were enrolled . Patients were assigned to receive either docetaxel 38 mg/m(2 ) or vinorelbine 25 mg/m(2 ) by intravenous ( I.V. ) infusion on days 1 and 8 every 3 weeks . RESULTS One hundred thirty elderly patients were enrolled in the study  ( docetaxel n = 66 and vinorelbine n = 64 patients ) . The objective response rate was 12.1 % and 14.1 % in patients treated with docetaxel and vinorelbine , respectively ( 2P = .799 ) . The median time to tumor progression ( TTP ) was 2.33 and 1.9 months ( 2P = .298 ) and the median overall survival ( OS ) was 6.07 and 3.87 months ( 2P = .090 ) in the docetaxel and vinorelbine arms , respectively . Grade 3/4 neutropenia occurred in 4.5 % and 29.7 % of patients in the docetaxel arm and vinorelbine arm , respectively ( 2P < .001 ) . Febrile neutropenia occurred in 1.5 % and 1.6 % of patients in the docetaxel arm and the vinorelbine arm , respectively ( 2P = .950 ) and the use of granulocyte colony-stimulating factor ( G-CSF ) was more frequent in patients treated with vinorelbine ( 37.1 % vs. 22.5 % ; 2P < .001 ) . There were no deaths from toxicity . Nonhematologic toxicity was mild . CONCLUSIONS Docetaxel has an efficacy comparable to that of vinorelbine as first-line treatment in elderly patients with NSCLC and has an acceptable toxicity profile . The trial was closed prematurely because of low accrual , thus limiting the strength of the conclusions derived BACKGROUND Patients with advanced non-squamous non-small-cell lung cancer ( NSCLC ) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing , non-pemetrexed doublet . The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin . METHODS In this double-blind , multicentre , phase 3 , r and omised placebo-controlled trial , patients with advanced non-squamous NSCLC aged 18 years or older , with no previous systemic chemotherapy for lung cancer , with at least one measurable lesion , and an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 or 1 participated . Before r and omisation , patients entered an induction phase which consisted of four cycles of induction pemetrexed ( 500 mg/m(2 ) ) plus cisplatin ( 75 mg/m(2 ) ) on day 1 of a 21-day cycle . Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage ( IIIB or IV ) , ECOG performance status ( 0 or 1 ) , and induction response ( complete or partial response , or stable disease ) , and r and omly assigned ( 2:1 ratio ) to receive maintenance therapy with either pemetrexed ( 500 mg/m(2 ) every 21 days ) plus best supportive care or placebo plus best supportive care until disease progression . R and omisation was done with the Pocock and Simon minimisation method . Patients and investigators were masked to treatment assignment . The primary endpoint was progression-free survival in the intention-to-treat population . This study is registered with Clinical Trials.gov , NCT00789373 . FINDINGS Of the 1022 patients enrolled , 939 participated in the induction phase . Of these , 539 patients were r and omly assigned to receive continuation maintenance with pemetrexed plus best supportive care ( n=359 ) or with placebo plus best supportive care ( n=180 ) . Among the 359 patients r and omised to continuation maintenance with pemetrexed , there was a significant reduction in the risk of disease progression over the placebo group ( HR 0·62 , 95 % CI 0·49 - 0·79 ; p<0·0001 ) . The median progression-free survival , measured from r and omisation , was 4·1 months ( 95 % CI 3·2 - 4·6 ) for pemetrexed and 2·8 months ( 2·6 - 3·1 ) for placebo . Possibly treatment-related laboratory grade 3 - 4 adverse events were more common in the pemetrexed group ( 33 [ 9 % ] of 359 patients ) than in the placebo group ( one [ < 1 % ] of 180 patients ; p<0·0001 ) , as were non-laboratory grade 3 - 5 adverse events ( 32 [ 9 % ] of 359 patients in the pemetrexed group ; eight [ 4 % ] of 180 patients in the placebo group ; p=0·080 ) ; one possibly treatment-related death was reported in each group . The most common adverse events of grade 3 - 4 in the pemetrexed group were anaemia ( 16 [ 4 % ] of 359 patients ) , neutropenia ( 13 [ 4 % ] ) , and fatigue ( 15 [ 4 % ] ) . In the placebo group , these adverse events were less common : anaemia ( one [ < 1 % ] of 180 patients ) , neutropenia ( none ) , and fatigue ( one < 1 % ] ) . The most frequent serious adverse events were anaemia ( eight [ 2 % ] of 359 patients in the pemetrexed group vs none in the placebo group ) and febrile neutropenia ( five [ 1 % ] vs none ) . Discontinuations due to drug-related adverse events occurred in 19 ( 5 % ) patients in the pemetrexed group and six ( 3 % ) patients in the placebo group . INTERPRETATION Continuation maintenance with pemetrexed is an effective and well tolerated treatment option for patients with advanced non-squamous NSCLC with good performance status who have not progressed after induction therapy with pemetrexed plus cisplatin . FUNDING Eli Lilly and Company PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin ( TC ) as first-line treatment of advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS This multicenter , open-label , phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB ( pleural effusion ) or IV NSCLC , without restrictions by histology or epidermal growth factor receptor expression . Patients were r and omly assigned to cetuximab/TC or TC . TC consisted of paclitaxel ( 225 mg/m(2 ) ) or docetaxel ( 75 mg/m(2 ) ) , at the investigator 's discretion , and carboplatin ( area under the curve = 6 ) on day 1 every 3 weeks for < or = six cycles ; cetuximab ( 400 mg/m(2 ) on day 1 , 250 mg/m(2 ) weekly ) was administered until progression or unacceptable toxicity . The primary end point was progression-free survival assessed by independent radiologic review committee ( PFS-IRRC ) ; overall response rate ( ORR ) , overall survival ( OS ) , quality of life ( QoL ) , and safety were key secondary end points . PFS and ORR assessed by investigators were also evaluated . Results Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC ( hazard ratio [ HR ] = 0.902 ; 95 % CI , 0.761 to 1.069 ; P = .236 ) . Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC ( HR = 0.890 ; 95 % CI , 0.754 to 1.051 ; P = .169 ) . ORR-IRRC was 25.7 % with cetuximab/TC versus 17.2 % with TC ( P = .007 ) . The safety profile of this combination was manageable and consistent with its individual components . CONCLUSION The addition of cetuximab to TC did not significantly improve the primary end point , PFS-IRRC . There was significant improvement in ORR by IRRC . The difference in OS favored cetuximab but did not reach statistical significance CONTEXT There are few r and omized controlled trials on the effectiveness of palliative care interventions to improve the care of patients with advanced cancer . OBJECTIVE To determine the effect of a nursing-led intervention on quality of life , symptom intensity , mood , and re source use in patients with advanced cancer . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted from November 2003 through May 2008 of 322 patients with advanced cancer in a rural , National Cancer Institute- design ated comprehensive cancer center in New Hampshire and affiliated outreach clinics and a VA medical center in Vermont . INTERVENTIONS A multicomponent , psychoeducational intervention ( Project ENABLE [ Educate , Nurture , Advise , Before Life Ends ] ) conducted by advanced practice nurses consisting of 4 weekly educational sessions and monthly follow-up sessions until death or study completion ( n = 161 ) vs usual care ( n = 161 ) . MAIN OUTCOME MEASURES Quality of life was measured by the Functional Assessment of Chronic Illness Therapy for Palliative Care ( score range , 0 - 184 ) . Symptom intensity was measured by the Edmonton Symptom Assessment Scale ( score range , 0 - 900 ) . Mood was measured by the Center for Epidemiological Studies Depression Scale ( range , 0 - 60 ) . These measures were assessed at baseline , 1 month , and every 3 months until death or study completion . Intensity of service was measured as the number of days in the hospital and in the intensive care unit ( ICU ) and the number of emergency department visits recorded in the electronic medical record . RESULTS A total of 322 participants with cancer of the gastrointestinal tract ( 41 % ; 67 in the usual care group vs 66 in the intervention group ) , lung ( 36 % ; 58 vs 59 ) , genitourinary tract ( 12 % ; 20 vs 19 ) , and breast ( 10 % ; 16 vs 17 ) were r and omized . The estimated treatment effects ( intervention minus usual care ) for all participants were a mean ( SE ) of 4.6 ( 2 ) for quality of life ( P = .02 ) , -27.8 ( 15 ) for symptom intensity ( P = .06 ) , and -1.8 ( 0.81 ) for depressed mood ( P = .02 ) . The estimated treatment effects in participants who died during the study were a mean ( SE ) of 8.6 ( 3.6 ) for quality of life ( P = .02 ) , -24.2 ( 20.5 ) for symptom intensity ( P = .24 ) , and -2.7 ( 1.2 ) for depressed mood ( P = .03 ) . Intensity of service did not differ between the 2 groups . CONCLUSION Compared with participants receiving usual oncology care , those receiving a nurse-led , palliative care-focused intervention addressing physical , psychosocial , and care coordination provided concurrently with oncology care had higher scores for quality of life and mood , but did not have improvements in symptom intensity scores or reduced days in the hospital or ICU or emergency department visits . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00253383 BACKGROUND Paclitaxel ( Taxol ) and vinorelbine have shown synergism of cytotoxic effects in vitro and clinical activity in phase I and II studies . This combination was compared prospect ively with the paclitaxel/gemcitabine regimen in non-operable non-small-cell lung cancer . PATIENTS AND METHODS Chemotherapy-naive patients , stage IIIbwet and IV with performance status ( 0 - 1 ) , were r and omized to receive paclitaxel 200 mg/m(2 ) on day 1 plus gemcitabine 1 gm/m(2 ) ( group A ) on days 1 and 8 every 3 weeks or paclitaxel 80 mg/m(2 ) plus vinorelbine 22.5 mg/m(2 ) ( group B ) on days 1 , 8 and 15 every 4 weeks . RESULTS A total of 398 out of 415 patients were eligible for analysis on intent-to-treat basis ( group A : 196 , group B : 202 ) . Progression-free survival ( PFS ) was 5.0 months [ 95 % confidence interval ( CI ) 4.3 - 5.6 ] and 4.4 months ( 95 % CI 3.7 - 5.2 ) for groups A and B respectively ( P=0.365 ) . Median survival was 11.1 months ( 95 % CI 9.2 - 13.0 ) and 8.6 months ( 95 % CI 7.0 - 10.2 ) for groups A and B respectively ( P = 0.147 ) . Grade 3/4 neutropenia and leukopenia were worse in group B ( P<0.001 , in both cases ) . Febrile neutropenia and severe infections were more prominent ( P<0.001 , P=0.029 respectively ) in group B. CONCLUSION Although response rate , PFS and survival were non-different in both groups , toxicity was significantly worse in group B and therefore further investigation of P-Vin is of no value PURPOSE An American Society of Clinical Oncology ( ASCO ) provisional clinical opinion ( PCO ) offers timely clinical direction to ASCO 's membership following publication or presentation of potentially practice -changing data from major studies . This PCO addresses the integration of palliative care services into st and ard oncology practice at the time a person is diagnosed with metastatic or advanced cancer . CLINICAL CONTEXT Palliative care is frequently misconstrued as synonymous with end-of-life care . Palliative care is focused on the relief of suffering , in all of its dimensions , throughout the course of a patient 's illness . Although the use of hospice and other palliative care services at the end of life has increased , many patients are enrolled in hospice less than 3 weeks before their death , which limits the benefit they may gain from these services . By potentially improving quality of life ( QOL ) , cost of care , and even survival in patients with metastatic cancer , palliative care has increasing relevance for the care of patients with cancer . Until recently , data from r and omized controlled trials ( RCTs ) demonstrating the benefits of palliative care in patients with metastatic cancer who are also receiving st and ard oncology care have not been available . RECENT DATA Seven published RCTs form the basis of this PCO . PROVISIONAL CLINICAL OPINION Based on strong evidence from a phase III RCT , patients with metastatic non-small-cell lung cancer should be offered concurrent palliative care and st and ard oncologic care at initial diagnosis . While a survival benefit from early involvement of palliative care has not yet been demonstrated in other oncology setting s , substantial evidence demonstrates that palliative care-when combined with st and ard cancer care or as the main focus of care-leads to better patient and caregiver outcomes . These include improvement in symptoms , QOL , and patient satisfaction , with reduced caregiver burden . Earlier involvement of palliative care also leads to more appropriate referral to and use of hospice , and reduced use of futile intensive care . While evidence clarifying optimal delivery of palliative care to improve patient outcomes is evolving , no trials to date have demonstrated harm to patients and caregivers , or excessive costs , from early involvement of palliative care . Therefore , it is the Panel 's expert consensus that combined st and ard oncology care and palliative care should be considered early in the course of illness for any patient with metastatic cancer and /or high symptom burden . Strategies to optimize concurrent palliative care and st and ard oncology care , with evaluation of its impact on important patient and caregiver outcomes ( eg , QOL , survival , health care services utilization , and costs ) and on society , should be an area of intense research . NOTE ASCO 's provisional clinical opinions ( PCOs ) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and setting s for further research . Because of the rapid flow of scientific information in oncology , new evidence may have emerged since the time a PCO was su bmi tted for publication . PCOs are not continually up date d and may not reflect the most recent evidence . PCOs can not account for individual variation among patients and can not be considered inclusive of all proper methods of care or exclusive of other treatments . It is the responsibility of the treating physician or other health care provider , relying on independent experience and knowledge of the patient , to determine the best course of treatment for the patient . Accordingly , adherence to any PCO is voluntary , with the ultimate determination regarding its application to be made by the physician in light of each patient 's individual circumstances . ASCO PCOs describe the use of procedures and therapies in clinical trials and can not be assumed to apply to the use of these interventions in the context of clinical practice . ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO 's PCOs , or for any errors or omissions BACKGROUND Gemcitabine plus cisplatin ( GC ) and vinorelbine plus cisplatin ( VC ) are active and well-tolerated regimens for the treatment of patients with advanced non-small-cell lung cancer ( NSCLC ) . We conducted this study to compare the safety and efficacy of these regimens as front-line chemotherapy for patients with NSCLC . METHODS Eligible patients were r and omized to receive either gemcitabine ( 1000 mg/m2 ) on days 1 , 8 , and 15 plus cisplatin ( 80 mg/m2 ) on day 15 ( arm GC ) , or vinorelbine ( 20 mg/m2 ) on days 1 , 8 , and 15 plus cisplatin ( 80 mg/m2 ) on day 15 ( arm VC ) . Treatments were repeated every 28 days . The costs of treatment were retrieved from the Health Care Reporting System of Chang Gung Memorial Hospital at the time of final data analysis . RESULTS Eighty-three patients ( GC , n=39 ; VC , n=44 ) were enrolled in the study . Seventy-three patients were analyzed .  Response rates were 38 % and 31 % and median survivals were 12.9 and 9.0 months for the 34 patients in the GC arm and 39 patients in the VC arm , respectively . One-year survival was 55.9 % in the GC arm and 33.3 % in the VC arm . There was no difference in the response rate ( p=0.622 ) , progression free survival ( p=0.443 ) and median survival ( p = 0.4197 ) between the two arms . Grade 3 - 4 toxicities were vomiting ( GC : 16.3 % vs. VC : 36.3 % ) , neutropenia ( GC : 14.7 % vs. VC : 20 % ) , and thrombocytopenia ( GC : 8.68 % vs. VC : 5 % ) . There was a significant increase in all- grade thrombocytopenia ( p=0.002 ) in the GC arm . The GC arm had higher total expenses than the VC arm ( p=0.020 ) . CONCLUSIONS Both vinorelbine plus cisplatin and gemcitabine plus cisplatin yielded similar efficacies for NSCLC Background : Bevacizumab , the anti-vascular endothelial growth factor agent , provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer . We report the final overall survival ( OS ) analysis from the phase III AVAiL trial . Patients and methods : Patients ( n = 1043 ) received cisplatin 80 mg/m2 and gemcitabine 1250 mg/m2 for up to six cycles plus bevacizumab 7.5 mg/kg ( n = 345 ) , bevacizumab 15 mg/kg ( n = 351 ) or placebo ( n = 347 ) every 3 weeks until progression . Primary end point was progression-free survival ( PFS ) ; OS was a secondary end point . Results : Significant PFS prolongation  with bevacizumab compared with placebo was maintained with longer follow-up { hazard ratio ( HR ) [ 95 % confidence interval ( CI ) ] 0.75 ( 0.64–0.87 ) , P = 0.0003 and 0.85 ( 0.73–1.00 ) , P = 0.0456 } for the 7.5 and 15 mg/kg groups , respectively . Median OS was > 13 months in all treatment groups ; nevertheless , OS was not significantly increased with bevacizumab [ HR ( 95 % CI ) 0.93 ( 0.78–1.11 ) , P = 0.420 and 1.03 ( 0.86–1.23 ) , P = 0.761 ] for the 7.5 and 15 mg/kg groups , respectively , versus placebo . Most patients ( ∼62 % ) received multiple lines of post study treatment . Up date d safety results are consistent with those previously reported . Conclusions : Final analysis of AVAiL confirms the  efficacy of bevacizumab when combined with cisplatin – gemcitabine . The PFS benefit did not translate into a significant OS benefit , possibly due to high use of efficacious second-line therapies BACKGROUND Elderly patients with advanced non-small-cell lung cancer ( NSCLC ) may derive similar benefit from platinum-based chemotherapy as younger patients .  Quality of life ( QoL ) and comprehensive geriatric assessment ( CGA ) is often advocated to assess benefits and risks . PATIENTS AND METHODS A total of 181 chemotherapy-naive patients [ ≥70 years , performance score ( PS ) of 0 - 2 ] with stage III-IV NSCLC received carboplatin and gemcitabine ( CG ) ( n = 90 ) or carboplatin and paclitaxel ( CP ) ( n = 91 ) every 3 weeks for up to four cycles . Primary end point was change in global QoL from baseline compared with week 18 . Pretreatment CGA and mini geriatric assessment during and after treatment were undertaken . A principal component ( PC ) analysis was carried out to determine the underlying dimensions of CGA and QoL and subsequently related to survival . RESULTS There were no changes in QoL after treatment . The number of QoL responders ( CG arm , 12 % ; CP arm , 5 % ) was not significantly different . CGA items were only associated with neuropsychiatric toxicity . Quality -adjusted survival was not different between treatment arms . The PC analysis derived from nine CGA , six QoL and one PS score indicated only one dominant dimension . This dimension was strongly prognostic , and physical and role functioning , Groningen Frailty Indicator and Geriatric Depression Scale were its largest contributors . CONCLUSIONS Paclitaxel or gemcitabine added to carboplatin did not have a differential effect on global QoL. CGA was associated with toxic effects in a very limited manner . CGA and QoL items measure one underlying dimension , which is highly prognostic BACKGROUND This r and omised phase III study investigated if in responsive and stable disease ( SD ) stage IV patients after two courses of cisplatin and gemcitabine , single-agent gemcitabine ( experimental arm ) was not inferior in terms of overall survival ( OS ) to cisplatin-gemcitabine ( st and ard arm ) . PATIENTS AND METHODS Noninferiority was defined as an increase in the hazard of death ( HR ) < or = 1.33 in the experimental arm . From January 2001 to February 2004 , 340 patients were registered and 250 were r and omised .  Cisplatin was administered on day 1 at 75 mg/m2 and Gemcitabine on days 1 and 8 at 1250 mg/m2 every 3 weeks . RESULTS Response rate after two courses was 29 % . The 1-year progression-free survival was 13 % in both arms . One-year survival was 52 % in the st and ard and 42 % in the experimental arm for an HR of 1.21 [ 90 % confidence interval ( CI ) 0.97 - 1.51 ] . Postprogression survival was in favour of the st and ard arm ( HR 1.30 , 95 % CI 0.99 - 1.70 , P = 0.051 ) . Grade s 3 - 4 toxicity favoured in the experimental arm . CONCLUSION In responsive and SD patients with stage IV non-small-cell lung cancer it was not possible to demonstrate that three courses of gemcitabine alone are not inferior , in terms of OS , to the st and ard approach of three courses of cisplatin-gemcitabine BACKGROUND Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor ( EGFR ) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib , but little is known about how its efficacy and safety profile compares with that of st and ard chemotherapy . METHODS We r and omly assigned 230 patients with metastatic , non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel .  The primary end point was progression-free survival ; secondary end points included overall survival , response rate , and toxic effects . RESULTS In the planned interim analysis of data for the first 200 patients , progression-free survival was significantly longer in the gefitinib group than in the st and ard-chemotherapy group ( hazard ratio for death or disease progression with gefitinib , 0.36 ; P<0.001 ) , result ing in early termination of the study . The gefitinib group had a significantly longer median progression-free survival ( 10.8 months , vs. 5.4 months in the chemotherapy group ; hazard ratio , 0.30 ; 95 % confidence interval , 0.22 to 0.41 ; P<0.001 ) , as well as a higher response rate ( 73.7 % vs. 30.7 % , P<0.001 ) . The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group ( P=0.31 ) . The most common adverse events in the gefitinib group were rash ( 71.1 % ) and elevated aminotransferase levels ( 55.3 % ) , and in the chemotherapy group , neutropenia ( 77.0 % ) , anemia ( 64.6 % ) , appetite loss ( 56.6 % ) , and sensory neuropathy ( 54.9 % ) . One patient receiving gefitinib  died from interstitial lung disease . CONCLUSIONS First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival , with acceptable toxicity , as compared with st and ard chemotherapy . ( UMIN-CTR number , C000000376 . BACKGROUND In single-group studies , chromosomal rearrangements of the anaplastic lymphoma kinase gene ( ALK ) have been associated with marked clinical responses to crizotinib , an oral tyrosine kinase inhibitor targeting ALK . Whether crizotinib is superior to st and ard chemotherapy with respect to efficacy is unknown . METHODS We conducted a phase 3 , open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen . Patients were r and omly assigned to receive oral treatment with crizotinib ( 250 mg ) twice daily or intravenous chemotherapy with either pemetrexed ( 500 mg per square meter of body-surface area ) or docetaxel ( 75 mg per square meter ) every 3 weeks . Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study . The primary end point was progression-free survival . RESULTS The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group ( hazard ratio for progression or death with crizotinib , 0.49 ; 95 % confidence interval [ CI ] , 0.37 to 0.64 ; P<0.001 ) . The response rates were 65 % ( 95 % CI , 58 to 72 ) with crizotinib , as compared with 20 % ( 95 % CI , 14 to 26 ) with chemotherapy ( P<0.001 ) . An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy ( hazard ratio for death in the crizotinib group , 1.02 ; 95 % CI , 0.68 to 1.54 ; P=0.54 ) . Common adverse events associated with crizotinib were visual disorder , gastrointestinal side effects , and elevated liver aminotransferase levels , whereas common adverse events with chemotherapy were fatigue , alopecia , and dyspnea . Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy . CONCLUSIONS Crizotinib is superior to st and ard chemotherapy in patients with previously treated , advanced non-small-cell lung cancer with ALK rearrangement . ( Funded by Pfizer ; Clinical Trials.gov number , NCT00932893 . ) Background : Patient-reported symptom and health-related quality of life ( HRQoL ) benefit of afatinib , a novel , irreversible , ErbB Family Blocker , was investigated in a double-blind , r and omized , phase IIb/III trial ( LUX-Lung 1 ) . Methods : Five hundred and eighty-five patients with lung adenocarcinoma ( stage IIIb/IV ) , who had progressed after chemotherapy ( 1–2 lines ) and at least 12 weeks of erlotinib or gefitinib , were r and omized ( 2:1 ) to receive either afatinib plus best supportive care ( BSC ) or placebo plus BSC .  Symptom and HRQoL benefit were measured using the lung cancer-specific European Organisation for Research and Treatment of Cancer ( QLQ-C30/LC13 ) and EuroQol ( EQ-5D ) question naires . Non – small-cell lung cancer – related symptoms ( cough , dyspnea , and pain ) were prespecified using three preplanned analyses ( percentage of patients improved/worsened/stable , change in scores over time , and time to deterioration of scores ) . Results : Compared with patients on placebo , a significantly higher proportion of afatinib-treated patients showed an improvement in cough ( p < 0.0001 ) , dyspnea ( p = 0.006 ) , and pain ( p < 0.0001 ) . Afatinib also significantly improved the mean scores over time for cough ( p < 0.0001 ) , dyspnea ( p = 0.0161 ) , and pain ( p = 0.0056 ) ; significantly delayed the time to deterioration for cough ( p < 0.001 ) ; and showed a trend in delaying dyspnea ( p = 0.170 ) and pain ( p = 0.287 ) . Consistent with the adverse-event profile of afatinib , a significantly ( p < 0.05 ) higher proportion of afatinib-treated patients showed worsening of diarrhea , sore mouth , dysphagia , and appetite scores . However , compared with placebo , afatinib significantly ( p < 0.05 ) improved QoL assessed with the EQ-5D question naire and global health status/QoL , physical functioning , and fatigue , which were assessed with the European Organisation for Research and Treatment of Cancer question naires . Conclusion : In the LUX-Lung 1 trial , the addition of afatinib to BSC significantly improved non – small-cell lung cancer – related symptoms ( cough , dyspnea , and pain ) , fatigue , physical functioning , and HRQoL and significantly delayed time to deterioration of cough BACKGROUND Erlotinib , docetaxel , and pemetrexed are approved for the second-line treatment of non-small-cell lung cancer ( NSCLC ) , but no head-to-head data from large clinical trials are available . We undertook the Tarceva In Treatment of Advanced NSCLC ( TITAN ) study to assess the efficacy and tolerability of second-line erlotinib versus chemotherapy in patients with refractory NSCLC . METHODS TITAN was an international , r and omised multicentre , open-label , phase 3 study that was done at 77 sites in 24 countries . Chemotherapy-naive patients with locally advanced , recurrent , or metastatic NSCLC received up to four cycles of first-line platinum doublet chemotherapy , after which patients with disease progression during or immediately after chemotherapy were offered enrolment into TITAN . Enrolled patients were r and omly assigned ( 1:1 ) by a minimisation method to ensure balanced stratification , to receive erlotinib 150 mg/day or chemotherapy ( st and ard docetaxel or pemetrexed regimens , at the treating investigators ' discretion ) , until unacceptable toxicity , disease progression , or death . Patients were stratified by disease stage , Eastern Cooperative Oncology Group performance status , smoking history , and region of residence . The primary endpoint was overall survival in the intention-to-treat population . TITAN was halted prematurely because of slow recruitment . This study is registered with Clinical Trials.gov , number NCT00556322 . FINDINGS Between April 10 , 2006 , and Feb 24 , 2010 , 2590 chemotherapy-naive patients were treated with first-line platinum doublet chemotherapy , of whom 424 had disease progression and were enrolled into TITAN . 203 patients were r and omly assigned to receive erlotinib and 221 were assigned to receive chemotherapy .  Median follow-up was 27·9 months ( IQR 11·0 - 36·0 ) in the erlotinib group and 24·8 months ( 12·1 - 41·6 ) in the chemotherapy  group . Median overall survival was 5·3 months ( 95 % CI 4·0 - 6·0 ) with erlotinib and 5·5 months ( 4·4 - 7·1 ) with chemotherapy ( hazard ratio [ HR ] 0·96 , 95 % CI 0·78 - 1·19 ; log-rank p=0·73 ) . The adverse-event profile of each group was in line with previous studies . Rash ( 98/196 [ 50 % ] in the erlotinib group vs 10/213 [ 5 % ] in the chemotherapy group for all grade s ; nine [ 5 % ] vs none for grade 3 or 4 ) and diarrhoea ( 36 [ 18 % ] vs four [ 2 % ] for all grade s ; five [ 3 % ] vs none for grade 3 or 4 ) were the most common treatment-related adverse events with erlotinib , whereas alopecia ( none vs 23 [ 11 % ] for all grade s ; none vs one [ < 1 % ] for grade 3/4 ) was the most common treatment-related adverse event with chemotherapy . INTERPRETATION No significant differences in efficacy were noted between patients treated with erlotinib and those treated with docetaxel or pemetrexed . Since the toxicity profiles of erlotinib and chemotherapy differ , second-line treatment decisions should take into account patient preference and specific toxicity risk profiles . FUNDING F Hoffmann-La Roche PURPOSE This phase III study ( V-15 - 32 ) compared gefitinib ( 250 mg/d ) with docetaxel ( 60 mg/m(2 ) ) in patients ( N = 489 ) with advanced/metastatic non-small-cell lung cancer ( NSCLC ) who had failed one or two chemotherapy regimens . METHODS The primary objective was to compare overall survival to demonstrate noninferiority for gefitinib relative to docetaxel . An unadjusted Cox regression model was used for the primary analysis . RESULTS Noninferiority in overall survival was not achieved ( hazard ratio [ HR ] , 1.12 ; 95.24 % CI , 0.89 to 1.40 ) according to the predefined criterion ( upper CI limit for HR < or= 1.25 ) ; however , no significant difference in overall survival ( P = .330 ) was apparent between treatments . Post study , 36 % of gefitinib-treated patients received subsequent docetaxel , and 53 % of docetaxel-treated patients received subsequent gefitinib . Gefitinib significantly improved objective response rate and quality of life versus docetaxel ;  progression-free survival , disease control rates , and symptom improvement were similar for the two treatments . Grade s 3 to 4 adverse events occurred in 40.6 % ( gefitinib ) and 81.6 % ( docetaxel ) of patients . Incidence of interstitial lung disease was 5.7 % ( gefitinib ) and 2.9 % ( docetaxel ) . Four deaths occurred due to adverse events in the gefitinib arm ( three deaths as a result of interstitial lung disease , judged to be treatment related ; one as a result of pneumonia , not treatment related ) , and none occurred in the docetaxel arm . CONCLUSION Noninferiority in overall survival between gefitinib and docetaxel was not demonstrated according to predefined criteria ; however , there was no statistically significant difference in overall survival . Secondary end points showed similar or superior efficacy for gefitinib compared with docetaxel . Gefitinib remains an effective treatment option for previously treated Japanese patients with NSCLC BACKGROUND Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer ( NSCLC ) with activating EGFR mutations . We aim ed to assess the safety and efficacy of erlotinib compared with st and ard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC . METHODS We undertook the open-label , r and omised phase 3 EURTAC trial at 42 hospitals in France , Italy , and Spain . Eligible participants were adults ( > 18 years ) with NSCLC and EGFR mutations ( exon 19 deletion or L858R mutation in exon 21 ) with no history of chemotherapy for metastatic disease ( neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed ) . We r and omly allocated participants ( 1:1 ) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of st and ard intravenous chemotherapy of cisplatin 75 mg/m(2 ) on day 1 plus docetaxel ( 75 mg/m(2 ) on day 1 ) or gemcitabine ( 1250 mg/m(2 ) on days 1 and 8) . Carboplatin ( AUC 6 with docetaxel 75 mg/m(2 ) or AUC 5 with gemcitabine 1000 mg/m(2 ) ) was allowed in patients unable to have cisplatin . Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status ( 0 vs 1 vs 2 ) . The primary endpoint was progression-free survival ( PFS ) in the intention-to-treat population . We assessed safety in all patients who received study drug ( ≥ 1 dose ) . This study is registered with Clinical Trials.gov , number NCT00446225 . FINDINGS Between Feb 15 , 2007 , and Jan 4 , 2011 , 174 patients with EGFR mutations were enrolled . One patient received treatment before r and omisation and was thus withdrawn from the study ; of the remaining patients , 86 were r and omly assigned to receive erlotinib and 87 to receive st and ard chemotherapy . The preplanned interim analysis showed that the study met its primary endpoint ; enrolment was halted , and full evaluation of the results was recommended . At data cutoff ( Jan 26 , 2011 ) , median PFS was 9·7 months ( 95 % CI 8·4 - 12·3 ) in the erlotinib group , compared with 5·2 months ( 4·5 - 5·8 ) in the st and ard chemotherapy group ( hazard ratio 0·37 , 95 % CI 0·25 - 0·54 ; p < 0·0001 ) . Main grade 3 or 4 toxicities were rash ( 11 [ 13 % ] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group ) , neutropenia ( none vs 18 [ 22 % ] ) , anaemia ( one [ 1 % ] vs three [ 4 % ] ) , and increased amino-transferase concentrations ( two [ 2 % ] vs 0 ) . Five ( 6 % ) patients on erlotinib  had treatment-related severe adverse events compared with 16 patients ( 20 % ) on chemotherapy . One patient in the erlotinib group and two in the st and ard chemotherapy group died from treatment-related causes . INTERPRETATION Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors . FUNDING Spanish Lung Cancer Group , Roche Farma , Hoffmann-La Roche , and Red Temática de Investigacion Cooperativa en Cancer BACKGROUND The results of FASTACT , a r and omised , placebo-controlled , phase 2 study , showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival ( PFS ) in patients with advanced non-small-cell lung cancer . We undertook FASTACT-2 , a phase 3 study in a similar patient population . METHODS In this phase 3 trial , patients with untreated stage IIIB/IV non-small-cell lung cancer were r and omly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm ( stratified by disease stage , tumour histology , smoking status , and chemotherapy regimen ) to receive six cycles of gemcitabine ( 1250 mg/m(2 ) on days 1 and 8 , intravenously ) plus platinum ( carboplatin 5 × area under the curve or cisplatin 75 mg/m(2 ) on day 1 , intravenously ) with intercalated erlotinib ( 150 mg/day on days 15 - 28 , orally ; chemotherapy plus erlotinib ) or placebo orally ( chemotherapy plus placebo ) every 4 weeks . With the exception of an independent group responsible for monitoring data and safety monitoring board , everyone outside the interactive internet response system company was masked to treatment allocation . Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death , and all patients in the placebo group were offered second-line erlotinib at the time of progression . The primary endpoint was PFS in the intention-to-treat population . This trial is registered with Clinical Trials.gov , number NCT00883779 . FINDINGS From April 29 , 2009 , to Sept 9 , 2010 , 451 patients were r and omly assigned to chemotherapy plus erlotinib ( n=226 ) or chemotherapy plus placebo ( n=225 ) . PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo ( median PFS 7·6 months [ 95 % CI 7·2 - 8·3 ] , vs 6·0 months [ 5·6 - 7·1 ] , hazard ratio [ HR ] 0·57 [ 0·47 - 0·69 ] ; p<0·0001 ) . Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months ( 16·3 - 20·8 ) and 15·2 months ( 12·7 - 17·5 ) , respectively ( HR 0·79 [ 0·64 - 0·99 ] ; p=0·0420 ) . Treatment benefit was noted only in patients with an activating EGFR gene mutation ( median PFS 16·8 months [ 12·9 - 20·4 ] vs 6·9 months [ 5·3 - 7·6 ] , HR 0·25 [ 0·16 - 0·39 ] ; p<0·0001 ; median overall survival 31·4 months [ 22·2-undefined ] , vs 20·6 months [ 14·2 - 26·9 ] , HR 0·48 [ 0·27 - 0·84 ] ; p=0·0092 ) . Serious adverse events were reported by 76 ( 34 % ) of 222 patients in the chemotherapy plus placebo group and 69 ( 31 % ) of 226 in the chemotherapy plus erlotinib group . The most common grade 3 or greater adverse events were neutropenia ( 65 [ 29 % ] patients and 55 [ 25 % ] , respectively ) , thrombocytopenia ( 32 [ 14 % ] and 31 [ 14 % ] , respectively ) , and anaemia ( 26 [ 12 % ] and 21 [ 9 % ] , respectively ) . INTERPRETATION Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status . FUNDING F Hoffmann-La Roche Platinum-based chemotherapy is the st and ard treatment for patients with advanced non-small cell lung cancer ( NSCLC ) , but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials ; concern exists about tolerability and feasibility of st and ard chemotherapy in these patients . No prospect i ve r and omized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2 . CAPPA-2 was a multicenter , r and omized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC . Patients , aged 18 - 70 , were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes ( TNM VI edition ) and adequate organ function . Patients in st and ard arm received gemcitabine 1200 mg/m(2 ) days 1 and 8 . Patients in experimental arm received cisplatin 60 mg/m(2 ) day 1 plus gemcitabine 1000 mg/m(2 ) days 1 and 8 . All treatments were repeated every 3 weeks , up to 4 cycles , unless disease progression or unacceptable toxicity . Primary endpoint was overall survival ( OS ) . To have 80 % power of detecting hazard ratio ( HR ) 0.71 , corresponding to an increase in median OS from 4.8 to 6.8 months , 285 deaths were required . The study was stopped in June 2012 after the enrolment of 57 patients , due to the slow accrual and the report of positive results from a similar study . Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine ( HR 0.52 , 95 % CI 0.28 - 0.98 , p = 0.039 ) . Combination chemotherapy produced longer PFS ( median 1.7 vs. 3.3 months , HR 0.49 , 95 % CI 0.27 - 0.89 , p = 0.017 ) and higher response rate ( 4 % vs. 18 % , p = 0.19 ) , without substantial increase in toxicity . The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC The search for new agents and for innovative strategies is warranted in the treatment of advanced non small cell lung cancer ( NSCLC ) because the outcomes remain unsatisfactory for most patients . Maintenance treatment with either a chemotherapeutic agent or a molecularly targeted agent after first-line chemotherapy is a very interesting strategy that has been largely investigated in the last years . Maintenance treatment can consist of drugs included in the induction regimen ( continuation maintenance ) or other non-cross-resistant agents not included in the induction regimen ( switch maintenance ) . The switch maintenance strategy with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor erlotinib ( in all the histologies ) or with pemetrexed ( in non-squamous histologies ) have been demonstrated to be two possible effective options versus the classic break from cytotoxic chemotherapy after a fixed course in the treatment of advanced NSCLC . However some biases may have influenced the outcomes of switch maintenance trials as the low rate of patients treated with erlotinib and pemetrexed in the placebo arms . Very recently , a r and omized phase III trial named PARAMOUNT has demonstrated a clinical ly significant benefit in overall survival with a good safety profile versus placebo in favour of continuation maintenance with pemetrexed after four cycles of induction with cisplatin plus pemetrexed . Continuation maintenance can be considered the true maintenance strategy because switch maintenance is an early second-line treatment . Continuation maintenance with pemetrexed after cisplatin plus pemetrexed induction for patients selected for a maintenance strategy is recommended as first-line treatment of advanced non-squamous NSCLC The analyses of the retrospective data base of the International Association for the Study of Lung Cancer ( IASLC ) , consisting of more than 81,000 evaluable patients diagnosed with lung cancer between 1990 and 2000 , formed the basis of recommendations to the Union for International Cancer Control and the American Joint Committee on Cancer for the revision of the sixth edition of the tumor , node , and metastasis ( TNM ) classification of lung cancer . However , despite the large number of patients , not all descriptors could be vali date d. This prompted a new collection of retrospective and prospect i ve data to overcome the limitations of the original retrospective data base . The new IASLC data base has information on 94,708 new patients diagnosed of lung cancer between 1999 and 2010 . They originated from 35 sources in 16 countries , and 4,667 were su bmi tted via the online electronic data capture system . Europe contributed 46,560 patients , Asia : 41,705 , North America : 4,660 , Australia : 1,593 , and South America : 190 . After exclusions , 77,156 ( 70,967 with nonsmall cell lung cancer and 6,189 with small cell lung cancer ) remained for analysis . This data base will be analyzed according to established objectives for the T , the N , and the M components to inform the eighth edition of the TNM classification of lung cancer due to be published in 2016 . The IASLC hopes for the continuing contribution of our partners around the world to improve the classification of anatomical extent of disease , but also to create prognostic groups in a parallel project of the IASLC Staging and Prognostic Factors Committee BACKGROUND This analysis evaluates safety and efficacy in elderly ( ≥ 70 years old ) versus younger patients enrolled in a phase III advanced non-small-cell lung cancer ( NSCLC ) trial . PATIENTS AND METHODS Untreated stage IIIB/IV patients with PS 0/1 were r and omly assigned ( 1:1 ) to carboplatin AUC6 , day 1 every 3 weeks , and either nab-paclitaxel ( Abraxane ) 100 mg/m(2 ) weekly ( nab-P/C ) or solvent-based paclitaxel ( Taxol ) 200 mg/m(2 ) day 1 every 3 weeks ( sb-P/C ) . The primary end-point was overall response rate ( ORR ) . RESULTS Fifteen percent of 1052 enrolled patients were elderly : nab-P/C , n = 74 ; sb-P/C , n = 82 . In both age cohorts , the ORR was higher with nab-P/C versus sb-P/C ( age ≥ 70 : 34 % versus 24 % , P = 0.196 ; age < 70 : 32 % versus 25 % , P = 0.013 ) . In elderly patients , progression-free survival ( PFS ) trended in favor of nab-P/C ( median 8.0 versus 6.8 months , hazard ratio ( HR ) 0.687 , P = 0.134 ) , and overall survival ( OS ) was significantly improved ( median 19.9 versus 10.4 months , HR 0.583 , P = 0.009 ) . In younger patients , PFS ( median 6.0 versus 5.8 months , HR 0.903 , P = 0.256 ) and OS ( median 11.4 versus 11.3 months , HR 0.999 , P = 0.988 ) were similar in both arms . Adverse events were similar in both age groups , with less neutropenia ( P = 0.015 ) , neuropathy ( P = 0.001 ) , and arthralgia ( P = 0.029 ) , and increased anemia ( P = 0.007 ) with nab-P/C versus sb-P/C. CONCLUSIONS In elderly NSCLC patients , nab-P/C as first-line therapy was well tolerated and improved the ORR and PFS , with substantially longer OS versus sb-PC BACKGROUND Despite recent advances in the treatment of advanced non-small-cell lung cancer , there remains a need for effective treatments for progressive disease . We assessed the efficacy of pembrolizumab for patients with previously treated , PD-L1-positive , advanced non-small-cell lung cancer . METHODS We did this r and omised , open-label , phase 2/3 study at 202 academic medical centres in 24 countries . Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1 % of tumour cells were r and omly assigned ( 1:1:1 ) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg , pembrolizumab 10 mg/kg , or docetaxel 75 mg/m(2 ) every 3 weeks . The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50 % of tumour cells . We used a threshold for significance of p<0.00825 ( one-sided ) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival . This trial is registered at Clinical Trials.gov , number NCT01905657 . FINDINGS Between Aug 28 , 2013 , and Feb 27 , 2015 , we enrolled 1034 patients : 345 allocated to pembrolizumab 2 mg/kg , 346 allocated to pembrolizumab 10 mg/kg , and 343 allocated to docetaxel . By Sept 30 , 2015 , 521 patients had died . In the total population , median overall survival was 10.4 months with pembrolizumab 2 mg/kg , 12.7 months with pembrolizumab 10 mg/kg , and 8.5 months with docetaxel .  Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel ( hazard ratio [ HR ] 0.71 , 95 % CI 0.58 - 0.88 ; p=0.0008 ) and for pembrolizumab 10 mg/kg versus docetaxel ( 0.61 , 0.49 - 0.75 ; p<0.0001 ) . Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg , 4.0 months with pembrolizumab 10 mg/kg , and 4.0 months with docetaxel , with no significant difference for pembrolizumab 2 mg/kg versus docetaxel ( 0.88 , 0.74 - 1.05 ; p=0.07 ) or for pembrolizumab 10 mg/kg versus docetaxel ( HR 0.79 , 95 % CI 0.66 - 0.94 ; p=0.004 ) . Among patients with at least 50 % of tumour cells expressing PD-L1 , overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel ( median 14.9 months vs 8.2 months ; HR 0.54 , 95 % CI 0.38 - 0.77 ; p=0.0002 ) and with pembrolizumab 10 mg/kg than with docetaxel ( 17.3 months vs 8.2 months ; 0.50 , 0.36 - 0.70 ; p<0.0001 ) . Likewise , for this patient population , progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel ( median 5.0 months vs 4.1 months ; HR 0.59 , 95 % CI 0.44 - 0.78 ; p=0.0001 ) and with pembrolizumab 10 mg/kg than with docetaxel ( 5.2 months vs 4.1 months ; 0.59 , 0.45 - 0.78 ; p<0.0001 ) . Grade 3 - 5 treatment-related adverse events were less common with pembrolizumab than with docetaxel ( 43 [ 13 % ] of 339 patients given 2 mg/kg , 55 [ 16 % ] of 343 given 10 mg/kg , and 109 [ 35 % ] of 309 given docetaxel ) . INTERPRETATION Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated , PD-L1-positive , advanced non-small-cell lung cancer . These data establish pembrolizumab as a new treatment option for this population and vali date the use of PD-L1 selection . FUNDING Merck & PURPOSE Maintenance therapy is associated with improved survival in patients with non-small-cell lung cancer ( NSCLC ) , but few studies have compared active agents in this setting . AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment . PATIENTS AND METHODS Patients with advanced nonsquamous NSCLC received first-line  bevacizumab 7.5 mg/kg , cisplatin 75 mg/m(2 ) , and pemetrexed 500 mg/m(2 ) once every 3 weeks for four cycles . Those achieving response or stable disease were r and omly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m(2 ) once every 3 weeks until disease progression or unacceptable toxicity . The primary end point was progression-free survival ( PFS ) after r and om assignment . RESULTS In total , 376 patients received induction treatment , 71.9 % achieved disease control , and 67.3 % were r and omly assigned to maintenance therapy , with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment , respectively . At a median follow-up of 8.1 months , PFS from r and om assignment was significantly improved in the bevacizumab plus pemetrexed arm ( median , 3.7 v 7.4 months ; hazard ratio , 0.48 ; 95 % CI , 0.35 to 0.66 ; P < .001 ) per a stratified model . The PFS benefit extended across age , performance status , smoking history , and induction response ( stable disease v partial response ) subgroups . Any grade , grade ≥ 3 , and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance . No new safety signals were observed . CONCLUSION In an unselected population of patients with nonsquamous NSCLC who had achieved  disease control  with platinum-based chemotherapy plus bevacizumab , bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone . The combination was well tolerated BACKGROUND Icotinib , an oral EGFR tyrosine kinase inhibitor , had shown antitumour activity and favourable toxicity in early-phase clinical trials . We aim ed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer . METHODS In this r and omised , double-blind , phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China . Eligible patients were those aged 18 - 75 years who had not responded to one or more platinum-based chemotherapy regimen . Patients were r and omly assigned ( 1:1 ) , using minimisation methods , to receive icotinib ( 125 mg , three times per day ) or gefitinib ( 250 mg , once per day ) until disease progression or unacceptable toxicity . The primary endpoint was progression-free survival , analysed in the full analysis set . We analysed EGFR status if tissue sample s were available . All investigators , clinicians , and participants were masked to patient distribution . The non-inferiority margin was 1·14 ; non-inferiority would be established if the upper limit of the 95 % CI for the hazard ratio ( HR ) of gefitinib versus icotinib was less than this margin . This study is registered with Clinical Trials.gov , number NCT01040780 , and the Chinese Clinical Trial Registry , number ChiCTR-TRC-09000506 . FINDINGS 400 eligible patients were enrolled between Feb 26 , 2009 , and Nov 13 , 2009 ; one patient was enrolled by mistake and removed from the study , 200 were assigned to icotinib and 199 to gefitinib  . 395 patients were included in the full analysis set ( icotinib , n=199 ; gefitinib , n=196 ) . Icotinib was non-inferior to gefitinib in terms of progression-free survival ( HR 0·84 , 95 % CI 0·67 - 1·05 ; median progression-free survival 4·6 months [ 95 % CI 3·5 - 6·3 ] vs 3·4 months [ 2·3 - 3·8 ] ; p=0·13 ) . The most common adverse events were rash ( 81 [ 41 % ] of 200 patients in the icotinib group vs 98 [ 49 % ] of 199 patients in the gefitinib group ) and diarrhoea ( 43 [ 22 % ] vs 58 [ 29 % ] ) . Patients given icotinib had less drug-related adverse events than did those given gefitinib ( 121 [ 61 % ] vs 140 [ 70 % ] ; p=0·046 ) , especially drug-related diarrhoea ( 37 [ 19 % ] vs 55 [ 28 % ] ; p=0·033 ) . INTERPRETATION Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer The purpose of this article is to provide up date d recommendations for the treatment of patients with stage IV non-small-cell lung cancer . A literature search identified relevant r and omized trials published since 2002 . The scope of the guideline was narrowed to chemotherapy and biologic therapy . An Up date Committee review ed the literature and made up date d recommendations . One hundred sixty-two publications met the inclusion criteria . Recommendations were based on treatment strategies that improve overall survival . Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life . For first-line therapy in patients with performance status of 0 or 1 , a platinum-based two-drug combination of cytotoxic drugs is recommended . Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy . For patients with performance status of 2 , a single cytotoxic drug is sufficient . Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment . Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy . The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor ( EGFR ) mutation ; for negative or unknown EGFR mutation status , cytotoxic chemotherapy is preferred . Bevacizumab is recommended with carboplatin-paclitaxel , except for patients with certain clinical characteristics . Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry . Docetaxel , erlotinib , gefitinib , or pemetrexed is recommended as second-line therapy . Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib . Data are insufficient to recommend the routine third-line use of cytotoxic drugs . Data are insufficient to recommend routine use of molecular markers to select chemotherapy Gefitinib was compared with pemetrexed as second‐line therapy in a clinical ly selected population previously treated with platinum‐based chemotherapy To compare the overall survival ( OS ) of patients with advanced non-small cell lung ( NSCLC ) treated with either docetaxel plus gemcitabine or single-agent docetaxel .  Chemotherapy-naive patients with advanced/metastatic NSCLC were r and omly assigned to receive either DG [ n=157 ; gemcitabine 1100mg/m(2 ) on days 1 and 8 ] , docetaxel 75mg/m(2 ) on day 8 or D [ n=155 ; docetaxel 100mg/m(2 ) on day 1 ] every 3 weeks . A total of 312 patients were evaluable for toxicity and response .  A predefined interim intention-to-treat analysis showed significantly longer median OS ( p=0.037 ) in favor of the DG regimen ( 9.4 months versus 8.3 months for DG and D regimens , respectively ) , result ing in the premature termination of the study . The DG regimen was also associated with a significantly higher response rate compared to D ( 26.8 % versus 11.6 % , p<0.001 ) . TTP were 3.5 and 2.3 months for the DG and D regimen , respectively ( p=0.054 ) . Although there were two treatment-related deaths in the DG arm , the toxicity profiles of the two regimens were comparable . The DG regimen was associated with a significantly better quality of life . The efficacy of the docetaxel plus gemcitabine combination is superior to single-agent docetaxel in chemonaive patients with advanced NSCLC Introduction : In a phase III , r and omized , double-blind study ( PARAMOUNT ) , maintenance pemetrexed demonstrated significant benefit in advanced non – small-cell lung cancer ( NSCLC ) . We present safety , re source use , and quality of life ( QoL ) results . Methods : After four 21-day cycles of pemetrexed-cisplatin  ( N = 939 ) , patients with advanced nonsquamous NSCLC , whose disease had not progressed and who had a performance status of 0/1 , were r and omized 2:1 ( N = 539 ) to maintenance pemetrexed 500 mg/m2 plus best supportive care or placebo plus best supportive care every 21 days until disease progression or unacceptable toxicity . QoL was measured using the EuroQol 5-dimensional question naire ( EQ-5D ) . Results : Frequently reported grade 3 to 4 drug-related toxicities with maintenance pemetrexed versus placebo were anemia ( 4.5 % versus 0.6 % ; p = 0.016 ) , fatigue ( 4.2 % versus 0.6 % ; p = 0.016 ) , and neutropenia ( 3.6 % versus 0.0 % ; p < 0.006 ) . No significant differences in drug-related grade 3 to 5 toxicities were observed with long-term pemetrexed exposure ( > 6 cycles ) , except grade 3 to 4 neutropenia , which did not result in increased infections . Patients on maintenance pemetrexed  required more transfusions ( 13.4 % versus 5.0 % ; p = 0.003 ) , granulocyte colony- or granulocyte-macrophage colony-stimulating factors ( 5.3 % versus 0.0 % ; p < 0.001 ) , anti-infectives ( 25.3 % versus 16.7 % ; p = 0.028 ) , and hospitalizations because of study drug ( 8.4 % versus 3.3 % , p = 0.028 ) than placebo-treated patients did . No significant treatment-by-time interactions , overall treatment differences , or clinical ly relevant changes from baseline were observed in EQ-5D scores during treatment . Conclusions : Long-term use of continuation maintenance pemetrexed was well tolerated ; re source use was low , corresponding with known pemetrexed toxicities . The EQ-5D results demonstrate that patients tolerate long-term maintenance pemetrexed without worsening BACKGROUND Findings from the phase 3 First-Line ErbituX in lung cancer ( FLEX ) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone ( hazard ratio [ HR ] 0·871 , 95 % CI 0·762 - 0·996 ; p=0·044 ) in patients with advanced non-small-cell lung cancer ( NSCLC ) . To define patients benefiting most from cetuximab , we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients . METHODS We used prospect ively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0 - 300 . We used response data to select an outcome -based discriminatory threshold immunohistochemistry score for EGFR expression of 200 . Treatment outcome was analysed in patients with low ( immunohistochemistry score < 200 ) and high ( ≥200 ) tumour EGFR expression . The primary endpoint in the FLEX study was overall survival . We analysed patients from the FLEX intention-to-treat ( ITT ) population . The FLEX study is registered with Clinical Trials.gov , number NCT00148798 . FINDINGS Tumour EGFR immunohistochemistry data were available for 1121 of 1125 ( 99·6 % ) patients from the FLEX study ITT population . High EGFR expression was scored for 345 ( 31 % ) evaluable patients and low for 776 ( 69 % ) patients . For patients in the high EGFR expression group , overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group ( median 12·0 months [ 95 % CI 10·2 - 15·2 ] vs 9·6 months [ 7·6 - 10·6 ] ; HR 0·73 , 0·58 - 0·93 ; p=0·011 ) , with no meaningful increase in side-effects . We recorded no corresponding survival benefit for patients in the low EGFR expression group ( median 9·8 months [ 8·9 - 12·2 ] vs 10·3 months [ 9·2 - 11·5 ] ; HR 0·99 , 0·84 - 1·16 ; p=0·88 ) . A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression ( p=0·044 ) . INTERPRETATION High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC . Assessment of EGFR expression could offer a personalised treatment approach in this setting . FUNDING Merck PURPOSE Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non-small-cell lung cancer ( NSCLC ) , based on the importance of the signaling pathways involved in tumor growth , angiogenesis , and metastasis . This phase III trial investigated overall survival ( OS ) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC . PATIENTS AND METHODS Patients previously treated with one to two chemotherapy regimens ( including one platinum-based regimen ) for recurrent NSCLC , and for whom erlotinib was indicated , were r and omly assigned ( 1:1 ) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d , stratified by prior bevacizumab use , smoking history , and epidermal growth factor receptor expression . The primary end point was OS . Key secondary end points included progression-free survival ( PFS ) , objective response rate ( ORR ) , and safety . RESULTS In all , 960 patients were r and omly assigned , and baseline characteristics were balanced . Median OS was 9.0 months for sunitinib plus erlotinib versus 8.5 months for erlotinib alone ( hazard ratio [ HR ] , 0.922 ; 95 % CI , 0.797 to 1.067 ; one-sided stratified log-rank P = .1388 ) . Median PFS was 3.6 months versus 2.0 months ( HR , 0.807 ; 95 % CI , 0.695 to 0.937 ; one-sided stratified log-rank P = .0023 ) , and ORR was 10.6 % versus 6.9 % ( two-sided stratified log-rank P = .0471 ) , respectively . Treatment-related toxicities of grade 3 or higher , including rash/dermatitis , diarrhea , and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm . CONCLUSION In patients with refractory NSCLC , sunitinib plus erlotinib did not improve OS compared with erlotinib alone , but the combination was associated with a statistically significantly longer PFS and greater ORR . The incidence of grade 3 or higher toxicities was greater with combination therapy PURPOSE To compare pemetrexed/carboplatin with a st and ard regimen as first-line therapy in advanced non-small-cell lung cancer NSCLC . PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC and performance status of 0 to 2 were r and omly assigned to receive pemetrexed 500 mg/m(2 ) plus carboplatin area under the curve ( AUC ) = 5 ( Calvert 's formula ) on day 1 or gemcitabine 1,000 mg/m(2 ) on days 1 and 8 plus carboplatin AUC = 5 on day 1 every 3 weeks for up to four cycles . The primary end point was health-related quality of life ( HRQoL ) defined as global quality of life , nausea/vomiting , dyspnea , and fatigue reported on the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 and the lung cancer-specific module LC13 during the first 20 weeks . Secondary end points were overall survival and toxicity . Results Four hundred thirty-six eligible patients were enrolled from April 2005 to July 2006 . Patients who completed the baseline question naire were analyzed for HRQoL ( n = 427 ) , and those who received > or = one cycle of chemotherapy were analyzed for toxicity ( n = 423 ) . Compliance of HRQoL question naires was 87 % . There were no significant differences for the primary HRQoL end points or in overall survival between the two treatment arms ( pemetrexed/carboplatin , 7.3 months ; gemcitabine/carboplatin , 7.0 months ; P = .63 ) . The patients who received gemcitabine/carboplatin had more grade 3 to 4 hematologic toxicity than patients who received pemetrexed/carboplatin , including leukopenia ( 46 % v 23 % , respectively ; P < .001 ) , neutropenia ( 51 % v 40 % , respectively ; P = .024 ) , and thrombocytopenia ( 56 % v 24 % , respectively ; P < .001 ) . More patients on the gemcitabine/carboplatin arm received transfusions of RBCs and platelets , whereas the frequencies of neutropenic infections and thrombocytopenic bleedings were similar on both arms . CONCLUSION Pemetrexed/carboplatin provides similar HRQoL and survival when compared with gemcitabine/carboplatin with less hematologic toxicity and less need for supportive care PURPOSE Erlotinib prolonged survival of unselected patients with advanced non-small-cell lung cancer ( NSCLC ) who were not eligible for further chemotherapy , and two phase II studies suggested it might be an alternative to first-line chemotherapy . A r and omized phase III trial was design ed to test whether first-line erlotinib followed at progression by cisplatin-gemcitabine was not inferior in terms of survival to the st and ard inverse sequence . PATIENTS AND METHODS Patients with stage IIIB ( with pleural effusion or supraclavicular nodes ) to IV NSCLC and performance status of 0 to 1 were eligible . With a 95 % CI upper limit of 1.25 for the hazard ratio ( HR ) for death , 80 % power , a one-sided α = .025 , and two interim analyses , a sample size of 900 patients was planned . RESULTS At the first planned interim analysis with half the events , the inferiority boundary was crossed , and the Independent Data Monitoring Committee recommended early termination of the study . Seven hundred sixty patients ( median age , 62 years ; range , 27 to 81 years ) had been r and omly assigned . Baseline characteristics were balanced between study arms . As of June 1 , 2011 , median follow-up was 24.3 months , and 536 deaths were recorded ( 263 in the st and ard treatment arm and 273 in the experimental arm ) . Median survival was 11.6 months ( 95 % CI , 10.2 to 13.3 months ) in the st and ard arm and 8.7 months ( 95 % CI , 7.4 to 10.5 months ) in the experimental arm . Adjusted HR of death in the experimental arm was 1.24 ( 95 % CI , 1.04 to 1.47 ) . There was no heterogeneity across sex , smoking habit , histotype , and epidermal growth factor receptor ( EGFR ) mutation . CONCLUSION In unselected patients with advanced NSCLC , first-line erlotinib followed at progression by cisplatin-gemcitabine was significantly inferior in terms of overall survival compared with the st and ard sequence of first-line chemotherapy followed by erlotinib BACKGROUND There is a major unmet need for effective treatments in patients with squamous cell carcinoma of the lung . LUX-Lung 8 compared afatinib ( an irreversible ErbB family blocker ) with erlotinib ( a reversible EGFR tyrosine kinase inhibitor ) , as second-line treatment for patients with advanced squamous cell carcinoma of the lung . METHODS We did this open-label , phase 3 r and omised controlled trial at 183 cancer centres in 23 countries worldwide . We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based-chemotherapy .  Participants were r and omly assigned ( 1:1 ) to receive afatinib ( 40 mg per day ) or erlotinib ( 150 mg per day ) until disease progression . The r and omisation was done central ly with an interactive voice or web-based response system and stratified by ethnic origin ( eastern Asian vs non-eastern Asian ) . Clinicians and patients were not masked to treatment allocation . The primary endpoint was progression-free survival assessed by independent central review ( intention-to-treat population ) . The key secondary endpoint was overall survival . This trial is registered with Clinical Trials.gov , NCT01523587 . FINDINGS 795 eligible patients were r and omly assigned ( 398 to afatinib , 397 to erlotinib ) . Median follow-up at the time of the primary analysis of progression-free survival was 6·7 months ( IQR 3·1 - 10·2 ) , at which point enrolment was not complete . Progression free-survival at the primary analysis was significantly longer with afatinib than with erlotinib ( median 2·4 months [ 95 % CI 1·9 - 2·9 ] vs 1·9 months [ 1·9 - 2·2 ] ; hazard ratio [ HR ] 0·82 [ 95 % CI 0·68 - 1·00 ] , p=0·0427 ) . At the time of the primary analysis of overall survival ( median follow-up 18·4 months [ IQR 13·8 - 22·4 ] ) , overall survival was significantly greater in the afatinib group than in the erloinib group ( median 7·9 months [ 95 % CI 7·2 - 8·7 ] vs 6·8 months [ 5·9 - 7·8 ] ; HR 0·81 [ 95 % CI 0·69 - 0·95 ] , p=0·0077 ) , as were progression-free survival ( median 2·6 months [ 95 % CI 2·0 - 2·9 ] vs 1·9 months [ 1·9 - 2·1 ] ; HR 0·81 [ 95 % CI 0·69 - 0·96 ] , p=0·0103 ) and disease control ( 201 [ 51 % ] of 398 patients vs 157 [ 40 % ] of 397 ; p=0·0020 ) . The proportion of patients with an objective response did not differ significantly between groups ( 22 [ 6 % ] vs 11 [ 3 % ] ; p=0·0551 ) . Tumour shrinkage occurred in 103 ( 26 % ) of 398 patients versus 90 ( 23 % ) of 397 patients . Adverse event profiles were similar in each group : 224 ( 57 % ) of 392 patients in the afatinib group versus 227 ( 57 % ) of 395 in the erlotinib group had grade 3 or higher adverse events . We recorded higher incidences of treatment-related grade 3 diarrhoea with afatinib ( 39 [ 10 % ] vs nine [ 2 % ] ) , of grade 3 stomatitis with afatinib ( 16 [ 4 % ] vs none ) , and of grade 3 rash or acne with erlotinib ( 23 [ 6 % ] vs 41 [ 10 % ] ) . INTERPRETATION The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib , along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung . FUNDING Boehringer Ingelheim PURPOSE Cyclooxygenase-2 ( COX-2 ) protein expression in patients with non-small-cell lung cancer ( NSCLC ) may be not only a prognostic marker but also predictive for COX-2 inhibition . We hypothesized that COX-2 expression is associated with shorter survival and that celecoxib , being a potent COX-2 inhibitor , increases tumor response and survival . PATIENTS AND METHODS A phase III study was performed in patients with stage IIIb/IV NSCLC who had pathologic confirmation , no prior chemotherapy , Eastern Cooperative Oncology Group performance status of 0 to 2 , and adequate organ function . Treatment consisted of docetaxel and carboplatin every 3 weeks for five cycles . Patients were r and omly assigned to receive celecoxib 400 mg or placebo twice daily . COX-2 expression on tumor cells was detected by immunohistochemistry . Primary end point was overall survival ( OS ) . RESULTS From July 2003 to December 2007 , 561 patients were r and omly assigned .  Toxicity was mild , and no increase in cardiovascular events was observed . Tumor response was 38 % in the celecoxib arm and 30 % in the placebo arm ( P = .08 ) . Median progression-free survival was 4.5 months ( 95 % CI , 4.0 to 4.8 ) for the celecoxib arm and 4.0 months ( 95 % CI , 3.6 to 4.9 ) for the placebo arm ( hazard ratio [ HR ] , 0.8 ; 95 % CI , 0.6 to 1.1 ; P = .25 ) . Median OS was 8.2 months ( 95 % CI , 7.5 to 8.8 ) for both treatment arms ( HR , 0.9 ; 95 % CI , 0.6 to 1.2 ; P = .32 ) . COX-2 expression did not independently predict survival . Benefit from celecoxib , restricted to patients with low COX-2 expression , was not significant when adjusted for prognostic factors . CONCLUSION In advanced NSCLC , celecoxib does not improve survival . In this study , COX-2 expression was not a prognostic biomarker and had no predictive value when celecoxib was added to chemotherapy PURPOSE An American Society of Clinical Oncology ( ASCO ) provisional clinical opinion ( PCO ) offers timely clinical direction to ASCO 's membership following publication or presentation of potentially practice -changing data from major studies . This PCO addresses the clinical utility of using epidermal growth factor receptor ( EGFR ) mutation testing for patients with advanced non-small-cell lung cancer ( NSCLC ) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor ( TKI ) . CLINICAL CONTEXT Patients with EGFR-mutated NSCLC have a significantly higher rate of partial responses to the EGFR TKIs gefitinib and erlotinib . In the United States , approximately 15 % of patients with adenocarcinoma of the lung harbor activating EGFR mutations . EGFR mutation testing is widespread at academic medical centers and in some locales in community practice . As of yet , there is no evidence of an overall survival ( OS ) benefit from selecting treatment based on performing this testing . RECENT DATA One large phase III trial ( the Iressa Pan-Asia Study [ IPASS ] trial ) , three smaller phase III r and omized controlled trials using progression-free survival as the primary end point , and one small phase III trial with OS as the primary end point , all involving first-line EGFR TKIs and chemotherapy doublets , form the basis of this PCO . PROVISIONAL CLINICAL OPINION On the basis of the results of five phase III r and omized controlled trials , patients with NSCLC who are being considered for first-line therapy with an EGFR TKI ( patients who have not previously received chemotherapy or an EGFR TKI ) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy . NOTE . ASCO 's provisional clinical opinions ( PCOs ) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and setting s for further research . Because of the rapid flow of scientific information in oncology , new evidence may have emerged since the time a PCO was su bmi tted for publication . PCOs are not continually up date d and may not reflect the most recent evidence . PCOs can not account for individual variation among patients and can not be considered inclusive of all proper methods of care or exclusive of other treatments . It is the responsibility of the treating physician or other health care provider , relying on independent experience and knowledge of the patient , to determine the best course of treatment for the patient . Accordingly , adherence to any PCO is voluntary , with the ultimate determination regarding its application to be made by the physician in light of each patient 's individual circumstances . ASCO PCOs describe the use of procedures and therapies in clinical practice and can not be assumed to apply to the use of these interventions in the context of clinical trials . ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO 's PCOs , or for any errors or omissions BACKGROUND The EGFR T790 M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation ( EGFR-mutated lung cancer ) . In pre clinical models , the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790 M resistance mutations . METHODS We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors . The study included dose-escalation cohorts and dose-expansion cohorts . In the expansion cohorts , pre study tumor biopsies were required for central determination of EGFR T790 M status . Patients were assessed for safety , pharmacokinetics , and efficacy . RESULTS A total of 253 patients were treated . Among 31 patients enrolled in the dose-escalation cohorts , no dose-limiting toxic effects occurred at the doses evaluated . An additional 222 patients were treated in five expansion cohorts . The most common all-cause adverse events were diarrhea , rash , nausea , and decreased appetite . The overall objective tumor response rate was 51 % ( 95 % confidence interval [ CI ] , 45 to 58 ) . Among 127 patients with central ly confirmed EGFR T790 M who could be evaluated for response , the response rate was 61 % ( 95 % CI , 52 to 70 ) . In contrast , among 61 patients without central ly detectable EGFR T790 M who could be evaluated for response , the response rate was 21 % ( 95 % CI , 12 to 34 ) . The median progression-free survival was 9.6 months ( 95 % CI , 8.3 to not reached ) in EGFR T790M-positive patients and 2.8 months ( 95 % CI , 2.1 to 4.3 ) in EGFR T790M-negative patients . CONCLUSIONS AZD9291 was highly active in patients with lung cancer with the EGFR T790 M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors . ( Funded by AstraZeneca ; Clinical Trials.gov number , NCT01802632 . ) PURPOSE V and etanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling . This phase III study assessed the efficacy of v and etanib versus erlotinib in unselected patients with advanced non-small-cell lung cancer ( NSCLC ) after treatment failure with one to two prior cytotoxic chemotherapy regimens . PATIENTS AND METHODS One thous and two hundred forty patients were r and omly assigned to receive v and etanib 300 mg/d ( n = 623 ) or erlotinib 150 mg/d ( n = 617 ) . The primary objective was to show superiority in progression-free survival ( PFS ) for v and etanib versus erlotinib . If the difference did not reach statistical significance for superiority , a noninferiority analysis was conducted . RESULTS There was no significant improvement in PFS for patients treated with v and etanib versus erlotinib ( hazard ratio [ HR ] , 0.98 ; 95.22 % CI , 0.87 to 1.10 ; P = .721 ) ; median PFS was 2.6 months for v and etanib and 2.0 months for erlotinib . There was also no significant difference for the secondary end points of overall survival ( HR , 1.01 ; P = .830 ) , objective response rate ( both 12 % ) , and time to deterioration of symptoms for pain ( HR , 0.92 ; P = .289 ) , dyspnea ( HR , 1.07 ; P = .407 ) , and cough ( HR , 0.94 ; P = .455 ) . Both agents showed equivalent PFS and overall survival in a preplanned noninferiority analysis . Adverse events ( AEs ; any grade ) more frequent with v and etanib than erlotinib included diarrhea ( 50 % v 38 % , respectively ) and hypertension ( 16 % v 2 % , respectively ) ; rash was more frequent with erlotinib than v and etanib ( 38 % v 28 % , respectively ) . The overall incidence of grade ≥ 3 AEs was also higher with v and etanib than erlotinib ( 50 % v 40 % , respectively ) . CONCLUSION In patients with previously treated advanced NSCLC  , v and etanib showed antitumor activity but did not demonstrate an efficacy advantage compared with erlotinib . There was a higher incidence of some AEs with v and etanib BACKGROUND Osimertinib ( AZD9291 ) is an oral , potent , irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations , and the EGFR Thr790Met resistance mutation . We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer ( NSCLC ) , who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor . METHODS In this phase 2 , open-label , single-arm study ( AURA2 ) , patients aged at least 18 years with central ly confirmed EGFR Thr790Met-positive mutations , locally advanced or metastatic ( stage IIIB/IV ) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy  received osimertinib 80 mg orally once daily ; treatment could continue beyond progression if the investigator observed a clinical benefit . Patients with asymptomatic , stable CNS metastases not requiring steroids were allowed to enrol . The primary endpoint was the proportion of patients achieving an objective response by blinded independent central review using Response Evaluation Criteria in Solid Tumors , version 1.1 . Response endpoints were assessed in the evaluable for response analysis set ( ie , all patients who received at least one dose of osimertinib and had measurable disease at baseline according to blinded independent central review ) . Other endpoints and safety were assessed in all patients receiving at least one osimertinib dose ( full analysis set ) . The study is ongoing and patients are still receiving treatment . This study is registered with Clinical Trials.gov , number NCT02094261 . FINDINGS Between May 20 , 2014 , and Sept 12 , 2014 , 472 patients were screened , of whom 210 started osimertinib treatment between June 13 , 2014 , and Oct 27 , 2014 ; 11 patients were excluded from the evaluable for response analysis set ( n=199 ) due to absence of measurable disease at baseline by blinded independent central review . At data cutoff ( Nov 1 , 2015 ) , 122 ( 58 % ) patients remained on treatment . The median duration of follow-up was 13·0 months ( IQR 7·6 - 14·2 ) . 140 ( 70 % ; 95 % CI 64 - 77 ) of 199 patients achieved an objective response by blinded independent central review : confirmed complete responses were achieved in six ( 3 % ) patients and partial responses were achieved in 134 ( 67 % ) patients . The most common all-causality grade 3 and 4 adverse events were pulmonary embolism ( seven [ 3 % ] ) , prolonged electrocardiogram QT ( five [ 2 % ] ) , decreased neutrophil count ( four [ 2 % ] ) , anaemia , dyspnoea , hyponatraemia , increased alanine aminotransferase , and thrombocytopenia ( three [ 1 % ] each ) . Serious adverse events were reported in 52 ( 25 % ) patients , of which 11 ( 5 % ) were investigator assessed as possibly treatment-related to osimertinib . Seven deaths were due to adverse events ; these were pneumonia ( n=2 ) , pneumonia aspiration ( n=1 ) , rectal haemorrhage ( n=1 ) , dyspnoea ( n=1 ) , failure to thrive ( n=1 ) , and interstitial lung disease ( n=1 ) . The only fatal event assessed as possibly treatment-related by the investigator was due to interstitial lung disease . INTERPRETATION Osimertinib showed clinical activity with manageable side-effects in patients with EGFR Thr790Met-positive NSCLC . Therefore , osimertinib could be a suitable treatment for patients with EGFR Thr790Met-positive disease who have progressed on an EGFR tyrosine-kinase inhibitor . FUNDING AstraZeneca PURPOSE This phase III trial compared the efficacy and safety of albumin-bound paclitaxel ( nab-paclitaxel ) plus carboplatin with solvent-based paclitaxel ( sb-paclitaxel ) plus carboplatin in advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS In all , 1,052 untreated patients with stage IIIB to IV NSCLC were r and omly assigned 1:1 to receive 100 mg/m(2 ) nab-paclitaxel weekly and carboplatin at area under the concentration-time curve ( AUC ) 6 once every 3 weeks ( nab-PC ) or 200 mg/m(2 ) sb-paclitaxel plus carboplatin AUC 6 once every 3 weeks ( sb-PC ) . The primary end point was objective overall response rate ( ORR ) . RESULTS On the basis of independent assessment , nab-PC demonstrated a significantly higher ORR than sb-PC ( 33 % v 25 % ; response rate ratio , 1.313 ; 95 % CI , 1.082 to 1.593 ; P = .005 ) and in patients with squamous histology ( 41 % v 24 % ; response rate ratio , 1.680 ; 95 % CI , 1.271 to 2.221 ; P < .001 ) . nab-PC was as effective as sb-PC in patients with nonsquamous histology ( ORR , 26 % v 25 % ; P = .808 ) . There was an approximately 10 % improvement in progression-free survival ( median , 6.3 v 5.8 months ; hazard ratio [ HR ] , 0.902 ; 95 % CI , 0.767 to 1.060 ; P = .214 ) and overall survival ( OS ; median , 12.1 v 11.2 months ; HR , 0.922 ; 95 % CI , 0.797 to 1.066 ; P = .271 ) in the nab-PC arm versus the sb-PC arm , respectively . Patients ≥ 70 years old and those enrolled in North America showed a significantly increased OS with nab-PC versus sb-PC . Significantly less grade ≥ 3 neuropathy , neutropenia , arthralgia , and myalgia occurred in the nab-PC arm , and less thrombocytopenia and anemia occurred in the sb-PC arm . CONCLUSION The administration of nab-PC as first-line therapy in patients with advanced NSCLC was efficacious and result ed in a significantly improved ORR versus sb-PC , achieving the primary end point . nab-PC produced less neuropathy than sb-PC BACKGROUND Available pre clinical and phase 2 clinical data suggest that the addition of cetuximab , a monoclonal antibody directed against the epidermal growth factor receptor ( EGFR ) , to chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer ( NSCLC ) . We aim ed to assess whether the addition of cetuximab to chemotherapy improved progression-free survival in patients with recurrent or progressive NSCLC after platinum-based therapy . METHODS In this unmasked , open-label r and omised phase 3 trial we enrolled patients with metastatic , unresectable , or locally advanced NSCLC from 121 sites in Canada and the USA . Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen . Initially , patients were r and omly assigned to receive either pemetrexed ( 500 mg/m(2 ) ) or docetaxel ( 75 mg/m(2 ) ) and then r and omly assigned within each group to receive their chemotherapy with or without cetuximab ( 400 mg/m(2 ) at first dose and 250 mg/m(2 ) weekly thereafter ) until disease progression or unacceptable toxicity . However , after a change in the st and ard of care , investigators chose whether to treat with pemetrexed or docetaxel on a patient-by-patient basis . The primary analysis was changed to compare progression-free survival with cetuximab plus pemetrexed versus pemetrexed , on an intention-to-treat basis . This study is registered with Clinical Trials.gov , number NCT00095199 . FINDINGS Between Jan 10 , 2005 , and Feb 10 , 2010 , we enrolled 939 patients ; data for one patient was accidentally discarded . Of the remaining 938 patients , 605 received pemetrexed ( 301 patients with cetuximab and 304 alone ) and 333 received docetaxel ( 167 in combination with cetuximab and 166 alone ) . Median progression-free survival  with cetuximab plus pemetrexed was 2·9 months ( 95 % CI 2·7 - 3·2 ) versus 2·8 months ( 2·5 - 3·3 ) with pemetrexed ( HR 1·03 , 95 % CI 0·87 - 1·21 ; p=0·76 ) . The most common grade 3 - 4 adverse events  with cetuximab plus pemetrexed  were fatigue ( 33 [ 11 % ] of 292 patients ) , acneiform rash ( 31 [ 11 % ] ) , dyspnoea ( 29 [ 10 % ] ) , and decreased neutrophil count ( 28 [ 10 % ] ) , and with pemetrexed alone were dyspnoea ( 35 [ 12 % ] of 289 patients ) , decreased neutrophil count ( 26 [ 9 % ] ) , and fatigue ( 23 [ 8 % ] ) . A significantly higher proportion of patients in the cetuximab plus pemetrexed group ( 119 [ 41 % ] of 292 patients ) experienced at least one serious adverse event than those patients in the pemetrexed group ( 85 [ 29 % ] of 289 patients ; p=0·0054 ) . Nine ( 3 % ) of 292 treated patients in the cetuximab and pemetrexed group died of adverse events compared with five ( 2 % ) of 289 treated patients in the pemetrexed alone group . INTERPRETATION The use of cetuximab is not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy . FUNDING Eli Lilly and Company and ImClone Systems LLC , a wholly owned subsidiary of Eli Lilly and Company BACKGROUND EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib , an oral tyrosine kinase inhibitor ( TKI ) , administered in patients with advanced non-small cell lung cancer ( NSCLC ) , not progressing following st and ard 1st-line chemotherapy . METHODS Patients with advanced NSCLC , not-progressing after four cycles of platinum-based chemotherapy  , were r and omised to receive either gefitinib 250mg/d or matched placebo until progression or unacceptable toxicity . The primary end-point was overall survival ( OS ) . Secondary end-points were progression-free survival ( PFS ) and toxicity . The study was powered to detect a 28 % increase in OS from a median of 11 - 14.1months ( HR=0.78 ) and planned to r and omise 598 patients to observe 514 deaths . RESULTS After inclusion of 173 patients , the trial was prematurely closed due to low accrual . Baseline characteristics for gefitinib ( n=86 ) and placebo ( n=87 ) arms were well balanced . After a median follow up of 41months , the difference in median OS in the gefitinib and placebo arms was not statistically significant ( 10.9 and 9.4months , HR 0.83 [ 95 % confidence interval ( 95 % CI ) 0.60 - 1.15 ] ; p=0.2 ) . The difference in median PFS significantly favoured gefitinib ( 4.1 and 2.9months , HR=0.61 , [ 95 % CI 0.45 , 0.83 ] ) , p=0.0015 ) . Adverse events reported in more than 10 % of patients were rash ( 47 % with gefitinib versus 13 % with placebo ) and diarrhoea ( 34 % with gefitinib versus13 % with placebo ) . CONCLUSIONS Despite its premature closure , this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS . However , no difference in OS was observed in this study ( NCT00091156 ) BACKGROUND The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer ( NSCLC ) . METHODS Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy , stratified by ECOG performance status , previous bevacizumab treatment , histology , and presence of brain metastases , were allocated ( by computer-generated sequence through an interactive third-party system , in 1:1 ratio ) , to receive docetaxel 75 mg/m(2 ) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2 - 21 , every 3 weeks until unacceptable adverse events or disease progression . Investigators and patients were masked to assignment . The primary endpoint was progression-free survival ( PFS ) by independent central review , analysed by intention to treat after 714 events in all patients . The key secondary endpoint was overall survival , analysed by intention to treat after 1121 events had occurred , in a prespecified stepwise order : first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy , then in all patients with adenocarcinoma , then in all patients . This trial is registered with Clinical Trials.gov , number NCT00805194 . FINDINGS Between Dec 23 , 2008 , and Feb 9 , 2011 , 655 patients were r and omly assigned to  receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo . The primary analysis was done after a median follow-up of 7·1 months ( IQR 3·8 - 11·0 ) . PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group ( median 3·4 months [ 95 % CI 2·9 - 3·9 ] vs 2·7 months [ 2·6 - 2·8 ] ; hazard ratio [ HR ] 0·79 [ 95 % CI 0·68 - 0·92 ] , p=0·0019 ) . After a median follow-up of 31·7 months ( IQR 27·8 - 36·1 ) , overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group ( 206 patients ) compared with those in the docetaxel plus placebo group ( 199 patients ; median 10·9 months [ 95 % CI 8·5 - 12·6 ] vs 7·9 months [ 6·7 - 9·1 ] ; HR 0·75 [ 95 % CI 0·60 - 0·92 ] , p=0·0073 ) . Similar results were noted for all patients with adenocarcinoma histology ( 322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group ; median overall survival 12·6 months [ 95 % CI 10·6 - 15·1 ] vs 10·3 months [ 95 % CI 8·6 - 12·2 ] ; HR 0·83 [ 95 % CI 0·70 - 0·99 ] , p=0·0359 ) , but not in the total study population ( median 10·1 months [ 95 % CI 8·8 - 11·2 ] vs 9·1 months [ 8·4 - 10·4 ] ; HR 0·94 , 95 % CI 0·83 - 1·05 , p=0·2720 ) . Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea ( 43 [ 6·6 % ] of 652 vs 17 [ 2·6 % ] of 655 ) , reversible increases in alanine aminotransferase ( 51 [ 7·8 % ] vs six [ 0·9 % ] ) , and reversible increases in aspartate aminotransferase ( 22 [ 3·4 % ] vs three [ 0·5 % ] ) . 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression ; the most common of these events were sepsis ( five with docetaxel plus nintedanib vs one with docetaxel plus  placebo ) , pneumonia ( two vs seven ) , respiratory failure ( four vs none ) , and pulmonary embolism ( none vs three ) . INTERPRETATION Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy , especially for patients with adenocarcinoma . FUNDING Boehringer Ingelheim OBJECTIVES To determine whether an in-home palliative care intervention for terminally ill patients can improve patient satisfaction , reduce medical care costs , and increase the proportion of patients dying at home .  DESIGN A r and omized , controlled trial . SETTING Two health maintenance organizations in two states . PARTICIPANTS Homebound , terminally ill patients ( N=298 ) with a prognosis of approximately 1 year or less to live plus one or more hospital or emergency department visits in the previous 12 months . INTERVENTION Usual versus in-home palliative care plus usual care delivered by an interdisciplinary team providing pain and symptom relief , patient and family education and training , and an array of medical and social support services . MEASUREMENTS Measured outcomes were satisfaction with care , use of medical services , site of death , and costs of care . RESULTS Patients r and omized to in-home palliative care  reported greater improvement in satisfaction with care at 30 and 90 days after enrollment ( P<.05 ) and were more likely to die at home than those receiving usual care ( P<.001 ) . In addition , in-home palliative care subjects were less likely to visit the emergency department ( P=.01 ) or be admitted to the hospital than those receiving usual care ( P<.001 ) , result ing in significantly lower costs of care for intervention patients ( P=.03 ) . CONCLUSION In-home palliative care significantly increased patient satisfaction while reducing use of medical services and costs of medical care at the end of life . This study , although modest in scope , presents strong evidence for reforming end-of-life care Non-small cell lung cancer ( NSCLC ) is associated with IL-2-dependent cell-mediated immunodeficiency . As IL-2 is the main lymphocyte growth factor , a phase III r and omized multicenter trial was conducted to evaluate the impact of subcutaneous low-dose IL-2 added to st and ard chemotherapy ( CT ) on overall survival ( OS ) in advanced NSCLC patients . Patients ( n=241 ) with histologically confirmed stage IIIb or IV non-operable NSCLC underwent stratified r and omization on the basis of center , ECOG PS , stage of disease and percentage of weight loss . Patients received gemcitabine ( 1000 mg/m2 ) on days 1 and 8 + cisplatin ( 100 mg/m2 ) on day 2 every 21 days for a maximum of 6 cycles [ chemotherapy ( CT ) arm ] . In the CT+IL-2 arm , patients also received low-dose subcutaneous IL-2 3,000,000 IU/die on days 3 - 5 , 9 - 11 , 15 - 17 . The study had 90 % power to detect a 20 % absolute increase in 1-year OS with 118 patients /arm . An overall response ( OR ) rate of 12.8 % ( 14 % in the CT+IL-2 arm and 11.4 % in CT arm ) was observed . Stable disease was 70 and 66.7 % , and progressive disease 16 and 21.8 % in the CT+IL-2 and CT arms , respectively . No differences in response were found in any subgroup analysis . At a median follow-up of 32 months , 1-year OS was 45 % for the CT+IL-2 arm vs. 51 % for the CT arm ( p=0.456 log-rank ) . Median progression-free survival was 6.6 months in the CT+IL-2 arm vs. 6.9 months in the CT arm ( p=0.573 , log-rank ) . A higher number of grade 4 toxicities were reported with CT+IL-2 . The most common grade ≥3 adverse events were gastrointestinal toxicity ( mainly nausea and diarrhea ) and myelosuppression . No relevant differences in clinical outcome were observed from the addition of IL-2 to CT . Future studies investigating the role of T-regulators in chemoimmunotherapeutic regimens could be performed PURPOSE Patient-reported symptoms and health-related quality of life ( QoL ) benefits were investigated in a r and omized , phase III trial of afatinib or cisplatin/pemetrexed . PATIENTS AND METHODS Three hundred forty-five patients with advanced epidermal growth factor receptor ( EGFR ) mutation-positive lung adenocarcinoma were r and omly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed .  Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 and Lung Cancer-13 question naires . Analyses of cough , dyspnea , and pain were preplanned , including percentage of patients who improved on therapy , time to deterioration of symptoms , and change in symptoms over time . RESULTS Question naire compliance was high . Compared with chemotherapy , afatinib significantly delayed the time to deterioration for cough ( hazard ratio [ HR ] , 0.60 ; 95 % CI , 0.41 to 0.87 ; P = .007 ) and dyspnea ( HR , 0.68 ; 95 % CI , 0.50 to 0.93 ; P = .015 ) , but not pain ( HR , 0.83 ; 95 % CI , 0.62 to 1.10 ; P = .19 ) . More patients on afatinib ( 64 % ) versus chemotherapy ( 50 % ) experienced improvements in dyspnea scores ( P = .010 ) . Differences in mean scores over time significantly favored afatinib over chemotherapy for cough ( P < .001 ) and dyspnea ( P < .001 ) . Afatinib showed significantly better mean scores over time in global health status/QoL ( P = .015 ) and physical ( P < .001 ) , role ( P = .004 ) , and cognitive ( P = .007 ) functioning compared with chemotherapy . Fatigue and nausea were worse with chemotherapy , whereas diarrhea , dysphagia , and sore mouth were worse with afatinib ( all P < .01 ) . CONCLUSION In patients with lung adenocarcinoma with EGFR mutations , first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy , although diarrhea , dysphagia , and sore mouth were worse . Global health status/QoL was also improved over time with afatinib compared with chemotherapy Introduction : Chemotherapy prolongs survival without substantially impairing quality of life for medically fit patients with advanced non-small cell lung cancer ( NSCLC ) , but population -based studies have shown that only 20 to 30 % of these patients receive chemotherapy . These earlier studies have relied on Medicare-linked Surveillance , Epidemiology , and End Results ( SEER ) data , thus excluding the 30 to 35 % of lung cancer patients younger than 65 years . Therefore , we determined the use of chemotherapy in a contemporary , diverse NSCLC population encompassing all patient ages . Methods : We performed a retrospective analysis of patients diagnosed with stage IV NSCLC from 2000 to 2007 at the University of Texas Southwestern Medical Center . Demographic , treatment , and outcome data were obtained from hospital tumor registries . The association between these variables was assessed using univariate analysis and multivariate logistic regression . Results : In all , 718 patients met criteria for analysis . Mean age was 60 years , 58 % were men , and 45 % were white . Three hundred fifty-three patients ( 49 % ) received chemotherapy . In univariate analysis , receipt of chemotherapy  was associated with age ( 53 % of patients younger than 65 years versus 41 % of patients aged 65 years and older ; p = 0.003 ) and insurance type ( p < 0.001 ) . In a multivariate model , age and insurance type remained associated with receipt of chemotherapy . For individuals receiving chemotherapy , median survival was 9.2 months , compared with 2.3 months for untreated patients ( p < 0.001 ) . Conclusions : In a contemporary population representing the full age range of patients with advanced NSCLC , chemotherapy was administered to approximately half of all patients —more than twice the rate reported in some earlier studies . Patient age and insurance type are associated with receipt of chemotherapy PURPOSE This study evaluated the efficacy and safety of pemetrexed , carboplatin , and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naive stage IIIB ( effusion ) or stage IV nonsquamous non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients received pemetrexed 500 mg/m(2 ) , carboplatin area under the concentration-time curve of 6 , and bevacizumab 15 mg/kg every 3 weeks for six cycles . For patients with response or stable disease , pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity . RESULTS Fifty patients were enrolled and received treatment . The median follow-up was 13.0 months , and the median number of treatment cycles was seven ( range , one to 51 ) . Thirty patients ( 60 % ) completed > or = six treatment cycles , and nine ( 18 % ) completed > or = 18 treatment cycles . Among the 49 patients assessable for response , the objective response rate was 55 % ( 95 % CI , 41 % to 69 % ) . Median progression-free and overall survival rates were 7.8 months ( 95 % CI , 5.2 to 11.5 months ) and 14.1 months ( 95 % CI , 10.8 to 19.6 months ) , respectively . Grade 3/4 hematologic toxicity was modest-anemia ( 6 % ; 0 ) , neutropenia ( 4 % ; 0 ) , and thrombocytopenia ( 0 ; 8 % ) . Grade 3/4 nonhematologic toxicities were proteinuria ( 2 % ; 0 ) , venous thrombosis ( 4 % ; 2 % ) , arterial thrombosis ( 2 % ; 0 ) , fatigue ( 8 % ; 0 ) , infection ( 8 % ; 2 % ) , nephrotoxicity ( 2 % ; 0 ) , and diverticulitis ( 6 % ; 2 % ) . There were no grade 3 or greater hemorrhagic events or hypertension cases . CONCLUSION This regimen , involving a maintenance component , was associated with acceptable toxicity and relatively long survival in patients with advanced nonsquamous NSCLC . These results justify a phase III comparison against the st and ard-of-care in this patient population Introduction : The TORCH ( Tarceva or Chemotherapy ) trial r and omized patients with advanced non – small-cell lung cancer to first-line erlotinib followed by second-line cisplatin/gemcitabine versus . st and ard inverse sequence . The trial , design ed to test noninferiority in overall survival , was stopped at interim analysis because of inferior survival in the experimental arm . Quality of life ( QoL ) , a secondary outcome , is reported here . Methods : QoL was assessed at baseline and every 3 weeks during first-line , using European Organization for Research and Treatment of Cancer Quality of Life Question naire - Core 30 and QLQ – lung cancer specific module ( LC13 ) . Mean changes from baseline within arms were reported . QoL response and time-to-deterioration of QoL using a competing-risk approach were compared between treatment arms . Results : Six hundred and thirty patients ( 83 % ) completed baseline question naires . Compliance was affected by differential treatment efficacy , but was similar between arms for patients without progression or death . Significant differences in QoL responses were observed favoring chemotherapy for pain , sleeping , dyspnea , diarrhea , and favoring erlotinib for vomiting , constipation , sore mouth , and alopecia . In the small subset of patients with EGFR-mutated tumors , all selected items ( global QoL , physical functioning , cough , dyspnea and pain ) improved , whereas worsening or no change was observed in wild-type patients . Improvement was particularly evident in the first-line erlotinib arm as for global QoL and physical functioning . Conclusions : QoL was impacted by differential toxicity and efficacy between arms . Functional domains and global QoL did not differ , although some symptoms were better controlled with chemotherapy in unselected non – small-cell lung cancer patients PURPOSE The results of the Iressa Pan-Asia Study ( IPASS ) , which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously . This report presents overall survival ( OS ) and efficacy according to epidermal growth factor receptor ( EGFR ) biomarker status . PATIENTS AND METHODS In all , 1,217 patients were r and omly assigned . Biomarkers analyzed were EGFR mutation ( amplification mutation refractory system ; 437 patients evaluable ) , EGFR gene copy number ( fluorescent in situ hybridization ; 406 patients evaluable ) , and EGFR protein expression ( immunohistochemistry ; 365 patients evaluable ) . OS analysis was performed at 78 % maturity . A Cox proportional hazards model was used to assess biomarker status by r and omly assigned treatment interactions for progression-free survival ( PFS ) and OS . RESULTS OS ( 954 deaths ) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall ( hazard ratio [ HR ] , 0.90 ; 95 % CI , 0.79 to 1.02 ; P = .109 ) or in EGFR  mutation-positive  ( HR , 1.00 ; 95 % CI , 0.76 to 1.33 ; P = .990 ) or EGFR mutation-negative  ( HR , 1.18 ; 95 % CI , 0.86 to 1.63 ; P = .309 ; treatment by EGFR mutation interaction P = .480 ) subgroups . A high proportion ( 64.3 % ) of EGFR mutation-positive patients r and omly assigned to carboplatin/paclitaxel received subsequent  EGFR tyrosine kinase inhibitors . PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation ( HR , 0.48 ; 95 % CI , 0.34 to 0.67 ) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation ( HR , 3.85 ; 95 % CI , 2.09 to 7.09 ) . CONCLUSION EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel . The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation ( post hoc analysis ) . Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS . OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment Palliative care is a fundamental component of cancer care . As part of the 2011 to 2012 Leadership Development Program ( LDP ) of the American Society of Clinical Oncology ( ASCO ) , a group of participants was charged with advising ASCO on how to develop a service model integrating palliative care throughout the continuum of cancer care . This article presents the findings of the LDP group . The group focused on the process of palliative care delivery in the oncology setting . We identified key elements for models of palliative care in various setting s to be potentially equitable , sustainable , feasible , and acceptable , and here we describe a dynamic model for the integrated , simultaneous implementation of palliative care into oncology practice . We also discuss critical considerations to better integrate palliative care into oncology , including raising consciousness and educating both providers and the public about the importance of palliative care ; coordinating palliative care efforts through strengthening affiliations and /or developing new partnerships ; prospect ively evaluating the impact of palliative care on patient and provider satisfaction , quality improvement , and cost savings ; and ensuring sustainability through adequate reimbursement and incentives , including linkage of performance data to quality indicators , and coordination with training efforts and maintenance of certification requirements for providers . In light of these findings , we believe the confluence of increasing importance of incorporation of palliative care education in oncology education , emphasis on value-based care , growing use of technology , and potential cost savings makes developing and incorporating palliative care into current service models a meaningful goal PURPOSE To compare vinflunine ( VFL ) to docetaxel in patients with stage IIIB/IV non-small-cell lung cancer ( NSCLC ) who have experienced treatment failure with first-line platinum-based chemotherapy . PATIENTS AND METHODS R and omized , multicenter , phase III study , 551 patients received either vinflunine 320 mg/m(2 ) or docetaxel 75 mg/m(2 ) every 21 days until disease progression or serious toxicity . The primary end point was progression-free survival ( PFS ) . The noninferiority analysis was based on a 10 % difference ( types I/II error rates : 5%/20 % ) . Secondary end points included response rate ( ORR ) , response duration , overall survival ( OS ) , clinical benefit , quality of life ( QOL ) , and safety . RESULTS Median PFS was 2.3 months for each arm ( HR , 1.004 ; 95 % CI , 0.841 to 1.199 ) . ORR , stable disease , median OS , were 4.4 % versus 5.5 % , 36.0 % versus 39.6 % , 6.7 versus 7.2 months ( HR , 0.973 ; 95 % CI , 0.805 to 1.176 ) , respectively . No significant difference in patient benefit and QOL ( Functional Assessment of Cancer Therapy-Lung ) . No unexpected adverse events were observed . Grade higher than 0 ( vinflunine v docetaxel ) anemia ( 82.1 % v 79.8 % ) , neutropenia ( 49.3 v 39.02 % ) , thrombocytopenia ( 30.6 % v 14.3 % ) , febrile neutropenia ( 3.3 % v 4.7 % ) , constipation ( 39.2 % v 11.7 % ) , fatigue ( 36.6 % v 33.9 % ) , injection site reaction ( 31.9 % v 0.7 % ) , nausea ( 26.7 % v 23.7 % ) , vomiting ( 23.8 % v 14.2 % ) , alopecia ( 19.8 % v 35.4 % ) , stomatis ( 19.4 % v 12.4 % ) , abdominal pain ( 20.1 % v 3.6 % ) , myalgia ( 14.7 % v 6.6 % ) , peripheral neuropathy ( 10.7 % v 15.0 % ) , arthralgia ( 7.0 % v 7.7 % ) , diarrhea ( 6.2 % v 12.4 % ) , edema ( 1.5 % v 5.4 % ) , and nail disorders ( 1.1 % v 5;1 % ) were observed . CONCLUSION This noninferiority phase III study showed similar efficacy end points for vinflunine and docetaxel . Despite higher rates of some adverse effects ( anemia , abdominal pain , constipation , fatigue ) the overall toxicity profile of vinflunine was manageable . Therefore , VFL may be another option in the second-line treatment of patients with advanced NSCLC Introduction : Evaluation of health-related quality -of-life ( HRQoL ) and symptom improvement were preplanned secondary objectives for the overall population and posthoc analyses for epidermal growth factor receptor ( EGFR ) mutation-positive/negative subgroups in IPASS . Methods : HRQoL was assessed using the Functional Assessment of Cancer Therapy-Lung ( FACT-L ) and Trial Outcome Index ( TOI ) ; symptom improvement by the Lung Cancer Subscale ( LCS ) . Improvements defined as : 6 or more ( FACT-L ; TOI ) , 2 or more ( LCS ) points increase maintained for 21 or more days . Results : Overall ( n = 1151/1217 evaluable ) , HRQoL improvement rates were significantly greater with gefitinib versus carboplatin/paclitaxel ;  symptom improvement rates were similar for both treatments . Significantly more patients recorded improvements in HRQoL and symptoms with gefitinib in the EGFR mutation-positive subgroup ( n = 259 ; FACT-L 70.2 % versus 44.5 % ; odds ratio , 3.01 [ 95 % confidence interval , 1.79–5.07 ] ; p < 0.001 ; TOI 70.2 % versus 38.3 % ; 3.96 [ 2.33–6.71 ] ; p < 0.001 ; LCS 75.6 % versus 53.9 % ; 2.70 [ 1.58–4.62 ] ; p < 0.001 ) , and with carboplatin/paclitaxel in the EGFR mutation-negative subgroup ( n = 169 ; FACT-L 14.6 % versus 36.3 % ; odds ratio , 0.31 [ 0.15–0.65 ] ; p = 0.002 ; TOI 12.4 % versus 28.8 % ; 0.35 [ 0.16–0.79 ] ; p = 0.011 ; LCS 20.2 % versus 47.5 % ; 0.28 [ 0.14–0.55 ] ; p < 0.001 ) . Median time-to-worsening ( months ) FACT-L score was longer with gefitinib versus carboplatin/paclitaxel for the overall population ( 8.3 versus 2.5 ) and EGFR mutation-positive subgroup ( 15.6 versus 3.0 ) , and similar for both treatments in the EGFR mutation-negative subgroup ( 1.4 versus 1.4 ) . Median time-to-improvement with gefitinib was 8 days in patients with EGFR mutation-positive tumors who improved . Conclusions : HRQoL and symptom endpoints were consistent with efficacy outcomes in IPASS and favored gefitinib in patients with EGFR mutation-positive tumors and carboplatin/paclitaxel in patients with EGFR mutation-negative tumors PURPOSE V and etanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling . This r and omized , placebo-controlled phase III study assessed the efficacy of v and etanib plus pemetrexed as second-line therapy in advanced non-small-cell lung cancer . PATIENTS AND METHODS Patients ( N = 534 ) were r and omly assigned to receive v and etanib 100 mg/d plus pemetrexed 500 mg/m(2 ) every 21 days ( n = 256 ) or placebo plus pemetrexed ( n = 278 ) . Progression-free survival ( PFS ) was the primary end point ; overall survival , objective response rate , disease control rate , time to deterioration of symptoms , and safety were secondary assessment s. RESULTS There was no significant difference in PFS between treatment arms ( hazard ratio [ HR ] , 0.86 ; 97.58 % CI , 0.69 to 1.06 ; P = .108 ) . Overall survival was also not significantly different ( HR , 0.86 ; 97.54 % CI , 0.65 to 1.13 ; P = .219 ) . Statistically significant improvements in objective response rate ( 19 % v 8 % ; P < .001 ) and time to deterioration of symptoms ( HR , 0.71 ; P = .0052 ; median , 18.1 weeks for v and etanib and 12.1 weeks for placebo ) were observed in patients receiving v and etanib . Adding v and etanib to pemetrexed increased the incidence of some adverse events , including rash , diarrhea , and hypertension , while showing a reduced incidence of nausea , vomiting , anemia , fatigue , and asthenia with no reduction in the dose intensity of pemetrexed . CONCLUSION This study did not meet the primary end point of statistically significant PFS prolongation with v and etanib plus pemetrexed versus placebo plus pemetrexed . The v and etanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population BACKGROUND Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor ( EGFR‐TKI ) that is selective for both EGFR‐TKI sensitizing and T790 M resistance mutations in patients with non – small‐cell lung cancer . The efficacy of osimertinib as compared with platinum‐based therapy plus pemetrexed in such patients is unknown . METHODS In this r and omized , international , open‐label , phase 3 trial , we assigned 419 patients with T790M‐positive advanced non – small‐cell lung cancer , who had disease progression after first‐line EGFR‐TKI therapy , in a 2:1 ratio to receive either oral osimertinib ( at a dose of 80 mg once daily ) or intravenous pemetrexed ( 500 mg per square meter of body‐surface area ) plus either carboplatin ( target area under the curve , 5 [ AUC5 ] ) or cisplatin ( 75 mg per square meter ) every 3 weeks for up to six cycles ; maintenance pemetrexed was allowed . In all the patients , disease had progressed during receipt of first‐line EGFR‐TKI therapy . The primary end point was investigator‐assessed progression‐free survival . RESULTS The median duration of progression‐free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed ( 10.1 months vs. 4.4 months ; hazard ratio ; 0.30 ; 95 % confidence interval [ CI ] , 0.23 to 0.41 ; P<0.001 ) . The objective response rate was significantly better with osimertinib ( 71 % ; 95 % CI , 65 to 76 ) than with platinum therapy plus pemetrexed ( 31 % ; 95 % CI , 24 to 40 ) ( odds ratio for objective response , 5.39 ; 95 % CI , 3.47 to 8.48 ; P<0.001 ) . Among 144 patients with metastases to the central nervous system ( CNS )  , the median duration of progression‐free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed ( 8.5 months vs. 4.2 months ; hazard ratio , 0.32 ; 95 % CI , 0.21 to 0.49 ) . The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib ( 23 % ) than with platinum therapy plus pemetrexed ( 47 % ) . CONCLUSIONS Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M‐positive advanced non – small‐cell lung cancer ( including those with CNS metastases ) in whom disease had progressed during first‐line EGFR‐TKI therapy . ( Funded by AstraZeneca ; AURA3 Clinical Trials.gov number , NCT02151981 . In this superiority study , pemetrexed was compared with erlotinib in pre‐treated patients with metastatic non – small cell lung cancer ( NSCLC ) BACKGROUND Erlotinib is registered for treatment of all patients with advanced non-small-cell lung cancer ( NSCLC ) . However , its efficacy for treatment of patients whose tumours are EGFR wild-type-which includes most patients -is still contentious . We assessed the efficacy of erlotinib compared with a st and ard second-line chemotherapy in such patients . METHODS We did this r and omised controlled trial in 52 Italian hospitals . We enrolled patients who had metastatic NSCLC , had had platinum-based chemotherapy , and had wild-type EGFR as assessed by direct sequencing . Patients were r and omly assigned central ly ( 1:1 ) to receive either erlotinib orally 150 mg/day or docetaxel intravenously 75 mg/m(2 ) every 21 days or 35 mg/m(2 ) on days 1 , 8 , and 15 , every 28 days . R and omisation was stratified by centre , stage , type of first-line chemotherapy , and performance status . Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation , investigators who analysed results were . The primary endpoint was overall survival in the intention-to-treat population . The study is registered at Clinical Trials.gov , number NCT00637910 . FINDINGS We screened 702 patients , of whom we genotyped 540 . 222 patients were enrolled ( 110 assigned to docetaxel vs 112 assigned to erlotinib )  . Median overall survival was 8·2 months ( 95 % CI 5·8 - 10·9 ) with docetaxel versus 5·4 months ( 4·5 - 6·8 ) with erlotinib ( adjusted hazard ratio [ HR ] 0·73 , 95 % CI 0·53 - 1·00 ; p=0·05 ) . Progression-free survival was significantly better with docetaxel than with erlotinib : median progression-free survival was 2·9 months ( 95 % CI 2·4 - 3·8 ) with docetaxel versus 2·4 months ( 2·1 - 2·6 ) with erlotinib ( adjusted HR 0·71 , 95 % CI 0·53 - 0·95 ; p=0·02 ) . The most common grade 3 - 4 toxic effects were : low absolute neutrophil count ( 21 [ 20 % ] of 104 in the docetaxel group vs none of 107 in the erlotinib group ) , skin toxic effects ( none vs 15 [ 14 % ] ) , and asthenia ( ten [ 10 % ] vs six [ 6 % ] ) . INTERPRETATION Our results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours BACKGROUND Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes . We assessed the activity of nivolumab , a fully human IgG4 PD-1 immune checkpoint inhibitor antibody , for patients with advanced , refractory , squamous non-small-cell lung cancer . METHODS We did this phase 2 , single-arm trial at 27 sites ( academic , hospital , and private cancer centres ) in France , Germany , Italy , and USA . Patients who had received two or more previous treatments received intravenous nivolumab ( 3 mg/kg ) every 2 weeks until progression or unacceptable toxic effects . The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee . We included all treated patients in the analyses . This study is registered with Clinical Trials.gov , number NCT01721759 . FINDINGS Between Nov 16 , 2012 , and July 22 , 2013 , we enrolled and treated 117 patients . 17 ( 14·5 % , 95 % CI 8·7 - 22·2 ) of 117 patients had an objective response as assessed by an independent radiology review committee . Median time to response was 3·3 months ( IQR 2·2 - 4·8 ) , and median duration of response was not reached ( 95 % CI 8·31-not applicable ) ; 13 ( 77 % ) of 17 of responses were ongoing at the time of analysis . 30 ( 26 % ) of 117 patients had stable disease ( median duration 6·0 months , 95 % CI 4·7 - 10·9 ) . 20 ( 17 % ) of 117 patients reported grade 3 - 4 treatment-related adverse events , including : fatigue ( five [ 4 % ] of 117 patients ) , pneumonitis ( four [ 3 % ] ) , and diarrhoea ( three [ 3 % ] ) . There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease . INTERPRETATION Nivolumab has clinical ly meaningful activity and a manageable safety profile in previously treated patients with advanced , refractory , squamous non-small cell lung cancer . These data support the assessment of nivolumab in r and omised , controlled , phase 3 studies of first-line and second-line treatment . FUNDING Bristol-Myers Squibb BACKGROUND Palliative care improves care and reduces costs for hospitalized patients with life-limiting illnesses . There have been no multicenter r and omized trials examining impact on patient satisfaction , clinical outcomes , and subsequent health care costs . OBJECTIVE Measure the impact of an interdisciplinary palliative care service ( IPCS ) on patient satisfaction , clinical outcomes , and cost of care for 6 months posthospital discharge . METHODS Multicenter , r and omized , controlled trial . IPCS provided consultative , interdisciplinary , palliative care to intervention patients . Controls received usual hospital care ( UC ) . SETTING AND SAMPLE Five hundred seventeen patients with life-limiting illnesses from a hospital in Denver , Portl and , and San Francisco enrolled June 2002 to December 2003 . MEASURES Modified City of Hope Patient Question naire , total health care costs , hospice utilization , and survival . RESULTS IPCS reported higher scores for the Care Experience scale ( IPCS : 6.9 versus UC : 6.6 , p = 0.04 ) and for the Doctors , Nurses/Other Care Providers Communication scale ( IPCS : 8.3 versus UC : 7.5 , p = 0.0004 ) . IPCS patients had fewer intensive care admissions ( ICU ) on hospital readmission ( 12 versus 21 , p = 0.04 ) , and lower 6-month net cost savings of $ 4,855 per patient ( p = 0.001 ) . IPCS had longer median hospice stays ( 24 days versus 12 days , p = 0.04 ) . There were no differences in survival or symptom control . CONCLUSIONS IPCS patients reported greater satisfaction with their care experience and providers ' communication , had fewer ICU admissions on readmission , and lower total health care costs following hospital discharge BACKGROUND This report describes quality of life ( QoL ) findings of a r and omized study comparing gefitinib with docetaxel in patients with advanced/metastatic pretreated non-small-cell lung cancer . PATIENTS AND METHODS This open-label , phase III study r and omized 490 Japanese patients to gefitinib ( 250 mg/day ) or docetaxel ( 60 mg/m(2)/3 weeks ) , with survival as the primary outcome . Preplanned QoL analyses included Functional Assessment of Cancer Therapy-Lung ( FACT-L ) , Trial Outcome Index ( TOI ) and Lung Cancer Subscale ( LCS ) improvement rates , and mean change from baseline . RESULTS Gefitinib showed statistically significant benefits over docetaxel in QoL improvement rates ( FACT-L 23 % versus 14 % , P = 0.023 ; TOI 21 % versus 9 % , P = 0.002 ) and mean change from baseline score [ mean treatment difference : FACT-L 3.72 points , 95 % confidence interval ( CI ) 0.55 - 6.89 , P = 0.022 ; TOI 4.31 points , 95 % CI 2.13 - 6.49 , P < 0.001 ] , although differences did not meet the clinical ly relevant six-point change . There were no significant differences between treatments in LCS improvement rates ( 23 % versus 20 % , P = 0.562 ) or mean change from baseline score ( 0.63 points , 95 % CI -0.07 to 1.34 , P = 0.077 ) . CONCLUSIONS Gefitinib improved aspects of QoL over docetaxel , with superior objective response rate and a more favorable tolerability profile and no statistically significant difference in overall survival ( although noninferiority was not statistically proven ) PURPOSE Ipilimumab , which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal antibody , showed a survival benefit in melanoma with adverse events ( AEs ) managed by protocol -defined guidelines . A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin . PATIENTS AND METHODS Patients ( N = 204 ) with chemotherapy-naive non-small-cell lung cancer ( NSCLC ) were r and omly assigned 1:1:1 to receive paclitaxel ( 175 mg/m(2 ) ) and carboplatin ( area under the curve , 6 ) with either placebo ( control ) or ipilimumab in one of the following two regimens : concurrent ipilimumab ( four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin ) or phased ipilimumab ( two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≤ 18 weeks ( induction ) . Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy . Response was assessed by using immune-related response criteria and modified WHO criteria . The primary end point was immune-related progression-free survival ( irPFS ) . Other end points were progression-free survival ( PFS ) , best overall response rate ( BORR ) , immune-related BORR ( irBORR ) , overall survival ( OS ) , and safety . RESULTS The study met its primary end point of improved irPFS for phased ipilimumab versus the control ( hazard ratio [ HR ] , 0.72 ; P = .05 ) , but not for concurrent ipilimumab ( HR , 0.81 ; P = .13 ) . Phased ipilimumab also improved PFS according to modified WHO criteria ( HR , 0.69 ; P = .02 ) . Phased ipilimumab , concurrent ipilimumab , and control treatments were associated with a median irPFS of 5.7 , 5.5 , and 4.6 months , respectively , a median PFS of 5.1 , 4.1 , and 4.2 months , respectively , an irBORR of 32 % , 21 % and 18 % , respectively , a BORR of 32 % , 21 % and 14 % , respectively , and a median OS of 12.2 , 9.7 , and 8.3 months . Overall rates of grade 3 and 4 immune-related AEs were 15 % , 20 % , and 6 % for phased ipilimumab , concurrent ipilimumab , and the control , respectively . Two patients ( concurrent , one patient ; control , one patient ) died from treatment-related toxicity . CONCLUSION Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS , which supports additional investigation of ipilimumab in NSCLC PURPOSE In the phase III PARAMOUNT trial , pemetrexed continuation maintenance therapy reduced the risk of disease progression versus placebo ( hazard ratio [ HR ] , 0.62 ; 95 % CI , 0.49 to 0.79 ; P < .001 ) . Here we report final overall survival ( OS ) and up date d safety data . PATIENTS AND METHODS In all , 939 patients with advanced nonsquamous non-small-cell lung cancer ( NSCLC ) received four cycles of pemetrexed-cisplatin induction therapy ;  then , 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were r and omly assigned ( 2:1 ) to maintenance pemetrexed ( 500 mg/m(2 ) on day 1 of 21-day cycles ; n = 359 ) or placebo ( n = 180 ) . Log-rank test compared OS between arms as measured from r and om assignment ( α = .0498 ) . RESULTS The mean number of maintenance cycles was 7.9 ( range , one to 44 ) for pemetrexed and 5.0 ( range , one to 38 ) for placebo . After 397 deaths  ( pemetrexed , 71 % ; placebo , 78 % ) and a median follow-up of 24.3 months for alive patients ( 95 % CI , 23.2 to 25.1 months ) , pemetrexed therapy result ed in a statistically significant 22 % reduction in the risk of death ( HR , 0.78 ; 95 % CI , 0.64 to 0.96 ; P = .0195 ; median OS : pemetrexed , 13.9 months ; placebo , 11.0 months ) . Survival on pemetrexed was consistently improved for all patient subgroups , including induction response : complete/partial responders ( n = 234 ) OS HR , 0.81 ; 95 % CI , 0.59 to 1.11 and stable disease ( n = 285 ) OS HR , 0.76 ; 95 % CI , 0.57 to 1.01 ) . Postdiscontinuation therapy use was similar : pemetrexed , 64 % ; placebo , 72 % . No new safety findings emerged . Drug-related grade 3 to 4 anemia , fatigue , and neutropenia were significantly higher in pemetrexed-treated patients . CONCLUSION Pemetrexed continuation maintenance therapy is well-tolerated and offers superior OS compared with placebo , further demonstrating that it is an efficacious treatment strategy for patients with advanced nonsquamous NSCLC and good performance status who did not progress during pemetrexed-cisplatin induction therapy PURPOSE This phase III trial was performed to assess the potential benefit of adding maintenance erlotinib to bevacizumab after a first-line chemotherapy regimen with bevacizumab for advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS One thous and one hundred forty-five patients with histologically or cytologically confirmed NSCLC ( stage IIIB with malignant pleural effusion , stage IV , or recurrent ) received four cycles of chemotherapy plus bevacizumab .  Seven hundred forty-three patients without disease progression or significant toxicity  were then r and omly assigned ( 1:1 ) to bevacizumab ( 15 mg/kg , day 1 , 21-day cycle ) plus either placebo or erlotinib ( 150 mg per day ) . The primary end point was progression-free survival ( PFS ) . RESULTS Median PFS from time of r and om assignment was 3.7 months with bevacizumab/placebo and 4.8 months with bevacizumab/erlotinib ( hazard ratio [ HR ] , 0.71 ; 95 % CI , 0.58 to 0.86 ; P < .001 ) . Median overall survival ( OS ) times from r and om assignment were 13.3 and 14.4 months with bevacizumab/placebo and bevacizumab/erlotinib , respectively ( HR , 0.92 ; 95 % CI , 0.70 to 1.21 ; P = .5341 ) . During the postchemotherapy phase , there were more adverse events ( AEs ) overall , more grade 3 and 4 AEs ( mainly rash and diarrhea ) , more serious AEs , and more AEs leading to erlotinib/placebo discontinuation in the bevacizumab/erlotinib arm versus the bevacizumab/placebo arm . The incidence of AEs leading to bevacizumab discontinuation was similar in both treatment arms . CONCLUSION The addition of erlotinib to bevacizumab significantly improved PFS but not OS . Although generally well tolerated , the modest impact on survival and increased toxicity associated with the addition of erlotinib to bevacizumab maintenance mean that this two-drug maintenance regimen will not lead to a new postchemotherapy st and ard of care
target: In the third-line setting , for patients who have not received erlotinib or gefitinib , treatment with erlotinib is recommended .
  There are insufficient data to recommend routine third-line cytotoxic therapy .
background: Purpose To provide evidence -based recommendations to up date the American Society of Clinical Oncology guideline on systemic therapy for stage IV non – small-cell lung cancer ( NSCLC ) .
  Results This guideline up date reflects changes in evidence since the previous guideline .