title: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study Isolating the Role of Bevacizumab in Elderly Patients With Previously Untreated Nonsquamous Non–Small Cell Lung Cancer Erlotinib in previously treated non-small-cell lung cancer. Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer) Alectinib for Patients with ALK Rearrangement–Positive Non–Small Cell Lung Cancer and a Poor Performance Status (Lung Oncology Group in Kyushu 1401) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study 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 Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. Time trend in treatment-related deaths of patients with advanced non-small-cell lung cancer enrolled into phase III trials of systemic treatment. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. 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. A prospective, multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911. BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent Nonsquamous Non-Small-Cell Lung Cancer. 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. A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. 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). 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. 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. Alectinib versus Crizotinib in Untreated ALK‐Positive Non–Small‐Cell Lung Cancer Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer – a randomized trial with quality of life as the primary outcome PRONOUNCE: Randomized, Open-Label, Phase III Study of First-Line Pemetrexed + Carboplatin Followed by Maintenance Pemetrexed versus Paclitaxel + Carboplatin + Bevacizumab Followed by Maintenance Bevacizumab in Patients ith Advanced Nonsquamous Non–Small-Cell Lung Cancer Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer or Other Tumors 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) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). 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. Phase II trial of erlotinib for Japanese patients with previously treated non-small-cell lung cancer harboring EGFR mutations: results of Lung Oncology Group in Kyushu (LOGiK0803). Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small-cell lung cancer: the intergroup trial JCOG0803/WJOG4307L. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial Gemcitabine versus Gemcitabine–Carboplatin for Patients with Advanced Non-small Cell Lung Cancer and a Performance Status of 2: A Prospective Randomized Phase II Study of the Hellenic Cooperative Oncology Group A prospective, phase II, open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. First-Line Gefitinib in Patients Aged 75 or Older With Advanced Non–Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations: NEJ 003 Study 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. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy. Safety and Efficacy of First-Line Bevacizumab Plus Chemotherapy in Elderly Patients with Advanced or Recurrent Nonsquamous Non-small Cell Lung Cancer: Safety of Avastin in Lung trial (MO19390) Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. 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. Pretreatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of the multicenter Italian lung cancer in the elderly study. Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial. Randomized phase II trial of paclitaxel plus carboplatin or gemcitabine plus cisplatin in Eastern Cooperative Oncology Group performance status 2 non-small-cell lung cancer patients: ECOG 1599. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. Retrospective evaluation of the clinical and radiographic risk factors associated with severe pulmonary hemorrhage in first-line advanced, unresectable non-small-cell lung cancer treated with Carboplatin and Paclitaxel plus bevacizumab. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. Osimertinib in Untreated EGFR‐Mutated Advanced Non–Small‐Cell Lung Cancer Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled 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. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Clinical outcomes in elderly patients with advanced non-small cell lung cancer: results from ARIES, a bevacizumab observational cohort 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.
abstract: BACKGROUND Several studies have shown the efficacy , tolerability , and ease of administration of pemetrexed-an antifolate antineoplastic agent-in  patients with advanced non-small-cell lung cancer . We assessed pemetrexed as maintenance therapy in patients with this disease . METHODS This r and omised double-blind study was undertaken in 83 centres in 20 countries . 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy  were r and omly assigned ( 2:1 ratio ) to receive pemetrexed ( 500 mg/m(2 ) , day 1 ) plus best supportive care ( n=441 ) or placebo plus best supportive care ( n=222 ) in 21-day cycles until disease progression . Treatment was r and omised with the Simon and Pocock minimisation method . Patients and investigators were masked to treatment . All patients received vitamin B(12 ) , folic acid , and dexamethasone . The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat . This study is registered with Clinical Trials.gov , number NCT00102804 . FINDINGS All r and omly assigned participants were analysed . Pemetrexed significantly improved progression-free survival ( 4.3 months [ 95 % CI 4.1 - 4.7 ] vs 2.6 months [ 1.7 - 2.8 ] ; hazard ratio [ HR ] 0.50 , 95 % CI 0.42 - 0.61 , p<0.0001 ) and overall survival ( 13.4 months [ 11.9 - 15.9 ] vs 10.6 months [ 8.7 - 12.0 ] ; HR 0.79 , 0.65 - 0.95 , p=0.012 ) compared with placebo . Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group ( 21 [ 5 % ] vs three [ 1 % ] ) . Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo ( 70 [ 16 % ] vs nine [ 4 % ] ; p<0.0001 ) , specifically fatigue ( 22 [ 5 % ] vs one [ 1 % ] , p=0.001 ) and neutropenia ( 13 [ 3 % ] vs 0 , p=0.006 ) . No  pemetrexed-related deaths occurred . Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy ( 227 [ 51 % ] vs 149 [ 67 % ] ; p=0.0001 ) . INTERPRETATION Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer . FUNDING Eli Lilly Background : Patient-level data from 2 phase III studies in patients with previously untreated , advanced-stage , nonsquamous non – small cell lung cancer ( NSCLC ) were pooled to examine outcomes with bevacizumab and chemotherapy based on age . Methods : Data from patients r and omized to paclitaxel – carboplatin (PC)+bevacizumab in the Eastern Cooperative Oncology Group 4599 ( E4599 ) and PointBreak studies were pooled and compared with E4599 patients r and omized to PC alone . Patients were grouped by age : below 65 , 65 to 74 , 70 to 74 , below 75 , and 75 years or above . A multivariable model was used to calculate hazard ratios ( HRs ) and corresponding 95 % confidence intervals ( CIs ) using time-to-event outcomes . Adverse events ( AEs ) were assessed by age group in each study . Results : The PC+bevacizumab and PC arms comprised 901 and 444 patients , respectively . PC+bevacizumab was associated with significant increases in overall survival relative to PC in patients below 65 years ( hazards ratio [ HR ] , 0.75 ; 95 % confidence interval [ CI ] , 0.62 - 0.89 ) , 65 to 74 years ( HR , 0.80 ; 95 % CI , 0.64 - 1.00 ) , 70 to 74 years ( HR , 0.68 ; 95 % CI , 0.48 - 0.96 ) , and below 75 years ( HR , 0.78 ; 95 % CI , 0.68 - 0.89 ) but not in those aged 75 years or above ( HR , 1.05 ; 95 % CI , 0.70 - 1.57 ) . Increased incidence of grade ≥3 AEs was reported with PC+bevacizumab versus PC in patients below 75 years ( 63 % vs. 48 % ; P<0.05 ) and 75 years or above ( 81 % vs. 56 % ; P < 0.05 ) in E4599 . Conclusions : This analysis suggests that the survival benefits  associated with PC+bevacizumab extend to patient subgroups below 75 years with advanced-stage NSCLC ; no benefit , however , was observed for bevacizumab-eligible patients who were 75 years or above BACKGROUND We conducted a r and omized , placebo-controlled , double-blind trial to determine whether the epidermal growth factor receptor inhibitor erlotinib prolongs survival in non-small-cell lung cancer after the failure of first-line or second-line chemotherapy . METHODS Patients with stage IIIB or IV non-small-cell lung cancer , with performance status from 0 to 3 , were eligible if they had received one or two prior chemotherapy regimens .  The patients were stratified according to center , performance status , response to prior chemotherapy , number of prior regimens , and prior platinum-based therapy and were r and omly assigned in a 2:1 ratio to receive oral erlotinib , at a dose of 150 mg daily , or placebo . RESULTS The median age of the 731 patients who underwent r and omization was 61.4 years ; 49 percent had received two prior chemotherapy regimens , and 93 percent had received platinum-based chemotherapy .  The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group ( P<0.001 ) ; the median duration of the response was 7.9 months and 3.7 months , respectively . Progression-free survival was 2.2 months and 1.8 months , respectively ( hazard ratio , 0.61 , adjusted for stratification categories ; P<0.001 ) . Overall survival was 6.7 months and 4.7 months , respectively ( hazard ratio , 0.70 ; P<0.001 ) , in favor of erlotinib . Five percent of patients discontinued erlotinib because of toxic effects . CONCLUSIONS Erlotinib can prolong survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy This r and omised multicentre trial was conducted to establish the optimal duration of palliative chemotherapy in advanced non-small-cell lung cancer ( NSCLC ) . We compared a policy of three vs six courses of new-generation platinum-based combination chemotherapy with regard to effects on quality of life ( QoL ) and survival .  Patients with stage IIIB or IV NSCLC and WHO performance status ( PS ) 0–2 were r and omised to receive three ( C3 ) or six ( C6 ) courses of carboplatin ( area under the curve ( AUC ) 4 , Chatelut 's formula , equivalent to Calvert 's AUC 5 ) on day 1 and vinorelbine 25 mg m−2 on days 1 and 8 of a 3-week cycle . Key end points were QoL at 18 weeks , measured with EORTC Quality of Life Question naire (QLQ)-C30 and QLQ-LC13 , and overall survival . Secondary end points were progression-free survival and need of palliative radiotherapy . Two hundred and ninety-seven patients were r and omised ( C3 150 , C6 147 ) . Their median age was 65 years , 30 % had PS 2 and 76 % stage IV disease . Seventy-eight and 54 % of C3 and C6 patients , respectively , completed all scheduled chemotherapy courses . Compliance with QoL question naires was 88 % . There were no significant group differences in global QoL , pain or fatigue up to 26 weeks . The dyspnoea palliation rate was lower in the C3 arm at 18 and 26 weeks ( P<0.05 ) , but this finding was inconsistent across different methods of analysis . Median survival in the C3 group was 28 vs 32 weeks in the C6 group ( P=0.75 , HR 1.04 , 95 % CI 0.82–1.31 ) . One- and 2-year survival rates were 25 and 9 % vs 25 and 5 % in the C3 and C6 arm , respectively . Median progression-free survival was 16 and 21 weeks in the C3 and C6 groups , respectively ( P=0.21 , HR 0.86 , 95 % CI 0.68–1.08 ) . In conclusion , palliative chemotherapy with carboplatin and vinorelbine beyond three courses conveys no survival or consistent QoL benefits in advanced NSCLC BACKGROUND The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) . We aim ed to compare the efficacy and safety of afatinib and gefitinib in this setting . METHODS This multicentre , international , open-label , exploratory , r and omised controlled phase 2B trial ( LUX-Lung 7 ) was done at 64 centres in 13 countries . Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation ( exon 19 deletion or Leu858Arg ) were r and omly assigned ( 1:1 ) to receive afatinib ( 40 mg per day ) or gefitinib ( 250 mg per day ) until disease progression , or beyond if deemed beneficial by the investigator . R and omisation , stratified by EGFR mutation type and status of brain metastases , was done central ly using a vali date d number generating system implemented via an interactive voice or web-based response system with a block size of four . Clinicians and patients were not masked to treatment allocation ; independent review of tumour response was done in a blinded manner . Co primary endpoints were progression-free survival by independent central review , time-to-treatment failure , and overall survival . Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug . This ongoing study is registered with Clinical Trials.gov , number NCT01466660 . FINDINGS Between Dec 13 , 2011 , and Aug 8 , 2013 , 319 patients were r and omly assigned ( 160 to afatinib and 159 to gefitinib ) . Median follow-up was 27·3 months ( IQR 15·3 - 33·9 ) . Progression-free survival ( median 11·0 months [ 95 % CI 10·6 - 12·9 ] with afatinib vs 10·9 months [ 9·1 - 11·5 ] with gefitinib ; hazard ratio [ HR ] 0·73 [ 95 % CI 0·57 - 0·95 ] , p=0·017 ) and time-to-treatment failure ( median 13·7 months [ 95 % CI 11·9 - 15·0 ] with afatinib vs 11·5 months [ 10·1 - 13·1 ] with gefitinib ; HR 0·73 [ 95 % CI 0·58 - 0·92 ] , p=0·0073 ) were significantly longer with afatinib than with gefitinib . Overall survival data are not mature . The most common treatment-related grade 3 or 4 adverse events were diarrhoea ( 20 [ 13 % ] of 160 patients given afatinib vs two [ 1 % ] of 159 given gefitinib ) and rash or acne ( 15 [ 9 % ] patients given afatinib vs five [ 3 % ] of those given gefitinib ) and liver enzyme elevations ( no patients given afatinib vs 14 [ 9 % ] of those given gefitinib ) . Serious treatment-related adverse events occurred in 17 ( 11 % ) patients in the afatinib group and seven ( 4 % ) in the gefitinib group . Ten ( 6 % ) patients in each group discontinued treatment due to drug-related adverse events . 15 ( 9 % ) fatal adverse events occurred in the afatinib group and ten ( 6 % ) in the gefitinib group . All but one of these deaths were considered unrelated to treatment ; one patient in the gefitinib group died from drug-related hepatic and renal failure . INTERPRETATION Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib , with a manageable tolerability profile . These data are potentially important for clinical decision making in this patient population . FUNDING Boehringer Ingelheim Background : A phase III trial was conducted to compare the safety and efficacy of erlotinib with that of gefitinib in advanced non-small cell lung cancer harbouring epidermal growth factor receptor mutations in exon 19 or 21 . Methods : Eligible patients were r and omised to receive erlotinib ( 150 mg per day ) or gefitinib ( 250 mg per day ) orally until disease progression or unacceptable toxicity . We aim ed to determine whether erlotinib is superior to gefitinib in efficacy . The primary end point was progression-free survival . Results : A total of 256 patients were r and omised to receive erlotinib ( N=128 ) or gefitinib ( N=128 ) . Median progression-free survival was not better with erlotinib than with gefitinib ( 13.0 vs 10.4 months , 95 % confidence interval ( CI ) 0.62–1.05 , P=0.108 ) . The corresponding response rates and median overall survival were 56.3 % vs 52.3 % ( P=0.530 ) and 22.9 vs 20.1 months ( 95 % CI 0.63–1.13 , P=0.250 ) , respectively . There were no significant differences in grade 3/4 toxicities between the two arms ( P=0.172 ) . Conclusions : The primary end point was not met . Erlotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21 , and the two treatments had similar toxicities Abstract Background Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer ( NSCLC ) despite recent advances in molecular targeted therapy and immunotherapy . We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with st and ard docetaxel therapy in patients with advanced NSCLC . Patients and methods Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were r and omized 1 : 1 to docetaxel ( 60 mg/m2 in Japan , 75 mg/m2 at all other study sites ; day 1 in a 3-week cycle ) or S-1 ( 80–120 mg/day , depending on body surface area ; days 1–28 in a 6-week cycle ) . The primary endpoint was overall survival . The non-inferiority margin was a hazard ratio ( HR ) of 1.2 . Results A total of 1154 patients ( 577 in each arm ) were enrolled , with balanced patient characteristics between the two arms . Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms , respectively [ HR 0.945 ; 95 % confidence interval ( CI ) 0.833–1.073 ; P = 0.3818 ] . The upper limit of 95 % CI of HR fell below 1.2 , confirming non-inferiority of S-1 to docetaxel  . Difference in progression-free survival between treatments was not significant ( HR 1.033 ; 95 % CI 0.913–1.168 ; P = 0.6080 ) . Response rate was 8.3 % and 9.9 % in the S-1 and docetaxel arms , respectively . Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm . The most common adverse drug reactions were decreased appetite ( 50.4 % ) , nausea ( 36.4 % ) , and diarrhea ( 35.9 % ) in the S-1 arm , and neutropenia ( 54.8 % ) , leukocytopenia ( 43.9 % ) , and alopecia ( 46.6 % ) in the docetaxel arm . Conclusion S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC . Clinical trial number Japan Pharmaceutical Information Center , JapicCTI-101155 Introduction : Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma receptor tyrosine kinase gene ( ALK ) rearrangement – positive NSCLC and a good performance status ( PS ) . It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS . Methods : Eligible patients with advanced ALK rearrangement – positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily . The primary end point of the study was objective response rate ( ORR ) , and the most informative secondary end point was rate of PS improvement . Results : Between September 2014 and December 2015 , 18 patients were enrolled in this phase II study . Of those patients , 12 , five , and one had a PS of 2 , 3 , or 4 , respectively , whereas four patients had received prior crizotinib treatment . The ORR was 72.2 % ( 90 % confidence interval : 52.9–85.8 % ) . The ORR did not differ significantly between patients with a PS of 2 and those with a PS of 3 or higher ( 58.3 % and 100 % , respectively [ p = 0.114 ] ) . The PS improvement rate was 83.3 % ( 90 % confidence interval : 64.8–93.1 % , p < 0.0001 ) , with the frequency of improvement to a PS of 0 or 1 being 72.2 % . The median progression‐free survival was 10.1 months . Toxicity was mild , with the frequency of adverse events of grade 3 or higher being low . Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary . Conclusions : Alectinib is a treatment option for patients with ALK rearrangement – positive NSCLC and a poor PS 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 The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer ( NSCLC ) is not known . We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients . METHODS This r and omised , open-label , phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries . Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ( [ cisplatin 75 mg/m2 or carboplatin AUC 5 - 6 plus pemetrexed 500 mg/m2 ] every 3 weeks for four cycles followed by maintenance pemetrexed ) ; r and omisation was stratified by World Health Organization performance status ( 0 vs 1 - 2 ) , previous neoadjuvant or adjuvant chemotherapy , and presence of brain metastases as per investigator 's assessment at screening . Investigators and patients were not masked to treatment assignment . The primary endpoint was blinded independent review committee assessed progression-free survival , based on all r and omly assigned patients ( the full analysis set ) . Efficacy analyses were done based on the full analysis set . All safety analyses were done based on the safety set , which included all patients who received at least one dose of study drug . This trial is registered with Clinical Trials.gov , number NCT01828099 . FINDINGS Between Aug 19 , 2013 , and May 11 , 2015 , 376 patients were r and omly assigned to ceritinib ( n=189 ) or chemotherapy ( n=187 ) . Median progression-free survival ( as assessed by blinded independent review committee ) was 16·6 months ( 95 % CI 12·6 - 27·2 ) in the ceritinib group and 8·1 months ( 5·8 - 11·1 ) in the chemotherapy group ( hazard ratio 0·55 [ 95 % CI 0·42 - 0·73 ] ; p<0·00001 ) . The most common adverse events were diarrhoea ( in 160 [ 85 % ] of 189 patients ) , nausea ( 130 [ 69 % ] ) , vomiting ( 125 [ 66 % ] ) , and an increase in alanine aminotransferase ( 114 [ 60 % ] ) in the ceritinib group and nausea ( in 97 [ 55 % ] of 175 patients ) , vomiting ( 63 [ 36 % ] ) , and anaemia ( 62 [ 35 % ] ) in the chemotherapy group . INTERPRETATION First-line ceritinib showed a statistically significant and clinical ly meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC . FUNDING Novartis Pharmaceuticals Corporation 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 BACKGROUND Outcomes are poor for patients with previously treated , advanced or metastatic non-small-cell lung cancer ( NSCLC ) . The anti-programmed death lig and 1 ( PD-L1 ) antibody atezolizumab is clinical ly active against cancer , including NSCLC , especially cancers expressing PD-L1 on tumour cells , tumour-infiltrating immune cells , or both . We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC , analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population . METHODS In this open-label , phase 2 r and omised controlled trial , patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practice s across 13 countries in Europe and North America . Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1 , measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 ( RECIST v1.1 ) , and adequate haematological and end-organ function . Patients were stratified by PD-L1 tumour-infiltrating immune cell status , histology , and previous lines of therapy , and r and omly assigned ( 1:1 ) by permuted block r and omisation ( with a block size of four ) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2 ) once every 3 weeks . Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells ( as percentage of PD-L1-expressing tumour cells TC3≥50 % , TC2≥5 % and < 50 % , TC1≥1 % and < 5 % , and TC0<1 % ) and tumour-infiltrating immune cells ( as percentage of tumour area : IC3≥10 % , IC2≥5 % and < 10 % , IC1≥1 % and < 5 % , and IC0<1 % ) . The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths . Biomarkers were assessed in an exploratory analysis . We assessed safety in all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT01903993 . FINDINGS Patients were enrolled between Aug 5 , 2013 , and March 31 , 2014 . 144 patients were r and omly allocated to the  atezolizumab group , and 143 to the docetaxel group . 142 patients received at least one dose of atezolizumab and 135 received docetaxel  . Overall survival in the intention-to-treat population was 12·6 months ( 95 % CI 9·7 - 16·4 ) for atezolizumab versus 9·7 months ( 8·6 - 12·0 ) for docetaxel ( hazard ratio [ HR ] 0·73 [ 95 % CI 0·53 - 0·99 ] ; p=0·04 ) . Increasing improvement in overall survival was associated with increasing PD-L1 expression ( TC3 or IC3 HR 0·49 [ 0·22 - 1·07 ; p=0·068 ] , TC2/3 or IC2/3 HR 0·54 [ 0·33 - 0·89 ; p=0·014 ] , TC1/2/3 or IC1/2/3 HR 0·59 [ 0·40 - 0·85 ; p=0·005 ] , TC0 and IC0 HR 1·04 [ 0·62 - 1·75 ; p=0·871 ] ) . In our exploratory analysis , patients with pre-existing immunity , defined by high T-effector-interferon-γ-associated gene expression , had improved overall survival  with atezolizumab . 11 ( 8 % ) patients in the atezolizumab group discontinued because of adverse events versus 30 ( 22 % ) patients in the docetaxel group . 16 ( 11 % ) patients in the atezolizumab group versus 52 ( 39 % ) patients in the docetaxel group had treatment-related grade 3 - 4 adverse events , and one ( < 1 % ) patient in the atezolizumab group versus three ( 2 % ) patients in the docetaxel group died from a treatment-related adverse event . INTERPRETATION Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC . Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells , suggesting that PD-L1 expression is predictive for atezolizumab benefit . Atezolizumab was well tolerated , with a safety profile distinct from chemotherapy . FUNDING F Hoffmann-La Roche/Genentech 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 PURPOSE Despite recent improvements in supportive care , treatment-related death ( TRD ) remains a serious problem for lung cancer patients undergoing systemic chemotherapy .  However , few studies have formally assessed possible changes in the TRD rate over the past two decades . PATIENTS AND METHODS We search ed phase III trials to address the role of systemic treatment of advanced non-small-cell lung cancer ( NSCLC ) . Time trend was assessed using linear regression analysis . RESULTS The overall incidence of TRD was calculated from 119 trials including 263 chemotherapy arms ( 46 477 patients ) , with information about the causes of deaths available for 197 arms ( 75 % , 30 147 patients ) .  Cisplatin-based regimens were the most frequently investigated . The crude TRD rate in the overall cohort of 119 trials was 1.26 % and has been notably consistent over the investigated time ( P = 0.762 ) . The most common cause of death was febrile neutropenia , with no significant change in its incidence over the years ( P = 0.139 ) . In contrast , deaths due to renal toxicity decreased significantly ( P = 0.042 ) , whereas deaths due to pulmonary disorder increased significantly ( P = 0.007 ) . Among the pharmacological agents investigated , docetaxel ( Taxotere ) and epidermal growth factor receptor-tyrosine kinase inhibitors ( EGFR-TKIs ) were associated with relatively high rates of deaths from pulmonary disorders , but EGFR-TKIs were not associated with death from any other cause . CONCLUSIONS Despite of potential confounders in our results , the overall TRD rate has remained low , but not negligible , in phase III trials for advanced NSCLC , over the past two decades . Notably , the incidence and pattern of TRD stratified by cause have changed considerably OBJECTIVE The phase III IUNO trial assessed the benefit of maintenance erlotinib versus erlotinib at progression in advanced/metastatic non-small-cell lung cancer ( NSCLC ) that had not progressed following four cycles of platinum-based chemotherapy .  MATERIAL S AND METHODS Patients had stage IIIB/IV NSCLC , no known epidermal growth factor receptor (EGFR)-activating mutation , and objective response or disease stabilization after platinum-based induction chemotherapy .  Central EGFR-mutation testing was undertaken on tumors from patients with unknown or wild-type EGFR status following local testing . Patients were r and omized to receive blinded maintenance erlotinib 150mg/day ( ' early erlotinib ' ) or placebo . Those who progressed on placebo received open-label erlotinib ( ' late erlotinib ' ) ; patients who progressed on erlotinib received approved second-line chemotherapy or best supportive care . Primary endpoint : overall survival ( OS ) . RESULTS 643 patients were r and omized to receive maintenance erlotinib ( n=322 ) or placebo ( n=321 ) . As of March 23 , 2015 , 242 ( 75.2 % ) OS events had occurred with ' early erlotinib ' versus 235 ( 73.2 % ) with ' late erlotinib ' . Median OS was 9.7 and 9.5 months with ' early erlotinib ' and ' late erlotinib ' , respectively ( HR , 1.02 , 95 % CI : 0.85 - 1.22 ; log-rank p=0.82 ) . No progression-free survival , objective response rate , or disease control rate benefit was observed with maintenance erlotinib . 410 patients entered the second-line phase of the study : 160 patients ( 50 % ) from the maintenance erlotinib arm and 250 patients ( 78 % ) from the maintenance placebo arm . The pattern of adverse events ( AEs ) was consistent with previous trials ; 11 patients who received blinded erlotinib and 3 who received placebo  died during the blinded maintenance phase due to nontreatment-related AEs . CONCLUSIONS OS with maintenance erlotinib was not superior to second-line treatment in patients whose tumor did not harbor an EGFR-activating mutation . Safety results were consistent with the established safety profile of erlotinib . Thus , maintenance treatment with erlotinib in patients with advanced/metastatic NSCLC without EGFR-activating mutations is considered unfavorable PURPOSE To confirm the promising phase II results of docetaxel monotherapy , this phase III trial was conducted of chemotherapy for patients with advanced non-small-cell lung cancer ( NSCLC ) who had previously failed platinum-containing chemotherapy . PATIENTS AND METHODS A total of 373 patients were r and omized to receive either docetaxel 100 mg/m(2 ) ( D100 ) or 75 mg/m(2 ) ( D75 ) versus a control regimen of vinorelbine or ifosfamide ( V/I ) . The three treatment groups were well-balanced for key patient characteristics . RESULTS Overall response rates were 10.8 % with D100 and 6.7 % with D75 , each significantly higher than the 0.8 % response with V/I ( P = .001 and P = .036 , respectively ) . Patients who received docetaxel had a longer time to progression ( P = .046 , by log-rank test ) and a greater progression-free survival at 26 weeks ( P = .005 , by chi(2 ) test ) . Although overall survival was not significantly different between the three groups , the 1-year survival was significantly greater with D75 than with the control treatment ( 32 % v 19 % ; P = .025 , by chi(2 ) test ) . Prior exposure to paclitaxel did not decrease the likelihood of response to docetaxel , nor did it impact survival . There was a trend toward greater efficacy in patients whose disease was platinum-resistant rather than platinum-refractory and in patients with performance status of 0 or 1 versus 2 . Toxicity was greatest with D100 , but the D75 arm was well-tolerated . CONCLUSION This first r and omized trial in this setting demonstrates that D75 every 3 weeks can offer clinical ly meaningful benefit to patients with advanced NSCLC whose disease has relapsed or progressed after platinum-based chemotherapy 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 BACKGROUND Low-dose erlotinib may be as effective as gefitinib or erlotinib at full dose in non-small cell lung cancer ( NSCLC ) patients with activating mutations of the epidermal growth factor receptor ( EGFR ) gene . METHODS Patients with chemotherapy pretreated NSCLC harbouring EGFR mutations received erlotinib at 50 mg/d until disease progression or unacceptable toxicities . The dose was escalated to 150 mg/d in patients showing no response ( i.e. without major tumour shrinkage according to Response Evaluation Criteria in Solid Tumours ( RECIST ) ) to the initial dose during the first 4 weeks . The primary end-point was the objective response rate at the dose of 50 mg/d . RESULTS Thirty-four patients from seven institutes were enrolled . The study was closed early when no response was confirmed in 15 patients , excluding the possibility that the primary end-point would be met . The objective response and disease control rates at the dose of 50 mg/d as determined by an independent review committee were 54.5 % and 84.8 % , respectively . Four additional patients achieved partial response with increased 150 mg/d dose . Progression-free survival and median survival times during the entire period of the study were 9.5 and 28.5 months , respectively . Treatment-related toxicities were generally mild , the most common being skin disorders and diarrhoea . Only one case experienced grade 3 toxicity , which was transient increase of hepatic enzymes . CONCLUSION The primary end-point was not met ; low-dose erlotinib is not recommended for fit patients with NSCLC harbouring EGFR mutations . However , it may merit further evaluation for elderly or frail patients PURPOSE The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies . PATIENTS AND METHODS Patients age ≥ 18 years with locally advanced , metastatic , or recurrent advanced nonsquamous non-small-cell lung cancer ( NSCLC ) were r and omly assigned to receive carboplatin ( area under the curve , 6 ) intravenously and paclitaxel ( 175 mg/m(2 ) ) intravenously ( CP ) on day 1 of each 3-week cycle , for ≤ six cycles , plus placebo ( Pl+CP ) or bevacizumab ( B+CP ) 15 mg/kg intravenously , on day 1 of each cycle , until progression , unacceptable toxicity , or death . The primary end point was progression-free survival ( PFS ) ; secondary end points were objective response rate , overall survival , exploratory biomarkers , safety . RESULTS A total of 276 patients were r and omly assigned , 138 to each arm . PFS was prolonged with B+CP versus Pl+CP ( median , 9.2 v 6.5 months , respectively ; hazard ratio [ HR ] , 0.40 ; 95 % CI , 0.29 to 0.54 ; P < .001 ) . Objective response rate was improved with B+CP compared with Pl+CP ( 54 % v 26 % , respectively ) . Overall survival was also prolonged with B+CP compared with Pl+CP ( median , 24.3 v 17.7 months , respectively ; HR , 0.68 ; 95 % CI , 0.50 to 0.93 ; P = .0154 ) . Median PFS was 12.4 months with B+CP and 7.9 months with Pl+CP ( HR , 0.27 ; 95 % CI , 0.12 to 0.63 ) in EGFR mutation-positive tumors and 8.3 and 5.6 months , respectively ( HR , 0.33 ; 95 % CI , 0.21 to 0.53 ) , in wild-type tumors . Safety was similar to previous studies of B+CP in NSCLC ; no new safety signals were observed . CONCLUSION The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and result ed in a clinical ly meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC 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 Oral S-1 plus cisplatin is noninferior to docetaxel plus cisplatin in terms of overall survival with favorable QoL data .  S-1 plus cisplatin is an option for the first-line treatment of patients with advanced NSCLC BACKGROUND With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) , median progression-free survival has been extended to about 12 months . Nevertheless , new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population . We aim ed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease . METHODS In this open-label , r and omised , multicentre , phase 2 study , patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations , Eastern Cooperative Oncology Group performance status 0 or 1 , and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity . The primary endpoint was progression-free survival , as determined by an independent review committee . R and omisation was done with a dynamic allocation method , and the analysis used a modified intention-to-treat approach , including all patients who received at least one dose of study treatment and had tumour assessment at least once after r and omisation . This study is registered with the Japan Pharmaceutical Information Center , number JapicCTI-111390 . FINDINGS Between Feb 21 , 2011 , and March 5 , 2012 , 154 patients were enrolled . 77 were r and omly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone , of whom 75 patients in the erlotinib plus bevacizumab  group and 77 in the erlotinib alone group were included in the efficacy analyses . Median progression-free survival was 16·0 months ( 95 % CI 13·9 - 18·1 ) with erlotinib plus bevacizumab and 9·7 months ( 5·7 - 11·1 ) with erlotinib alone ( hazard ratio 0·54 , 95 % CI 0·36 - 0·79 ; log-rank test p=0·0015 ) . The most common grade 3 or worse adverse events were rash ( 19 [ 25 % ] patients in the erlotinib plus bevacizumab group vs 15 [ 19 % ] patients in the erlotinib alone group ) , hypertension ( 45 [ 60 % ] vs eight [ 10 % ] ) , and proteinuria ( six [ 8 % ] vs none ) . Serious adverse events occurred at a similar frequency in both groups ( 18 [ 24 % ] patients in the erlotinib plus bevacizumab group and 19 [ 25 % ] patients in the erlotinib alone group ) . INTERPRETATION Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC . Further investigation of the regimen is warranted . FUNDING Chugai Pharmaceutical Co PURPOSE To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy .  Secondary end points included assessment of response ( docetaxel arm only ) , toxicity , and quality of life . PATIENTS AND METHODS Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters . They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel .  Patients were stratified by performance status and best response to cisplatin chemotherapy and were then r and omized to treatment with docetaxel 100 mg/m(2 ) ( 49 patients ) or 75 mg/m(2 ) ( 55 patients ) or best supportive care . Patients in both arms were assessed every 3 weeks . RESULTS One hundred four patients ( 103 of whom were eligible for entry onto the study ) were well balanced for prognostic factors . Of 84 patients with measurable lesions , six ( 7 . 1 % ) achieved partial responses ( three patients at each dose level ) . Time to progression was longer for docetaxel patients than for best supportive care patients ( 10.6 v 6.7 weeks , respectively ; P < .001 ) , as was median survival ( 7.0 v 4.6 months ; log-rank test , P = .047 ) . The difference was more significant for docetaxel 75 mg/m(2 ) patients , compared with corresponding best supportive care patients ( 7.5 v 4.6 months ; log-rank test , P = .010 ; 1-year survival , 37 % v 11 % ; chi(2 ) test , P = .003 ) . Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m(2 ) , three of whom died , and in one patient treated with docetaxel 75 mg/m(2 ) . Grade 3 or 4 nonhematologic toxicity , with the exception of diarrhea , occurred at a similar rate in both the docetaxel and best supportive care groups . CONCLUSION Treatment with docetaxel is associated with significant prolongation of survival , and at a dose of 75 mg/m(2 ) , the benefits of docetaxel therapy outweigh the risks 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 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 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 Alectinib , a highly selective inhibitor of anaplastic lymphoma kinase ( ALK ) , has shown systemic and central nervous system ( CNS ) efficacy in the treatment of ALK‐positive non – small‐cell lung cancer ( NSCLC ) . We investigated alectinib as compared with crizotinib in patients with previously untreated , advanced ALK‐positive NSCLC , including those with asymptomatic CNS disease . Methods In a r and omized , open‐label , phase 3 trial , we r and omly assigned 303 patients with previously untreated , advanced ALK‐positive NSCLC to receive either alectinib ( 600 mg twice daily ) or crizotinib ( 250 mg twice daily ) . The primary end point was investigator‐assessed progression‐free survival . Secondary end points were independent review committee – assessed progression‐free survival , time to CNS progression , objective response rate , and overall survival . Results During a median follow‐up of 17.6 months ( crizotinib ) and 18.6 months ( alectinib ) , an event of disease progression or death occurred in 62 of 152 patients ( 41 % ) in the alectinib group and 102 of 151 patients ( 68 % ) in the crizotinib group . The rate of investigator‐assessed progression‐free survival was significantly higher with alectinib than with crizotinib ( 12‐month event‐free survival rate , 68.4 % [ 95 % confidence interval ( CI ) , 61.0 to 75.9 ] with alectinib vs. 48.7 % [ 95 % CI , 40.4 to 56.9 ] with crizotinib ; hazard ratio for disease progression or death , 0.47 [ 95 % CI , 0.34 to 0.65 ] ; P<0.001 ) ; the median progression‐free survival with alectinib was not reached . The results for independent review committee – assessed progression‐free survival were consistent with those for the primary end point . A total of 18 patients ( 12 % ) in the alectinib group had an event of CNS progression , as compared with 68 patients ( 45 % ) in the crizotinib group ( cause‐specific hazard ratio , 0.16 ; 95 % CI , 0.10 to 0.28 ; P<0.001 ) . A response occurred in 126 patients in the alectinib group ( response rate , 82.9 % ; 95 % CI , 76.0 to 88.5 ) and in 114 patients in the crizotinib group ( response rate , 75.5 % ; 95 % CI , 67.8 to 82.1 ) ( P=0.09 ) . Grade 3 to 5 adverse events were less frequent with alectinib ( 41 % vs. 50 % with crizotinib ) . Conclusions As compared with crizotinib , alectinib showed superior efficacy and lower toxicity in primary treatment of ALK‐positive NSCLC . ( Funded by F. Hoffmann – La Roche ; ALEX Clinical Trials.gov number , NCT02075840 . Three hundred patients with symptomatic , locally advanced or metastatic NSCLC not requiring immediate radiotherapy were enrolled into this r and omized multicentre trial comparing gemcitabine + BSC vs BSC alone . Patients allocated gemcitabine received 1000 mg/m2on days 1 , 8 and 15 of a 28-day cycle , for a maximum of six cycles . The main aim of this trial was to compare patient assessment of a predefined subset of commonly reported symptoms ( SS14 ) from the EORTC QLQ-C30 and LC13 scales . The primary end-points were defined as ( 1 ) the percentage change in mean SS14 score between baseline and 2 months and ( 2 ) the proportion of patients with a marked ( ≥ 25 % ) improvement in SS14 score between baseline and 2 months sustained for ≥4 weeks . The secondary objectives were to compare treatments with respect to overall survival , and multidimensional QL parameters . The treatment groups were balanced with regard to age , gender , Karnofsky performance status ( KPS ) and disease stage ( 40 % had metastatic disease ) . The percentage change in mean SS14 score from baseline to 2 months was a 10 % decrease ( i.e. improvement ) for gemcitabine plus BSC and a 1 % increase ( i.e. deterioration ) for BSC alone ( P = 0.113 , two- sample t -test ) . A sustained ( ≥ 4 weeks ) improvement ( ≥25 % ) on SS14 was recorded in a significantly higher proportion of gemcitabine + BSC patients ( 22 % ) than in BSC alone patients ( 9 % ) ( P = 0.0014 , Pearson 's chi-squared test ) . The QLQ-C30 and L13 subscales showed greater improvement in the gemcitabine plus BSC arm ( in 11 domains ) than in the BSC arm ( one symptom item ) . There was greater deterioration in the BSC alone arm ( six domains/items ) than in the gemcitabine + BSC arm ( three QL domains ) . Tumour response occurred in 19 % ( 95 % CI 13–27 ) of gemcitabine patients . There was no difference in overall survival : median 5.7 months ( 95 % CI 4.6–7.6 ) for gemcitabine + BSC patients and 5.9 months ( 95 % CI 5.0–7.9 ) ( log-rank , P = 0.84 ) for BSC  patients , and 1-year survival was 25 % for gemcitabine + BSC and 22 % for BSC . Overall , 74 ( 49 % ) gemcitabine + BSC patients and 119 ( 79 % ) BSC patients received palliative radiotherapy .  The median time to radiotherapy was 29 weeks for gemcitabine + BSC patients and 3.8 weeks for BSC . Patients treated with gemcitabine + BSC reported better QL and reduced disease-related symptoms compared with those receiving BSC alone . These improvements in patient-assessed QL were significant in magnitude and were sustained . © 2000 Cancer Research Introduction : PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed ( Pem+Cb ) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab ( Pac+Cb+Bev ) in patients with advanced nonsquamous non – small-cell lung cancer ( NSCLC ) . Methods : Patients ≥18 years of age with stage IV nonsquamous NSCLC ( American Joint Committee on Cancer v7.0 ) , and Eastern Cooperative Oncology Group performance status 0/1 were r and omized ( 1:1 ) to four cycles of induction Pem+Cb ( pemetrexed , 500 mg/m2 , carboplatin , area under the curve = 6 ) followed by Pem maintenance or Pac+Cb+Bev ( paclitaxel , 200 mg/m2 , carboplatin , area under the curve = 6 , and bevacizumab , 15 mg/kg ) followed by Bev maintenance in the absence of progressive disease or discontinuation . The primary objective was progression-free survival ( PFS ) without grade 4 toxicity ( G4PFS ) . Secondary end points were PFS , overall survival ( OS ) , overall response rate ( ORR ) , disease control rate ( DCR ) , and safety . Re source utilization was also assessed . Results : Baseline characteristics of the patients r and omized to Pem+Cb ( N = 182 ) and Pac+Cb+Bev ( N = 179 ) were well balanced between the arms . Median ( months ) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev ( hazard ratio = 0.85 , 90 % confidence interval , 0.7–1.04 ; p = 0.176 ) ; PFS , OS , ORR , or DCR did not differ significantly between the arms . Significantly more drug-related grade 3/4 anemia ( 18.7 % versus 5.4 % ) and thrombocytopenia ( 24.0 % versus 9.6 % ) were reported for Pem+Cb . Significantly more grade 3/4 neutropenia ( 48.8 % versus 24.6 % ) , grade 1/2 alopecia ( 28.3 % versus 8.2 % ) , and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev . Number of hospitalizations and overall length of stay did not differ significantly between the arms . Conclusions : Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev . Pem+Cb was not superior in PFS , OS , ORR , or DCR compared with Pac+Cb+Bev . Both regimens were well tolerated , although , toxicity profiles differed BACKGROUND To compare the efficacy and toxicity of three platinum-based combination regimens against cisplatin plus irinotecan ( IP ) in patients with untreated advanced non-small-cell lung cancer ( NSCLC ) by a non-inferiority design . PATIENTS AND METHODS A total of 602 patients were r and omly assigned to one of four regimens : cisplatin 80 mg/m(2 ) on day 1 plus irinotecan 60 mg/m(2 ) on days 1 , 8 , 15 every 4 weeks ( IP ) carboplatin AUC 6.0 min x mg/mL ( area under the concentration-time curve ) on day 1 plus paclitaxel 200 mg/m(2 ) on day 1 every 3 weeks ( TC ) ; cisplatin 80 mg/m(2 ) on day 1 plus gemcitabine 1000 mg/m(2 ) on days 1 , 8 every 3 weeks ( GP ) ; and cisplatin 80 mg/m(2 ) on day 1 plus vinorelbine 25 mg/m(2 ) on days 1 , 8 every 3 weeks ( NP ) . RESULTS The response rate , median survival time , and 1-year survival rate were 31.0 % , 13.9 months , 59.2 % , respectively , in IP ; 32.4 % , 12.3 months , 51.0 % in TC ; 30.1 % , 14.0 months , 59.6 % in GP ; and 33.1 % , 11.4 months , 48.3 % in NP . No statistically significant differences were found in response rate or overall survival , but the non-inferiority of none of the experimental regimens could be confirmed . All the four regimens were well tolerated . CONCLUSION The four regimens have similar efficacy and different toxicity profiles , and they can be used to treat advanced NSCLC patients Introduction : Anaplastic lymphoma kinase (ALK)-rearranged non – small-cell lung cancer ( NSCLC ) is sensitive to ALK inhibitors , but resistance develops . This study assessed the maximum-tolerated dose , safety , pharmacokinetics ( PK ) , and antitumor activity of ceritinib , a novel ALK inhibitor ( ALKi ) , in Japanese patients with ALK-rearranged malignancies . Methods : This phase I , multicenter , open-label study ( NCT01634763 ) enrolled adult patients with ALK-rearranged ( by fluorescence in situ hybridization and /or immunohistochemistry ) locally advanced/metastatic malignancy that had progressed despite st and ard therapy . The study comprised two parts : dose escalation and dose expansion . Ceritinib ( single-dose ) was administered orally in the 3-day PK run-in period , then once daily , in 21-day cycles . Adaptive dose escalations were guided by a Bayesian model . Results : Twenty patients ( 80 % with ALKi treatment history [ ALKi-pretreated ] ; 19 NSCLC ; one inflammatory myofibroblastic tumor ) received ceritinib 300 to 750 mg ( 19 during dose escalation , one in dose expansion ) . Two dose-limiting toxicities occurred : grade 3 lipase increase ( 600 mg ) ; grade 3 drug-induced liver injury ( 750 mg ) . The most common adverse events were gastrointestinal ( nausea : 95 % ; diarrhea , vomiting : 75 % ) . Ceritinib  PK profile was dose proportional across 300 to 750 mg dosages ; steady state was reached by day 15 . Overall response rate was 55 % ( 11 of 20 patients ) . Among patients with NSCLC , partial response was observed in two of four ALKi-naive patients , five of nine crizotinib-pretreated patients , two of four alectinib-pretreated patients , and one of two crizotinib and alectinib/ASP3026 pretreated patients . The ASP3026-pretreated inflammatory myofibroblastic tumor patient achieved partial response . Conclusions : Ceritinib maximum-tolerated dose was 750 mg once daily in Japanese patients .  Antitumor activity was observed irrespective of prior ALKi treatment history . Dose expansion , examining the activity of ceritinib in alectinib-resistant patients , is ongoing 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 Bevacizumab , a monoclonal antibody against vascular endothelial growth factor , has been shown to benefit patients with a variety of cancers . METHODS Between July 2001 and April 2004 , the Eastern Cooperative Oncology Group ( ECOG ) conducted a r and omized study in which 878 patients with recurrent or advanced non-small-cell lung cancer ( stage IIIB or IV ) were assigned to chemotherapy with paclitaxel and carboplatin alone ( 444 ) or paclitaxel and carboplatin plus bevacizumab ( 434 ) . Chemotherapy was administered every 3 weeks for six cycles , and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable . Patients with squamous-cell tumors , brain metastases , clinical ly significant hemoptysis , or inadequate organ function or performance status ( ECOG performance status , > 1 ) were excluded . The primary end point was overall survival . RESULTS The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab , as compared with 10.3 months in the chemotherapy-alone group ( hazard ratio for death , 0.79 ; P=0.003 ) . The median progression-free survival in the two groups was 6.2 and 4.5 months , respectively ( hazard ratio for disease progression , 0.66 ; P<0.001 ) , with corresponding response rates of 35 % and 15 % ( P<0.001 ) . Rates of clinical ly significant bleeding were 4.4 % and 0.7 % , respectively ( P<0.001 ) . There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group , including 5 from pulmonary hemorrhage . CONCLUSIONS The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths . ( Clinical Trials.gov number , NCT00021060 . BACKGROUND Vinorelbine prolongs survival and improves quality of life in elderly patients with advanced non-small-cell lung cancer ( NSCLC ) . Some studies have also suggested that gemcitabine is well tolerated and effective in such patients . We compared the effectiveness and toxicity of the combination of vinorelbine plus gemcitabine with those of each drug given alone in an open-label , r and omized phase III trial in elderly patients with advanced NSCLC . METHODS Patients aged 70 years and older , enrolled between December 1997 and November 2000 , were r and omly assigned to receive intravenous vinorelbine ( 30 mg/m(2 ) of body surface area ) , gemcitabine ( 1200 mg/m(2 ) ) , or vinorelbine ( 25 mg/m(2 ) ) plus gemcitabine ( 1000 mg/m(2 ) ) . All treatments were delivered on days 1 and 8 every 3 weeks for a maximum of six cycles . The primary endpoint was survival . Survival curves were drawn using the Kaplan-Meier method and analyzed by the Mantel-Haenszel test . Secondary endpoints were quality of life and toxicity . RESULTS Of 698 patients available for intention-to-treat analysis , 233 were assigned to receive vinorelbine , 233 to gemcitabine , and 232 to vinorelbine plus gemcitabine . Compared with each single drug , the combination treatment did not improve survival . The hazard ratio of death for patients receiving the combination treatment was 1.17 ( 95 % confidence interval [ CI ] = 0.95 to 1.44 ) that of patients receiving vinorelbine and 1.06 ( 95 % CI = 0.86 to 1.29 ) that of patients receiving gemcitabine . Although quality of life was similar across the three treatment arms , the combination treatment was more toxic than the two drugs given singly . CONCLUSION The combination of vinorelbine plus gemcitabine is not more effective than single-agent vinorelbine or gemcitabine in the treatment of elderly patients with advanced NSCLC 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 . PURPOSE Phase I data ( ASCEND-1 ) showed ceritinib  efficacy in patients with ALK-rearranged non-small-cell lung cancer ( NSCLC ) , regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein . Data are presented from a phase II trial ( ASCEND-2 ) in which ceritinib  efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy . PATIENTS AND METHODS Patients with advanced ALK-rearranged NSCLC , including those with asymptomatic or neurologically stable baseline brain metastases , received oral ceritinib 750 mg/d . Whole-body and intracranial responses were investigator assessed ( according to RECIST version 1.1 ) . Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys ( the core-30 and the 13-item lung cancer-specific quality -of-life question naires ) . RESULTS All 140 patients enrolled had received two or more previous treatment regimens , and all patients had received crizotinib . The median duration of exposure and the follow-up time with ceritinib were 8.8 months ( range , 0.1 to 19.4 months ) and 11.3 months ( range , 0.1 to 18.9 months ) , respectively . Investigator-assessed overall response rate was 38.6 % ( 95 % CI , 30.5 % to 47.2 % ) . Secondary end points , all investigator assessed , included disease control rate ( 77.1 % ; 95 % CI , 69.3 % to 83.8 % ) , time to response ( median , 1.8 months ; range , 1.6 to 5.6 months ) , duration of response ( median , 9.7 months ; 95 % CI , 7.1 to 11.1 months ) , and progression-free survival ( median , 5.7 months ; 95 % CI , 5.4 to 7.6 months ) . Of 100 patients with baseline brain metastases , 20 had active target lesions at baseline ; investigator-assessed intracranial overall response rate was 45.0 % ( 95 % CI , 23.1 % to 68.5 % ) . The most common adverse events ( majority , grade 1 or 2 ) for all treated patients were nausea ( 81.4 % ) , diarrhea ( 80.0 % ) , and vomiting ( 62.9 % ) . Patient-reported outcomes showed a trend toward improved symptom burden . The global quality -of-life score was maintained during treatment . CONCLUSION Consistent with its activity in ASCEND-1 , ceritinib treatment provided clinical ly meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients , including those with brain metastases BACKGROUND The r and omized , phase III AVAPERL trial evaluated the safety and efficacy of bevacizumab maintenance with or without pemetrexed in nonsquamous nonsmall-cell lung cancer ( nsNSCLC ) .  Progression-free survival ( PFS ) was significantly prolonged with bevacizumab-pemetrexed , but overall survival ( OS ) data were immature . In this article , we report an independent , up date d analysis of survival outcomes in AVAPERL . PATIENTS AND METHODS Patients with advanced nsNSCLC received first-line bevacizumab ( 7.5 mg/kg ) , cisplatin ( 75 mg/m(2 ) ) , and pemetrexed ( 500 mg/m(2 ) ) every 3 weeks ( q3w ) for four cycles . Nonprogressing patients were r and omized to maintenance bevacizumab ( 7.5 mg/kg ) or bevacizumab-pemetrexed ( 500 mg/m(2 ) ) q3w until progression or consent withdrawal . The primary end point of the trial was PFS ; in this independent OS analysis , participating study centers were contacted to collect survival data on patients still alive at the time of the first analysis . RESULTS A total of 376 patients received induction treatment . Disease control was confirmed in 71.9 % of patients ; 253 patients were r and omized to maintenance treatment with bevacizumab ( n = 125 ) or bevacizumab-pemetrexed ( n = 128 ) . At a median follow-up of 14.8 months , patients allocated to bevacizumab-pemetrexed had significantly improved PFS versus those on bevacizumab when measured from r and omization [ 7.4 versus 3.7 months , hazard ratio ( HR ) , 0.57 , 95 % confidence interval ( CI ) 0.44 - 0.75 ) ; P < 0.0001 ] . OS events occurred in 58 % of all patients . OS was numerically longer with bevacizumab-pemetrexed versus bevacizumab when measured from r and omization [ 17.1 versus 13.2 months , HR 0.87 ( 0.63 - 1.21 ) ; P = 0.29 ] . Second-line therapy was administered in 77 % and 70 % of patients in the bevacizumab and bevacizumab-pemetrexed arms , respectively . No new adverse events were reported during this up date d analysis . CONCLUSION In an unselected population of nsNSCLC patients achieving disease control on platinum-based induction therapy , maintenance with bevacizumab-pemetrexed was associated with a nonsignificant increase in OS over bevacizumab alone BACKGROUND Recent studies of pemetrexed have identified a predictive role for non-small cell lung cancer ( NSCLC ) histology . We further review ed the differential efficacy of pemetrexed according to histology in two large , phase III NSCLC trials . METHODS One study tested pemetrexed versus docetaxel in previously treated patients ( n = 571 ) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients ( n = 1,725 ) with advanced NSCLC . Cox proportional hazard models were used to test for covariate-adjusted treatment-by-histology interactions ( THIs ) for overall survival ( OS ) and progression-free survival ( PFS ) . For each histologic subgroup , the Kaplan-Meier method was used to estimate unadjusted within-arm medians , and Cox models were used to estimate covariate-adjusted between-arm hazard ratios ( HRs ) . RESULTS In both studies , treatment arms were well balanced for histology . THIs were statistically significant ( p < .005 ) for both OS and PFS . Nonsquamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators ( HR , 0.78 and 0.84 , respectively ) , whereas squamous patients had shorter survival ( HR , 1.56 and 1.23 , respectively ) . Whereas the efficacy of pemetrexed regimens differed according to histology , it did not differ for docetaxel or for cisplatin plus gemcitabine . Pemetrexed was well tolerated across histologic groups . CONCLUSIONS The consistency of these results across studies confirms the predictive effect of histology for pemetrexed and the survival advantage for pemetrexed in patients with nonsquamous histology . These analyses suggest pemetrexed should not be recommended for the treatment of squamous cell carcinoma , but , because of efficacy and safety advantages , pemetrexed may be preferable to other agents for treatment of patients with nonsquamous NSCLC PURPOSE We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer . PATIENTS AND METHODS A total of 561 eligible patients were r and omly assigned to receive paclitaxel alone or in combination with carboplatin . RESULTS The response rate was 17 % in the paclitaxel arm and 30 % in the carboplatin-paclitaxel arm ( P < .0001 ) . Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm ( P = .0002 ) . Median survival times were 6.7 months ( 95 % CI , 5.8 to 7.8 ) and 8.8 months ( 95 % CI , 8.0 to 9.9 ) , and 1-year survival rates were 32 % ( 95 % CI , 27 % to 38 % ) , and 37 % ( 95 % CI , 32 % to 43 % ) , respectively . The overall survival distributions were not statistically different : hazard ratio = 0.91 ( 95 % CI , 0.77 to 1.17 ; P = .25 ) . Hematological toxicity and nausea were more frequent in the combination arm , but febrile neutropenia and toxic deaths were equally low in both arms . There was no significant survival difference  in elderly patients . Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy ( P = .019 ) . CONCLUSION Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy , but there was no statistically significant difference in the primary end point of overall survival . The results in elderly patients were similar to younger patients . Performance status 2 patients had a superior outcome when treated with combination chemotherapy 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 OBJECTIVE Erlotinib has been reported to be useful for treatment of non-small-cell lung cancer harboring mutation of the epidermal growth factor receptor gene EGFR-mt . However , no prospect i ve trial has yet assessed the utility of erlotinib in Japanese patients . METHODS Patients with EGFR-mt ( exon 19/21 ) non-small-cell lung cancer who had previously received one to two chemotherapy regimens were enrolled in this trial . Erlotinib was initially administered at a dose of 150 mg/day orally until disease progression or unacceptable toxicities occurred . The primary endpoint was the objective response rate . RESULTS Twenty-six patients were enrolled between February 2009 and January 2011 .  Objective response was observed in 14 patients ( 53.8 % , 95 % confidence interval : 33.4 - 73.4 % ) , and the disease control rate reached 80.8 % ( 95 % confidence interval : 60.7 - 93.5 % ) . After a median follow-up time of 17.3 months ( range : 5.8 - 29.5 months ) , the median progression-free survival was 9.3 months ( 95 % confidence interval : 7.6 - 11.6 months ) . The median survival time is yet to be determined . Major toxicities were skin disorder and liver dysfunction ; most episodes were grade 2 or less , and all were tolerable . Only one patient with grade 3 skin rash discontinued the study . No patients developed interstitial lung disease , and there were no treatment-related deaths . CONCLUSIONS This prospect i ve study is the first to have investigated the usefulness of erlotinib in Japanese patients with previously treated EGFR-mt non-small-cell lung cancer . Although this trial could not meet the primary endpoint , erlotinib was well tolerated and showed clinical benefit such as promising disease control rate or progression-free survival in this population , similar to gefitinib BACKGROUND We aim ed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label , r and omised , phase 3 trials . METHODS Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 ( n=345 ) and LUX-Lung 6 ( n=364 ) . These patients were r and omly assigned in a 2:1 ratio to receive afatinib or chemotherapy ( pemetrexed-cisplatin [ LUX-Lung 3 ] or gemcitabine-cisplatin [ LUX-Lung 6 ] ) , stratified by EGFR mutation ( exon 19 deletion [ del19 ] , Leu858Arg , or other ) and ethnic origin ( LUX-Lung 3 only ) . We planned analyses of mature overall survival data in the intention-to-treat population after 209 ( LUX-Lung 3 ) and 237 ( LUX-Lung 6 ) deaths . These ongoing studies are registered with Clinical Trials.gov , numbers NCT00949650 and NCT01121393 . FINDINGS Median follow-up in LUX-Lung 3 was 41 months ( IQR 35 - 44 ) ; 213 ( 62 % ) of 345 patients had died . Median follow-up in LUX-Lung 6 was 33 months ( IQR 31 - 37 ) ; 246 ( 68 % ) of 364 patients had died . In LUX-Lung 3 , median overall survival was 28.2 months ( 95 % CI 24.6 - 33.6 ) in the afatinib group and 28.2 months ( 20.7 - 33.2 ) in the pemetrexed-cisplatin group ( HR 0.88 , 95 % CI 0.66 - 1.17 , p=0.39 ) . In LUX-Lung 6 , median overall survival was 23.1 months ( 95 % CI 20.4 - 27.3 ) in the afatinib group and 23.5 months ( 18.0 - 25.6 ) in the gemcitabine-cisplatin group ( HR 0.93 , 95 % CI 0.72 - 1.22 , p=0.61 ) . However , in preplanned analyses , overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials : in LUX-Lung 3 , median overall survival was 33.3 months ( 95 % CI 26.8 - 41.5 ) in the afatinib group versus 21.1 months ( 16.3 - 30.7 ) in the chemotherapy group ( HR 0.54 , 95 % CI 0.36 - 0.79 , p=0.0015 ) ; in LUX-Lung 6 , it was 31.4 months ( 95 % CI 24.2 - 35.3 ) versus 18.4 months ( 14.6 - 25.6 ) , respectively ( HR 0.64 , 95 % CI 0.44 - 0.94 , p=0.023 ) . By contrast , there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial : in LUX-Lung 3 , median overall survival was 27.6 months ( 19.8 - 41.7 ) in the afatinib group versus 40.3 months ( 24.3-not estimable ) in the chemotherapy group ( HR 1.30 , 95 % CI 0.80 - 2.11 , p=0.29 ) ; in LUX-Lung 6 , it was 19.6 months ( 95 % CI 17.0 - 22.1 ) versus 24.3 months ( 19.0 - 27.0 ) , respectively ( HR 1.22 , 95 % CI 0.81 - 1.83 , p=0.34 ) . In both trials , the most common afatinib-related grade 3 - 4 adverse events were rash or acne ( 37 [ 16 % ] of 229 patients in LUX-Lung 3 and 35 [ 15 % ] of 239 patients in LUX-Lung 6 ) , diarrhoea ( 33 [ 14 % ] and 13 [ 5 % ] ) , paronychia ( 26 [ 11 % ] in LUX-Lung 3 only ) , and stomatitis or mucositis ( 13 [ 5 % ] in LUX-Lung 6 only ) . In LUX-Lung 3 , neutropenia ( 20 [ 18 % ] of 111 patients ) , fatigue ( 14 [ 13 % ] ) and leucopenia ( nine [ 8 % ] ) were the most common chemotherapy-related grade 3 - 4 adverse events , while in LUX-Lung 6 , the most common chemotherapy-related grade 3 - 4 adverse events were neutropenia ( 30 [ 27 % ] of 113 patients ) , vomiting ( 22 [ 19 % ] ) , and leucopenia ( 17 [ 15 % ] ) . INTERPRETATION Although afatinib did not improve overall survival in the whole population of either trial , overall survival was improved with the drug for patients with del19 EGFR mutations . The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials . FUNDING Boehringer Ingelheim PURPOSE To investigate the efficacy of erlotinib versus docetaxel in previously treated patients with advanced non-small-cell lung cancer ( NSCLC ) in an epidermal growth factor receptor ( EGFR ) -unselected patient population . PATIENTS AND METHODS The primary end point was progression-free survival ( PFS ) . Secondary end points included overall survival ( OS ) , response rate , safety , and analyses on EGFR wild-type tumors . Patients with stage IIIB or IV NSCLC , previous treatment with one or two chemotherapy regimens , evaluable or measurable disease , and performance status of 0 to 2 were eligible . RESULTS From August 2009 to July 2012 , 150 and 151 patients were r and omly assigned to erlotinib ( 150 mg daily ) and docetaxel ( 60 mg/m(2 ) every 3 weeks ) , respectively . EGFR wild-type NSCLC was present in 109 and 90 patients in the erlotinib and docetaxel groups , respectively . Median PFS  for erlotinib versus docetaxel was 2.0 v 3.2 months ( hazard ratio [ HR ] , 1.22 ; 95 % CI , 0.97 to 1.55 ; P = .09 ) , and median OS was 14.8 v 12.2 months ( HR , 0.91 ; 95 % CI , 0.68 to 1.22 ; P = .53 ) , respectively . In a subset analysis of EGFR wild-type tumors , PFS  for erlotinib versus docetaxel was 1.3 v 2.9 months ( HR , 1.45 ; 95 % CI , 1.09 to 1.94 ; P = .01 ) , and OS was 9.0 v 10.1 months ( HR , 0.98 ; 95 % CI , 0.69 to 1.39 ; P = .91 ) , respectively . CONCLUSION Erlotinib failed to show an improvement in PFS or OS compared with docetaxel in an EGFR-unselected patient population PURPOSE This phase III trial aim ed to confirm the superiority of weekly docetaxel and cisplatin over docetaxel monotherapy in elderly patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Chemotherapy-naïve patients with stage III , stage IV , or recurrent NSCLC age ≥ 70 years with a performance status of 0 or 1 who were considered unsuitable for bolus cisplatin administration were r and omly assigned to receive docetaxel 60 mg/m(2 ) on day 1 , every 3 weeks , or docetaxel 20 mg/m(2 ) plus cisplatin 25 mg/m(2 ) on days 1 , 8 , and 15 , every 4 weeks . The primary end point was overall survival ( OS ) . RESULTS In the first interim analysis , OS of the doublet arm was inferior to that of the monotherapy arm ( hazard ratio [ HR ] , 1.56 ; 95 % CI , 0.98 to 2.49 ) , and the predictive probability that the doublet arm would be statistically superior to the monotherapy arm on final analysis was 0.996 % , which led to early study termination . In total , 276 patients with a median age of 76 years ( range , 70 to 87 years ) were enrolled . At the up date d analysis , the median survival time was 14.8 months for the monotherapy arm and 13.3 months for the doublet arm ( HR , 1.18 ; 95 % CI , 0.83 to 1.69 ) . The rates of grade ≥ 3 neutropenia and febrile neutropenia were higher in the monotherapy arm , and those of anorexia and hyponatremia were higher in the doublet arm . CONCLUSION This study failed to demonstrate any survival advantage of weekly docetaxel plus cisplatin over docetaxel monotherapy as first-line chemotherapy for advanced NSCLC in elderly patients 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 & Background : The purpose of this study was to evaluate gemcitabine – carboplatin ( GCb ) versus single-agent gemcitabine ( G ) in patients with advanced non-small cell lung cancer ( NSCLC ) and a performance status ( PS ) of 2 . The primary endpoint was clinical benefit . Patients and Methods : Patients were r and omly assigned to either 1250 mg/m2 of G ( arm A ) or 1250 mg/m2 of G plus carboplatin area under the curve of 3 ( arm B ) . Both treatments were given on days 1 and 14 and were repeated every 28 days for up to four cycles . Results : Among the 90 eligible patients ( 47 in arm A and 43 in arm B ) , in arm A , two ( 4 % ) had partial responses ( 95 % CI , 0.52%–14.5 % ) and 10 ( 21 % ) had stable disease ( 95 % CI , 10.7%–35.7 % ) . In arm B , six ( 14 % ) had partial responses ( 95 % CI , 5.3%–27.9 % ) and nine ( 21 % ) had stable disease ( 95 % CI , 10%–36 % ) ( p = 0.14 ) . No significant difference was found in terms of clinical benefit between the two treatment groups after two cycles of treatment or at the end of chemotherapy . Furthermore , no association was found between clinical benefit and response to treatment ( p > 0.05 ) . Median survival was 4.8 months ( 95 % CI , 2.45–7.25 ) for arm A and 6.7 months ( 95 % CI , 2.47–10.8 ) for arm B ( p = 0.49 ) . Neutropenia ( p = 0.007 ) and thrombocytopenia ( p < 0.001 ) were more common in group B. Nevertheless , no significant differences were found in terms of severe toxicities ( p > 0.05 in all cases ) . Conclusion : No significant difference was found in terms of clinical benefit in patients with NSCLC and PS 2 who received single-agent G or GCb . Nevertheless , GCb caused more toxicity , particularly neutropenia and thrombocytopenia INTRODUCTION The epidermal growth factor receptor ( EGFR ) tyrosine-kinase inhibitor erlotinib is associated with survival benefits in patients with EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) . This phase II , single-arm study examined the efficacy and safety of first-line erlotinib in Japanese patients with EGFR mutation-positive NSCLC . METHODS Eligible patients  received erlotinib 150 mg/day until disease progression or unacceptable toxicity . The primary endpoints were progression-free survival ( PFS ) and safety . RESULTS A high degree of concordance was observed between different mutation testing method ologies , suggesting feasibility of early , rapid detection of EGFR mutations . Median PFS was 11.8 months ( 95 % confidence interval [ CI ] : 9.7 - 15.3 ) at data cut-off ( 1 June 2012 ) ( n = 102 ) . Exon 19 deletions seemed to be associated with longer PFS compared with L858R mutations ; T790 M mutations were tentatively linked with shorter PFS . The safety profile was as expected : rash ( any grade ; 83 % ) and diarrhea ( any grade ; 81 % ) were most common . Six interstitial lung disease (ILD)-like cases were reported , and 5 were confirmed as ILD-like events by the extramural committee . Two patients died of treatment-related pneumonitis ( JAPIC Clinical Trials Information number : Japic CTI-101085 ) . CONCLUSION Erlotinib should be considered for first-line treatment in this subset of Japanese patients , with close monitoring for ILD-like events RATIONALE Interstitial lung disease ( ILD ) occurs in Japanese patients with non-small cell lung cancer ( NSCLC ) receiving gefitinib .  OBJECTIVES To eluci date risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy .  METHODS In a prospect i ve epidemiologic cohort , 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib ( n = 1,872 treatment periods ) or chemotherapy ( n = 2,551 ) . Patients who developed acute ILD ( n = 122 ) and r and omly selected control subjects ( n = 574 ) entered a case-control study . Adjusted incidence rate ratios were estimated from case-control data by odds ratios ( ORs ) with 95 % confidence intervals ( CIs ) using logistic regression . Crude ( observed ) incidence rates and risks were calculated from cohort data . MEASUREMENTS AND MAIN RESULTS The observed ( unadjusted ) incidence rate over 12 weeks was 2.8 ( 95 % CI , 2.3 - 3.3 ) per 1,000 person-weeks , 4.5 ( 3.5 - 5.4 ) for gefitinib versus 1.7 ( 1.2 - 2.2 ) for chemotherapy ; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0 % ( 3.0 - 5.1 % ) and 2.1 % ( 1.5 - 2.9 % ) , respectively . Adjusted for imbalances in risk factors between treatments , the overall OR for gefitinib versus chemotherapy was 3.2 ( 1.9 - 5.4 ) , elevated chiefly during the first 4 weeks ( 3.8 [ 1.9 - 7.7 ] ) . Other ILD risk factors in both groups included the following : older age , poor World Health Organization performance status , smoking , recent NSCLC diagnosis , reduced normal lung on computed tomography scan , preexisting chronic ILD , concurrent cardiac disease . ILD-related deaths in patients with ILD were 31.6 % ( gefitinib ) versus 27.9 % ( chemotherapy ) ; adjusted OR , 1.05 ( 95 % CI , 0.3 - 3.2 ) . CONCLUSIONS ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy , being higher in the older , smoking patient with preexisting ILD or poor performance status . The risk of developing ILD was higher with gefitinib than chemotherapy , mainly in the first 4 weeks Introduction : Recent studies have demonstrated that first-line treatment with gefitinib , an epidermal growth factor receptor (EFGR)–targeted tyrosine kinase inhibitor , is significantly superior to st and ard chemotherapy for advanced non – small-cell lung cancer ( NSCLC ) harboring EGFR sensitive mutations . Meanwhile , the efficacy of gefitinib therapy among elderly population s diagnosed with EGFR-mutated NSCLC has not yet been eluci date d. The purpose of this study was to investigate the efficacy and feasibility of gefitinib for chemotherapy-naive patients aged 75 or older with NSCLC harboring EGFR mutations ; generally , these patients have no indication for treatment with platinum doublets . Methods : Chemotherapy-naive patients aged 75 years or older with performance status 0 to 1 and advanced NSCLC harboring EGFR mutations , as determined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method , were enrolled . The enrolled patients received 250 mg/day of gefitinib orally . Results : Between January 2008 and May 2009 , 31 patients were enrolled , all of whom were eligible . The median age was 80 ( range , 75–87 ) years . Twenty-five patients ( 81 % ) were women , and 30 patients ( 97 % ) had adenocarcinoma . The overall response rate was 74 % ( 95 % confidence interval , 58%–91 % ) , and the disease control rate was 90 % . The median progression-free survival was 12.3 months . The common adverse events were rash , diarrhea , and liver dysfunction . One treatment-related death because of interstitial lung disease occurred . Conclusions : This is the first study that verified safety and efficacy of first-line treatment with gefitinib in elderly patients having advanced NSCLC with EGFR mutation . Considering its strong antitumor activity and mild toxicity , first-line gefitinib may be preferable to st and ard chemotherapy for this population 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 BACKGROUND Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor ( EGFR ) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib . However , whether gefitinib is better than st and ard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain . METHODS We did an open label , phase 3 study ( WJTOG3405 ) with recruitment between March 31 , 2006 , and June 22 , 2009 , at 36 centres in Japan . 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations ( either the exon 19 deletion or L858R point mutation ) were r and omly assigned , using a minimisation technique , to receive either gefitinib ( 250 mg/day orally ; n=88 ) or cisplatin ( 80 mg/m(2 ) , intravenously ) plus docetaxel ( 60 mg/m(2 ) , intravenously ; n=89 ) , administered every 21 days for three to six cycles . The primary endpoint was progression-free survival . Survival analysis was done with the modified intention-to-treat population . This study is registered with UMIN ( University Hospital Medical Information Network in Japan ) , number 000000539 . FINDINGS Five patients were excluded ( two patients were found to have thyroid and colon cancer after r and omisation , one patient had an exon 18 mutation , one patient had insufficient consent , and one patient showed acute allergic reaction to docetaxel ) . Thus , 172 patients ( 86 in each group ) were included in the survival analyses . The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup , with a median progression-free survival time of 9.2 months ( 95 % CI 8.0 - 13.9 ) versus 6.3 months ( 5.8 - 7.8 ; HR 0.489 , 95 % CI 0.336 - 0.710 , log-rank p<0.0001 ) . Myelosuppression , alopecia , and fatigue were more frequent in the cisplatin plus docetaxel group , but skin toxicity , liver dysfunction , and diarrhoea were more frequent in the gefitinib group . Two patients in the gefitinib group developed interstitial lung disease ( incidence 2.3 % ) , one of whom died . INTERPRETATION Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel . FUNDING West Japan Oncology Group ( WJOG ) : a non-profit organisation supported by unrestricted donations from several pharmaceutical companies BACKGROUND Alectinib , a potent , highly selective , CNS-active inhibitor of anaplastic lymphoma kinase ( ALK ) , showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer . Given those promising results , we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib . METHODS J-ALEX was a r and omised , open-label , phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer , who were chemotherapy-naive or had received one previous chemotherapy regimen , from 41 study sites in Japan . Patients were r and omly assigned ( 1:1 ) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status , treatment line , and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease , unacceptable toxicity , death , or withdrawal . The primary endpoint was progression-free survival assessed by an independent review facility . The efficacy analysis was done in the intention-to-treat population , and safety analyses were done in all patients who received at least one dose of the study drug . The study is ongoing and patient recruitment is closed . This study is registered with the Japan Pharmaceutical Information Center ( number JapicCTI-132316 ) . FINDINGS Between Nov 18 , 2013 , and Aug 4 , 2015 , 207 patients were recruited and assigned to the alectinib ( n=103 ) or crizotinib ( n=104 ) groups . At data cutoff for the second interim analysis , 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group , mostly due to lack of efficacy or adverse events . At the second interim analysis ( data cutoff date Dec 3 , 2015 ) , an independent data monitoring committee determined that the primary endpoint of the study had been met ( hazard ratio 0·34 [ 99·7 % CI 0·17 - 0·71 ] , stratified log-rank p<0·0001 ) and recommended an immediate release of the data . Median progression-free survival had not yet been reached with alectinib ( 95 % CI 20·3-not estimated ) and was 10·2 months ( 8·2 - 12·0 ) with crizotinib  . Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib ( 54 [ 52 % ] of 104 ) than alectinib ( 27 [ 26 % ] of 103 ) . Dose interruptions due to adverse events were also more prevalent with crizotinib ( 77 [ 74 % ] of 104 ) than with alectinib ( 30 [ 29 % ] of 103 ) , and more patients receiving crizotinib ( 21 [ 20 % ] ) than alectinib ( nine [ 9 % ] ) discontinued the study drug because of an adverse event . No adverse events with a fatal outcome occurred in either treatment group . INTERPRETATION These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the st and ard of care for the first-line treatment of ALK-positive non-small-cell lung cancer . The dose of alectinib ( 300 mg twice daily ) used in this study is lower than the approved dose in countries other than Japan ; however , this limitation is being addressed in the ongoing ALEX study . FUNDING Chugai Pharmaceutical Co , PURPOSE This multicenter phase II study was undertaken to investigate the efficacy and feasibility of gefitinib for patients with advanced non-small-cell lung cancer ( NSCLC ) harboring epidermal growth factor receptor ( EGFR ) mutations without indication for chemotherapy as a result of poor performance status ( PS ) . PATIENTS AND METHODS  Chemotherapy-naïve patients with poor PS ( patients 20 to 74 years of age with Eastern Cooperative Oncology Group PS 3 to 4 , 75 to 79 years of age with PS 2 to 4 , and > or= 80 years of age with PS 1 to 4 ) who had EGFR mutations examined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method were enrolled and received gefitinib ( 250 mg/d ) alone . RESULTS Between February 2006 and May 2007 , 30 patients with NSCLC and poor PS , including 22 patients with PS 3 to 4 , were enrolled . The overall response rate was 66 % ( 90 % CI , 51 % to 80 % ) , and the disease control rate was 90 % . PS improvement rate was 79 % ( P < .00005 ) ; in particular , 68 % of the 22 patients improved from > or= PS 3 at baseline to < or= PS 1 . The median progression-free survival , median survival time , and 1-year survival rate were 6.5 months , 17.8 months , and 63 % , respectively . No treatment-related deaths were observed . CONCLUSION This is the first report indicating that EGFR mutation-positive patients with extremely poor PS benefit from first-line gefitinib . Because there previously has been no st and ard treatment for these patients with short life expectancy other than best supportive care , examination of EGFR mutations as a biomarker is recommended in this patient population BACKGROUND Dacomitinib is a second-generation , irreversible EGFR tyrosine kinase inhibitor . We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer ( NSCLC ) . METHODS In this international , multicentre , r and omised , open-label , phase 3 study ( ARCHER 1050 ) , we enrolled adults ( aged ≥18 years or ≥20 years in Japan and South Korea ) with newly diagnosed advanced NSCLC and one EGFR mutation ( exon 19 deletion or Leu858Arg ) at 71 academic medical centres and university hospitals in seven countries or special administrative regions . We r and omly assigned participants ( 1:1 ) to receive oral dacomitinib 45 mg/day ( in 28-day cycles ) or oral gefitinib 250 mg/day ( in 28-day cycles ) until disease progression or another discontinuation criterion was met . R and omisation , stratified by race and EGFR mutation type , was done with a computer-generated r and om code assigned by a central interactive web response system . The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population . Safety was assessed in all patients who received at least one dose of study treatment . This study is registered with Clinical Trials.gov , number NCT01774721 , and is ongoing but no longer recruiting patients . FINDINGS Between May 9 , 2013 , and March 20 , 2015 , 452 eligible patients were r and omly assigned to receive dacomitinib ( n=227 ) or gefitinib ( n=225 ) . Median duration of follow-up for progression-free survival was 22·1 months ( 95 % CI 20·3 - 23·9 ) . Median progression-free survival according to masked independent review was 14·7 months ( 95 % CI 11·1 - 16·6 ) in the dacomitinib group and 9·2 months ( 9·1 - 11·0 ) in the gefitinib group ( hazard ratio 0·59 , 95 % CI 0·47 - 0·74 ; p<0·0001 ) . The most common grade 3 - 4 adverse events were dermatitis acneiform ( 31 [ 14 % ] of 227 patients given dacomitinib vs none of 224 patients given gefitinib ) , diarrhoea ( 19 [ 8 % ] vs two [ 1 % ] ) , and raised alanine aminotransferase levels ( two [ 1 % ] vs 19 [ 8 % ] ) . Treatment-related serious adverse events were reported in 21 ( 9 % ) patients given dacomitinib and in ten ( 4 % ) patients given gefitinib . Two treatment-related deaths occurred in the dacomitinib group ( one related to untreated diarrhoea and one to untreated cholelithases/liver disease ) and one in the gefitinib group ( related to sigmoid colon diverticulitis/rupture complicated by pneumonia ) . INTERPRETATION Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population . FUNDING SFJ Pharmaceuticals Group and Pfizer BACKGROUND Ceritinib is a next-generation anaplastic lymphoma kinase ( ALK ) inhibitor , which has shown robust anti-tumour efficacy , along with intracranial activity , in patients with ALK-rearranged non-small-cell lung cancer . In phase 1 and 2 studies , ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy ( mostly multiple lines ) . In this study , we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy . METHODS In this r and omised , controlled , open-label , phase 3 trial , we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer ( with at least one measurable lesion ) who had received previous chemotherapy ( one or two lines , including a platinum doublet ) and crizotinib and had subsequent disease progression , from 99 centres across 20 countries . Other inclusion criteria were a WHO performance status of 0 - 2 , adequate organ function and laboratory test results , a life expectancy of at least 12 weeks , and having recovered from previous anticancer treatment-related toxicities . We r and omly allocated patients ( 1:1 ; with blocking [ block size of four ] ; stratified by WHO performance status [ 0 vs 1 - 2 ] and presence or absence of brain metastases ) to oral ceritinib 750 mg per day fasted ( in 21 day treatment cycles ) or chemotherapy ( intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [ investigator choice ] , every 21 days ) . Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group . The primary endpoint was progression-free survival , assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population , assessed every 6 weeks until month 18 and every 9 weeks thereafter . This trial is registered with Clinical Trials.gov , number NCT01828112 , and is ongoing but no longer recruiting patients . FINDINGS Between June 28 , 2013 , and Nov 2 , 2015 , we r and omly allocated 231 patients ; 115 ( 50 % ) to ceritinib and 116 ( 50 % ) to chemotherapy ( 40 [ 34 % ] to pemetrexed , 73 [ 63 % ] to docetaxel , and three [ 3 % ] discontinued before receiving treatment ) . Median follow-up was 16·5 months ( IQR 11·5 - 21·4 ) . Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy ( 5·4 months [ 95 % CI 4·1 - 6·9 ] for ceritinib vs 1·6 months [ 1·4 - 2·8 ] for chemotherapy ; hazard ratio 0·49 [ 0·36 - 0·67 ] ; p<0·0001 ) . Serious adverse events were reported in 49 ( 43 % ) of 115 patients in the ceritinib group and 36 ( 32 % ) of 113 in the chemotherapy group . Treatment-related serious adverse events were similar between groups ( 13 [ 11 % ] in the ceritinib group vs 12 [ 11 % ] in the chemotherapy group ) . The most frequent grade 3 - 4 adverse events in the ceritinib group were increased alanine aminotransferase concentration ( 24 [ 21 % ] of 115 vs two [ 2 % ] of 113 in the chemotherapy group ) , increased γ glutamyltransferase concentration ( 24 [ 21 % ] vs one [ 1 % ] ) , and increased aspartate aminotransferase concentration ( 16 [ 14 % ] vs one [ 1 % ] in the chemotherapy group ) . Six ( 5 % ) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight ( 7 % ) of 116 in the chemotherapy group . 15 ( 13 % ) of 115 patients in the ceritinib group and five ( 4 % ) of 113 in the chemotherapy group died during the treatment period ( from the day of the first dose of study treatment to 30 days after the final dose ) . 13 ( 87 % ) of the 15 patients who died in the ceritinib group died because of disease progression and two ( 13 % ) died because of an adverse event ( one [ 7 % ] cerebrovascular accident and one [ 7 % ] respiratory failure ) ; neither of these deaths were considered by the investigator to be treatment related . The five ( 4 % ) deaths in the chemotherapy group were all due to disease progression . INTERPRETATION These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib , and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population . FUNDING Novartis Pharmaceuticals Corporation Summary Background Many patients with advanced non-small-cell lung cancer ( NSCLC ) receive only active supportive care because of poor performance status or presence of several comorbidities . We investigated whether erlotinib improves clinical outcome in these patients . Methods TOPICAL was a double-blind , r and omised , placebo-controlled , phase 3 trial , done at 78 centres in the UK . Eligibility criteria were newly diagnosed , pathologically confirmed NSCLC ; stage IIIb or IV ; chemotherapy naive ; no symptomatic brain metastases ; deemed unsuitable for chemotherapy because of poor ( ≥2 ) Eastern Cooperative Oncology Group performance status or presence of several comorbidities , or both ; and estimated life expectancy of at least 8 weeks . Patients were r and omly assigned ( by phone call , in a 1:1 ratio , stratified by disease stage , performance status , smoking history , and centre , block size 10 ) to receive oral placebo or erlotinib ( 150 mg per day ) until disease progression or unacceptable toxicity . Investigators , clinicians , and patients were masked to assignment . The primary endpoint was overall survival . Analyses were by intention to treat , and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment . This study is registered , number IS RCT N 77383050 . Findings Between April 14 , 2005 , and April 1 , 2009 , we r and omly assigned 350 patients to receive erlotinib and 320 to receive placebo . We followed up patients until March 31 , 2011 . 657 patients died ; median overall survival did not differ between groups ( erlotinib , 3·7 months , 95 % CI 3·2–4·2 , vs placebo , 3·6 months , 3·2–3·9 ; unadjusted hazard ratio [ HR ] 0·94 , 95 % CI 0·81–1·10 , p=0·46 ) . 59 % ( 178 of 302 ) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash , which was the only independent factor associated with overall survival . Patients with first-cycle rash had better overall survival ( HR 0·76 , 95 % CI 0·63–0·92 , p=0·0058 ) , compared with placebo . Compared with  placebo , overall survival seemed to be worse in the group that did not develop first-cycle rash ( 1·30 , 1·05–1·61 , p=0·017 ) . Grade 3 or 4 diarrhoea was more common with erlotinib than placebo ( 8 % [ 28 of 334 ] vs 1 % [ four of 313 ] , p=0·0001 ) , as was high- grade rash ( 23 % [ 79 of 334 ] vs 2 % [ five of 313 ] , p<0·0001 ) ; other adverse events were much the same between groups . Interpretation Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib . Patients who develop a first-cycle rash should continue to receive erlotinib , whereas those who do not have a rash after 28 days should discontinue erlotinib , because of the possibility of decreased survival . Funding Cancer Research UK , Roche OBJECTIVES Ramucirumab plus docetaxel prolongs survival in patients with non-small cell lung cancer ( NSCLC ) with disease progression after platinum-based therapy . This phase II , double-blind , r and omized , placebo-controlled study assessed efficacy and safety of second-line ramucirumab-docetaxel in Japanese patients with NSCLC . MATERIAL S AND METHODS Patients with NSCLC with progression after platinum-based therapy ( 28 Japanese sites ; 19 December , 2012 to 22 May , 2015 ) were r and omized ( computer-generated sequence ) to ramucirumab 10mg/kg or placebo , followed by docetaxel 60mg/m(2 ) ( Day 1 , 21-day cycle ) . Prior epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor ( TKI ) monotherapy was prohibited in the primary population , but EGFR mutation-positive NSCLC patients who were treated with EGFR-TKI were enrolled as a separate exploratory population . Primary endpoint was progression-free survival ( PFS ) ; secondary outcomes included overall survival , tumor response rates , and safety . Investigator tumor assessment s were used for the efficacy endpoints . RESULTS In the primary population ( N=160 r and omized , n=157 treated ) , median ( 95 % CI ) PFS was longer with ramucirumab-docetaxel ( 5.22 [ 3.52 - 6.97 ] months ; n=76 ) than with placebo-docetaxel ( 4.21 [ 2.83 - 5.62 ] months ; n=81 ) ; hazard ratio 0.83 ( 95 % CI 0.59 - 1.16 ) . Median ( 95 % CI ) overall survival was 15.15 ( 12.45 - 26.55 ) months with ramucirumab-docetaxel and 14.65 ( 11.93 - 24.44 ) months with placebo-docetaxel ( hazard ratio [ 95 % CI ] 0.86 [ 0.56 - 1.32 ] ) . Objective response rate ( 28.9 % vs 18.5 % ) and disease control rate ( 78.9 % vs 70.4 % ) were numerically greater with ramucirumab-docetaxel than with placebo-docetaxel . Incidence and severity of most adverse events were similar , but febrile neutropenia was more common with ramucirumab-docetaxel ( 34.2 % ) than with placebo-docetaxel ( 19.8 % ) . CONCLUSION Second-line ramucirumab-docetaxel improved PFS similar to that seen in the REVEL trial with a manageable safety profile in Japanese patients with NSCLC Introduction : Safety of Avastin in Lung ( MO19390 ) was an international , open-label , single-arm study , which assessed the safety and efficacy of first-line bevacizumab ( Avastin ® ) in combination with st and ard chemotherapy in patients ( n = 2212 ) with advanced or recurrent non-small cell lung cancer ( NSCLC ) . A preplanned subgroup analysis was performed to examine these outcomes in elderly patients older than 65 years . Methods : Eligible patients with nonsquamous NSCLC received up to six cycles of bevacizumab ( 7.5 or 15 mg/kg ) plus any st and ard of care chemotherapy . Patients who did not experience disease progression after induction therapy continued bevacizumab therapy until disease progression or unacceptable toxicity . The primary end point was safety ; secondary end points included time to disease progression ( TTP ) and overall survival ( OS ) . Results : Data were evaluated for 623 patients older than 65 years ( mean age 70.6 ) . The majority were Whites ( 86.2 % ) with stage IV disease ( 79.7 % ) and had adenocarcinoma ( 83.5 % ) . The incidence of adverse events ( AEs ) of special interest was similar for elderly and younger patients ( any grade bleeding 38.2 % versus 38.3 % ; any grade hypertension 33.1 % versus 30.6 % ; any grade proteinuria 33.4 % versus 29.3 % ) . Most AEs were grade less than or equal to 2 . Serious AEs were reported in 45.3 and 34.7 % of elderly and younger patients , respectively . Median OS was similar in elderly and younger patients ( 14.6 months in both age groups ) , as were TTP ( 8.2 versus 7.6 months ) , response rate ( 49.3 % versus 52.4 % ) , and disease control rate ( 89.3 % versus 88.4 % ) . Similar results were seen in a post hoc comparison of the older than 70 years and 70 years or younger subgroups : TTP was 8.6 months versus 7.7 months , respectively ; OS was 14.6 months in both subgroups ; response rate was 49 % and 52 % , respectively ; incidence of AEs of special interest was comparable . Conclusion : Patients older than 65 years with nonsquamous NSCLC derive a similar clinical benefit from first-line bevacizumab-based therapy as their younger counterparts and do not experience increased toxicity BACKGROUND Afatinib-an oral irreversible ErbB family blocker-improves progression-free survival compared with pemetrexed and cisplatin for first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer ( NSCLC ) . We compared afatinib with gemcitabine and cisplatin-a chemotherapy regimen widely used in Asia-for first-line treatment of Asian patients with EGFR mutation-positive advanced NSCLC . METHODS This open-label , r and omised phase 3 trial was done at 36 centres in China , Thail and , and South Korea . After central testing for EGFR mutations , treatment-naive patients ( stage IIIB or IV cancer [ American Joint Committee on Cancer version 6 ] , performance status 0 - 1 ) were r and omly assigned ( 2:1 ) to receive either oral afatinib ( 40 mg per day ) or intravenous gemcitabine 1000 mg/m(2 ) on day 1 and day 8 plus cisplatin 75 mg/m(2 ) on day 1 of a 3-week schedule for up to six cycles . R and omisation was done central ly with a r and om number-generating system and an interactive internet and voice-response system . R and omisation was stratified by EGFR mutation ( Leu858Arg , exon 19 deletions , or other ; block size three ) . Clinicians and patients were not masked to treatment assignment , but the independent central imaging review group were . Treatment continued until disease progression , intolerable toxic effects , or withdrawal of consent . The primary endpoint was progression-free survival assessed by independent central review ( intention-to-treat population ) . This study is registered with Clinical Trials.gov , NCT01121393 . FINDINGS 910 patients were screened and 364 were r and omly assigned ( 242 to afatinib , 122 to gemcitabine and cisplatin ) . Median progression-free survival was significantly longer in the afatinib group ( 11·0 months , 95 % CI 9·7 - 13·7 ) than in the gemcitabine and cisplatin group ( 5·6 months , 5·1 - 6·7 ; hazard ratio 0·28 , 95 % CI 0·20 - 0·39 ; p<0·0001 ) . The most common treatment-related grade 3 or 4 adverse events in the afatinib group were rash or acne ( 35 [ 14·6 % ] of 239 patients ) , diarrhoea ( 13 [ 5·4 % ] ) , and stomatitis or mucositis ( 13 [ 5·4 % ] ) , compared with neutropenia ( 30 [ 26·5 % ] of 113 patients ) , vomiting ( 22 [ 19·5 % ] ) , and leucopenia ( 17 [ 15·0 % ] ) in the gemcitabine and cisplatin group . Treatment-related serious adverse events occurred in 15 ( 6·3 % ) patients in the afatinib group and nine ( 8·0 % ) patients in the gemcitabine and cisplatin group . INTERPRETATION First-line afatinib significantly improves progression-free survival with a tolerable and manageable safety profile in Asian patients with EGFR mutation-positive advanced lung NSCLC . Afatinib should be considered as a first-line treatment option for this patient population . FUNDING Boehringer Ingelheim 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 PURPOSE To study the prognostic value for overall survival of baseline assessment of functional status , comorbidity , and quality of life ( QoL ) in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy .  PATIENTS AND METHODS Data from 566 patients enrolled onto the phase III r and omized Multicenter Italian Lung Cancer in the Elderly Study ( MILES ) study were analyzed . Functional status was measured as activities of daily living ( ADL ) and instrumental ADL ( IADL ) . The presence of comorbidity was assessed with a checklist of 33 items ; items 29 and 30 of the European Organisation for Research and Treatment of Cancer ( EORTC ) core question naire QLQ-C30 ( EORTC QLQ-C30 ) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency . For IADL and QoL , three categories were defined using first and third quartiles as cut points . Comorbidity was summarized using the Charlson scale . Analysis was performed by Cox model , and stratified by treatment arm . RESULTS Better values of baseline QoL ( P = .0003 ) and IADL ( P = .04 ) were significantly associated with better prognosis , whereas ADL ( P = .44 ) and Charlson score ( P = .66 ) had no prognostic value . Performance status 2 ( P = .006 ) and a higher number of metastatic sites ( P = .02 ) also predicted shorter overall survival . CONCLUSIONS Pretreatment global QoL and IADL scores , but not ADL and comorbidity , have significant prognostic value for survival of elderly patients with advanced non-small-cell lung cancer who were treated with chemotherapy .  Using these scores in clinical practice might improve prognostic prediction for treatment planning BACKGROUND The combination of nedaplatin , a cisplatin derivative , and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1 - 2 study . We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival . METHODS We did a r and omised , open-label , phase 3 study at 53 institutions in Japan . Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence , age 20 - 74 years , Eastern Cooperative Oncology Group performance status of 0 - 1 , no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy , and adequate organ function . Patients were r and omly assigned ( 1:1 ) to 100 mg/m(2 ) nedaplatin and 60 mg/m(2 ) docetaxel intravenously , or 80 mg/m(2 ) cisplatin and 60 mg/m(2 ) docetaxel , every 3 weeks for four to six cycles ( at the treating oncologist 's discretion ) . R and omisation was done central ly at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage ( IIIB/IV or postoperative recurrent ) , sex , and institution . The primary endpoint was overall survival in the modified intention-to-treat population ( ie , all patients who were r and omly assigned and met the inclusion criteria ) . Safety analyses were done in all r and omly assigned patients who received at least one dose of the study regimen . This trial is registered with the UMIN Clinical Trials Registry , number UMIN000002015 , and is closed to new participants . FINDINGS Between July 6 , 2009 , and July 26 , 2012 , 355 patients were r and omly assigned . 349 patients were included in the modified intention-to-treat analysis ( 177 in the nedaplatin group and 172 in the cisplatin group ) . Overall survival was significantly longer in the nedaplatin group ( median 13·6 months , 95 % CI 11·6 - 15·6 ) than in the cisplatin group ( 11·4 months,10·2 - 12·2 ; hazard ratio 0·81 , 95 % CI 0·65 - 1·02 ; p=0·037 , one-sided stratified log-rank test ) . Grade 3 or worse nausea ( seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group ) , fatigue ( six vs 20 ) , hyponatraemia ( 24 vs 53 ) , and hypokalaemia ( four vs 15 ) were more frequent in the cisplatin group than in the nedaplatin group , whereas grade 3 or worse leucopenia ( 98 vs 77 ) , neutropenia ( 146 vs 123 ) , and thrombocytopenia ( 16 vs none ) were more frequent in the nedaplatin group than in the cisplatin group . Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups , respectively . INTERPRETATION Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel , and the regimens had different safety profiles . Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer . FUNDING West Japan Oncology Group and Sanofi PURPOSE Appropriate therapy for Eastern Cooperative Oncology Group ( ECOG ) performance status ( PS ) -2 patients with advanced non-small-cell lung cancer ( NSCLC ) remains challenging . PS-2 patients on ECOG 1594 had a median survival ( MS ) of only 4.1 months and 1-year overall survival ( OS ) of 19 % . Three percent had grade 5 toxicity . PATIENTS AND METHODS ECOG 1599 , the first PS 2-specific , US cooperative group trial for treatment-naïve advanced NSCLC , r and omly assigned patients to dose-attenuated carboplatin/paclitaxel ( the least toxic regimen in ECOG 1594 ) or gemcitabine/cisplatin ( which yielded an MS of 7.9 months in PS-2 patients ) . Patients received either carboplatin ( area under the concentration-time curve , 6 ) and paclitaxel 200 mg/m2 every 3 weeks ( CbP ) or gemcitabine 1 g/m2 days 1 and 8 and cisplatin 60 mg/m2 day 1 every 3 weeks ( CG ) . RESULTS One hundred three patients were enrolled ; 100 proved eligible . Median age was 66 years ; 46 % had at least 5 % weight loss ; 88 % had stage IV or recurrent disease . Median number of cycles administered was three per arm . CbP featured more grade 3 neutropathy ( 10 % v 0 % ) and more grade > or = 3 neutropenia ( 59 % v 33 % ) , whereas CG yielded more grade 3 thrombocytopenia ( 33 % v 14 % ) , more grade 3 fatigue ( 22 % v 14 % ) , and more grade > or = 1 creatinine elevations ( 43 % v 6 % ) . One grade 5 toxicity , confined to the CbP arm , occurred . Response rate , time to progression , MS , and 1-year OS rates for CG and CbP , were 23 % , 4.8 months , 6.9 months , and 25 % , and 14 % , 4.2 months , 6.2 months , and 19 % , respectively . CONCLUSION Platinum-based combination chemotherapy for PS-2 patients with NSCLC is feasible with acceptable toxicity , but survival in these patients remains inferior to that of PS-0 to -1 patients PURPOSE To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer ( NSCLC ) previously treated with chemotherapy . PATIENTS AND METHODS Eligible patients had a performance status 0 to 2 , previous treatment with one prior chemotherapy regimen for advanced NSCLC , and adequate organ function . Patients received pemetrexed 500 mg/m(2 ) intravenously ( i.v . ) day 1 with vitamin B(12 ) , folic acid , and dexamethasone or docetaxel 75 mg/m(2 ) i.v . day 1 with dexamethasone every 21 days . The primary end point was overall survival . RESULTS Five hundred seventy-one patients were r and omly assigned . Overall response rates were 9.1 % and 8.8 % ( analysis of variance P = .105 ) for pemetrexed and docetaxel , respectively . Median progression-free survival was 2.9 months for each arm , and median survival time was 8.3 versus 7.9 months ( P = not significant ) for pemetrexed and docetaxel , respectively . The 1-year survival rate for each arm was 29.7 % . Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia ( 40.2 % v 5.3 % ; P < .001 ) , febrile neutropenia ( 12.7 % v 1.9 % ; P < .001 ) , neutropenia with infections ( 3.3 % v 0.0 % ; P = .004 ) , hospitalizations for neutropenic fever ( 13.4 % v 1.5 % ; P < .001 ) , hospitalizations due to other drug related adverse events ( 10.5 % v 6.4 % ; P = .092 ) , use of granulocyte colony-stimulating factor support ( 19.2 % v 2.6 % , P < .001 ) and all grade alopecia ( 37.7 % v 6.4 % ; P < .001 ) compared with patients receiving pemetrexed . CONCLUSION Treatment with pemetrexed result ed in clinical ly equivalent efficacy outcomes , but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a st and ard treatment option for second-line NSCLC when available PURPOSE To compare single-agent pemetrexed ( P ) versus the combination of carboplatin and pemetrexed ( CP ) in first-line therapy for patients with advanced non-small-cell lung cancer ( NSCLC ) with an Eastern Cooperative Oncology Group ( ECOG ) performance status ( PS ) of 2 . PATIENTS AND METHODS In a multicenter phase III r and omized trial , patients with advanced NSCLC , ECOG PS of 2 , any histology at first and later amended to nonsquamous only , no prior chemotherapy , and adequate organ function were r and omly assigned to P alone ( 500 mg/m(2 ) ) or CP ( area under the curve of 5 and 500 mg/m(2 ) , respectively ) administered every 3 weeks for a total of four cycles . The primary end point was overall survival ( OS ) . RESULTS A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011 . The response rates were 10.3 % for P and 23.8 % for CP ( P = .032 ) . In the intent-to-treat population , the median PFS was 2.8 months for P and 5.8 months for CP ( hazard ratio [ HR ] , 0.46 ; 95 % CI , 0.35 to 0.63 ; P < .001 ) , and the median OS was 5.3 months for P and 9.3 months for CP ( HR , 0.62 ; 95 % CI , 0.46 to 0.83 ; P = .001 ) . One-year survival rates were 21.9 % and 40.1 % , respectively . Similar results were seen when patients with squamous disease were excluded from the analysis . Anemia ( grade 3 , 3.9 % ; grade 4 , 11.7 % ) and neutropenia ( grade 3 , 1 % ; grade 4 , 6.8 % ) were more frequent with CP . There were four treatment-related deaths in the CP arm . CONCLUSION Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2 PURPOSE Docetaxel has shown activity in elderly patients with advanced non-small-cell lung cancer ( NSCLC ) . This r and omized phase III trial evaluated the efficacy and safety of docetaxel versus vinorelbine ( the current st and ard treatment ) in elderly patients . PATIENTS AND METHODS Chemotherapy-naïve patients age 70 years or older with stage IIIB/IV NSCLC and performance status 2 or lower were eligible . Patients r and omly received docetaxel 60 mg/m2 ( day 1 ) or vinorelbine 25 mg/m2 ( days 1 and 8) every 21 days for four cycles . The primary end point was overall survival . Overall disease-related symptom improvement was assessed using an eight-item question naire . RESULTS In total , 182 patients were enrolled . Median age was 76 years ( range , 70 years to 86 years ) . There was no statistical difference in median overall survival with docetaxel versus vinorelbine ( 14.3 months v 9.9 months ; hazard ratio , 0.780 ; 95 % CI , 0.561 to 1.085 ; P = .138 ) . There was a significant difference in median progression-free survival ( 5.5 months v 3.1 months ; P < .001 ) . Response rates were also significantly improved with docetaxel versus vinorelbine ( 22.7 % v 9.9 % ; P = .019 ) . The most common grade 3 to 4 toxicities were neutropenia ( 82.9 % for docetaxel ; 69.2 % for vinorelbine ; P = .031 ) and leukopenia ( 58.0 % for docetaxel ; 51.7 % for vinorelbine ) . Other toxicities were mild and generally well tolerated . Docetaxel improved overall disease-related symptoms over vinorelbine ( odds ratio , 1.86 ; 95 % CI , 1.09 to 3.20 ) . CONCLUSION Docetaxel improved progression-free survival , response rate , and disease-related symptoms versus vinorelbine . Overall survival was not statistically significantly improved at this time . Docetaxel monotherapy may be considered as an option in the st and ard treatment of elderly patients with advanced NSCLC BACKGROUND Vinorelbine , a semisynthetic vinca alkaloid , represents a well-tolerated treatment for elderly patients with advanced non-small-cell lung cancer ( NSCLC ) . We explored the quality of life ( QoL ) of such patients in a multicenter r and omized trial that compared vinorelbine treatment with supportive care alone . METHODS Eligible patients were 70 years of age or older , had stage IV or IIIB NSCLC that was ineligible for radiotherapy , and had a performance status of 0 - 2 ( a status of fully active to a status of capable of all self-care but unable to work ) .  Vinorelbine was given intravenously on days 1 and 8 of a 21-day treatment cycle , for a total of six cycles . QoL was evaluated with European Organization for Research and Treatment of Cancer question naires QLQ-C30 and QLQ-LC13 , and the QoL data were analyzed by fitting a linear mixed model for each QoL scale . Survival curves were plotted and were compared with the Mantel-Haenszel test . Relative hazards of death and 95 % confidence intervals ( CIs ) were estimated by the Cox model . RESULTS Investigators , blinded to the results , stopped the trial early because of a low enrollment rate . ( From April 1996 to November 1997 , 191 of the 350 targeted patients were r and omly assigned . ) Data from 161 patients have been analyzed . Vinorelbine-treated patients scored better than control patients on QoL functioning scales , and they reported fewer lung cancer-related symptoms but reported worse toxicity-related symptoms . There was a statistically significant ( two-sided P = .03 ) survival advantage for patients receiving vinorelbine ; median survival increased from 21 to 28 weeks in the vinorelbine-treated group . The relative hazard of death for vinorelbine-treated patients was 0.65 ( 95 % CI = 0.45 - 0.93 ) . CONCLUSION Vinorelbine improves survival of elderly patients with advanced NSCLC and possibly improves overall PURPOSE Severe ( grade > or= 3 ) pulmonary hemorrhage ( PH ) in advanced non-small-cell lung cancer was observed in two prospect i ve , r and omized , phase II ( N = 99 ) and phase III ( N = 878 ) trials of bevacizumab plus carboplatin and paclitaxel . Retrospective case-control and cohort analyses were conducted to identify associated radiographic and clinical risk factors for PH . PATIENTS AND METHODS Six patients with PH from the phase II trial , 15 potential PH patients with hemorrhage at any site from the phase III trial , and their matched controls were evaluated with review of baseline and on-treatment radiographs by an independent radiology facility , blinded to patient/control status . Patients with severe ( grade > or= 3 ) PH from each trial were matched with up to three controls based on sex , age group , histology ( phase II ) , or sex and age group ( phase III ) . RESULTS Seven PH patients in the phase III trial were identified as severe PH . Six of the patients were early onset ( occurred < 150 days of initiating bevacizumab ) and one was late onset . Baseline tumor cavitation , not tumor location , was identified as the only potential risk factor for patients with early onset . Combined analysis of severe PH patients from the phase II and phase III trials ( n = 13 ) , compared with their pooled matched controls ( n = 42 ) , did not identify any additional baseline radiographic or clinical variables associated with PH . CONCLUSION PH was an uncommon event . Based on these analyses , baseline tumor cavitation may be a potential risk factor for PH . No other baseline clinical variables were predictive for PH although the number of events was small PURPOSE Fit elderly patients with advanced non-small-cell lung cancer ( NSCLC ) benefit from platinum-based , two-drug chemotherapy . Bevacizumab ( B ) in combination with carboplatin ( C ) and paclitaxel ( P ) improves survival for advanced , nonsquamous NSCLC , as evidence d in Eastern Cooperative Oncology Group ( ECOG ) 4599 . We conducted a subset analysis of ECOG 4599 to determine the outcome for elderly patients . PATIENTS AND METHODS ECOG 4599 r and omly assigned patients with advanced nonsquamous NSCLC to PC or to PCB .  We analyzed outcome in patients who were at least 70 years of age at the time of study entry .  Patient characteristics , efficacy , and toxicity data were compared between PC and PCB for the elderly . Outcomes for elderly and younger patients ( < 70 years ) treated with PCB were also compared . RESULTS Among elderly patients ( n = 224 ; 26 % ) , there was a trend towards higher response rate ( 29 % v 17 % ; P = .067 ) and progression-free survival ( 5.9 v 4.9 months ; P = .063 ) with PCB compared with PC , although overall survival ( PCB = 11.3 months ; PC = 12.1 months ; P = .4 ) was similar . Grade 3 to 5 toxicities occurred in 87 % of elderly patients with PCB versus 61 % with PC ( P < .001 ) , with seven treatment-related deaths in the PCB arm compared with two with PC . Elderly patients had higher incidence of grade 3 to 5 neutropenia , bleeding , and proteinuria with PCB compared with younger patients . CONCLUSION In elderly NSCLC patients , PCB was associated with a higher degree of toxicity , but no obvious improvement in survival compared with PC . Data from this unplanned , retrospective analysis justify prospect i ve evaluation of the therapeutic index of PCB regimen in elderly patients Purpose ARCHER 1050 , a r and omized , open-label , phase III study of dacomitinib versus gefitinib in treatment-naïve patients with advanced non-small-cell lung cancer ( NSCLC ) and activating mutations in EGFR , reported significant improvement in progression-free survival with dacomitinib . The mature overall survival ( OS ) analysis for the intention-to-treat population is presented here . Patients and Methods In this multinational , multicenter study , patients age 18 years or older ( ≥ 20 years in Japan and Korea ) who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and newly diagnosed NSCLC with activating mutations in EGFR ( exon 19 deletion or exon 21 L858R ) were enrolled and r and omly assigned in a 1:1 manner to dacomitinib ( n = 227 ) or gefitinib ( n = 225 ) . R and om assignment was stratified by race ( Japanese , Chinese , other East Asian , or non-Asian ) and EGFR mutation type . The final OS analysis was conducted with a data cutoff date of February 17 , 2017 ; at that time 220 deaths ( 48.7 % ) were observed . Results During a median follow-up time of 31.3 months , 103 ( 45.4 % ) and 117 ( 52.0 % ) deaths occurred in the dacomitinib and gefitinib arms , respectively . The estimated hazard ratio for OS was 0.760 ( 95 % CI , 0.582 to 0.993 ; two-sided P = .044 ) . The median OS was 34.1 months with dacomitinib versus 26.8 months with gefitinib . The OS probabilities at 30 months were 56.2 % and 46.3 % with dacomitinib and gefitinib , respectively . Preliminary subgroup analyses for OS that are based on baseline characteristics were consistent with the primary OS analysis . Conclusion In patients with advanced NSCLC and EGFR activating mutations  , dacomitinib is the first second-generation epidermal growth factor receptor tyrosine kinase inhibitor ( TKI ) to show significant improvement in OS in a phase III r and omized study compared with a st and ard-of-care TKI . Dacomitinib should be considered one of the st and ard treatment options for these patients BACKGROUND Alectinib -- a highly selective , CNS-active , ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged ( ALK-positive ) non-small-cell lung cancer ( NSCLC ) . We aim ed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib . METHODS We did a phase 2 study at 27 centres in the USA and Canada . We enrolled patients aged 18 years or older with stage IIIB-IV , ALK-positive NSCLC who had progressed after crizotinib . Patients were treated with oral alectinib 600 mg twice daily until progression , death , or withdrawal . The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors , version 1.1 . Response endpoints were assessed in the response-evaluable population ( ie , patients with measurable disease at baseline who received at least one dose of study drug ) , and efficacy and safety analyses were done in the intention-to-treat population ( all enrolled patients ) . This study is registered with Clinical Trials.gov , number NCT01871805 . The study is ongoing and patients are still receiving treatment . FINDINGS Between Sept 4 , 2013 , and Aug 4 , 2014 , 87 patients were enrolled into the study ( intention-to-treat population ) . At the time of the primary analysis ( median follow-up 4·8 months [ IQR 3·3 - 7·1 ] ) , 33 of 69 patients with measurable disease at baseline had a confirmed partial response ; thus , the proportion of patients achieving an objective response by the independent review committee was 48 % ( 95 % CI 36 - 60 ) . Adverse events were predominantly grade 1 or 2 , most commonly constipation ( 31 [ 36 % ] ) , fatigue ( 29 [ 33 % ] ) , myalgia 21 [ 24 % ] ) , and peripheral oedema 20 [ 23 % ] ) . The most common grade 3 and 4 adverse events were changes in laboratory values , including increased blood creatine phosphokinase ( seven [ 8 % ] ) , increased alanine aminotransferase ( five [ 6 % ] ) , and increased aspartate aminotransferase ( four [ 5 % ] ) . Two patients died : one had a haemorrhage ( judged related to study treatment ) , and one had disease progression and a history of stroke ( judged unrelated to treatment ) . INTERPRETATION Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib . Therefore , alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib . FUNDING F Hoffmann-La Roche IMPORTANCE Targeting oncogenic drivers ( genomic alterations critical to cancer development and maintenance ) has transformed the care of patients with lung adenocarcinomas . The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials . OBJECTIVES To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s ) and measure survival . DESIGN , SETTING , AND PARTICIPANTS From 2009 through 2012 , 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers . Information was collected on patients , therapies , and survival . INTERVENTIONS Tumors were tested for 10 oncogenic drivers , and results were used to select matched targeted therapies . MAIN OUTCOMES AND MEASURES Determination of the frequency of oncogenic drivers , the proportion of patients treated with genotype-directed therapy , and survival . RESULTS From 2009 through 2012 , tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes ( patients with full genotyping ) . An oncogenic driver was found in 466 of 733 patients ( 64 % ) . Among these 733 tumors , 182 tumors ( 25 % ) had the KRAS driver ; sensitizing EGFR , 122 ( 17 % ) ; ALK rearrangements , 57 ( 8 % ) ; other EGFR , 29 ( 4 % ) ; 2 or more genes , 24 ( 3 % ) ; ERBB2 ( formerly HER2 ) , 19 ( 3 % ) ; BRAF , 16 ( 2 % ) ; PIK3CA , 6 ( < 1 % ) ; MET amplification , 5 ( < 1 % ) ; NRAS , 5 ( < 1 % ) ; MEK1 , 1 ( < 1 % ) ; AKT1 , 0 . Results were used to select a targeted therapy or trial in 275 of 1007 patients ( 28 % ) . The median survival was 3.5 years ( interquartile range [ IQR ] , 1.96 - 7.70 ) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years ( IQR , 0.88 - 6.20 ) for the 318 patients with any oncogenic driver(s ) who did not receive genotype-directed therapy ( propensity score-adjusted hazard ratio , 0.69 [ 95 % CI , 0.53 - 0.9 ] , P = .006 ) . CONCLUSIONS AND RELEVANCE Actionable drivers were detected in 64 % of lung adenocarcinomas . Multiplexed testing aided physicians in selecting therapies . Although individuals with drivers receiving a matched targeted agent lived longer , r and omized trials are required to determine if targeting therapy based on oncogenic drivers improves survival . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01014286 Background Osimertinib is an oral , third‐generation , irreversible epidermal growth factor receptor tyrosine kinase inhibitor ( EGFR‐TKI ) that selectively inhibits both EGFR‐TKI – sensitizing and EGFR T790 M resistance mutations . We compared osimertinib with st and ard EGFR‐TKIs in patients with previously untreated , EGFR mutation – positive advanced non – small‐cell lung cancer ( NSCLC ) . Methods In this double‐blind , phase 3 trial , we r and omly assigned 556 patients with previously untreated , EGFR mutation – positive ( exon 19 deletion or L858R ) advanced NSCLC in a 1:1 ratio to receive either osimertinib ( at a dose of 80 mg once daily ) or a st and ard EGFR‐TKI ( gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily ) . The primary end point was investigator‐assessed progression‐free survival . Results The median progression‐free survival was significantly longer with osimertinib than with st and ard EGFR‐TKIs ( 18.9 months vs. 10.2 months ; hazard ratio for disease progression or death , 0.46 ; 95 % confidence interval [ CI ] , 0.37 to 0.57 ; P<0.001 ) . The objective response rate was similar in the two groups : 80 % with osimertinib and 76 % with st and ard EGFR‐TKIs ( odds ratio , 1.27 ; 95 % CI , 0.85 to 1.90 ; P=0.24 ) . The median duration of response was 17.2 months ( 95 % CI , 13.8 to 22.0 ) with osimertinib versus 8.5 months ( 95 % CI , 7.3 to 9.8 ) with st and ard EGFR‐TKIs . Data on overall survival were immature at the interim analysis ( 25 % maturity ) . The survival rate at 18 months was 83 % ( 95 % CI , 78 to 87 ) with osimertinib and 71 % ( 95 % CI , 65 to 76 ) with st and ard EGFR‐TKIs ( hazard ratio for death , 0.63 ; 95 % CI , 0.45 to 0.88 ; P=0.007 [ nonsignificant in the interim analysis ] ) . Adverse events of grade 3 or higher were less frequent with osimertinib than with st and ard EGFR‐TKIs ( 34 % vs. 45 % ) . Conclusions Osimertinib showed efficacy superior to that of st and ard EGFR‐TKIs in the first‐line treatment of EGFR mutation – positive advanced NSCLC , with a similar safety profile and lower rates of serious adverse events . ( Funded by AstraZeneca ; FLAURA Clinical Trials.gov number , NCT02296125 . BACKGROUND First-line chemotherapy for advanced non-small-cell lung cancer ( NSCLC ) is usually limited to four to six cycles . Maintenance therapy can delay progression and prolong survival . The oral epidermal growth factor receptor ( EGFR ) tyrosine-kinase inhibitor erlotinib has proven efficacy and tolerability in second-line NSCLC . We design ed the phase 3 , placebo-controlled Sequential Tarceva in Unresectable NSCLC ( SATURN ; BO18192 ) study to assess use of erlotinib as maintenance therapy in patients with non-progressive disease following first-line platinum-doublet chemotherapy .  METHODS Between December , 2005 , and May , 2008 , 1949 patients were included in the run-in phase ( four cycles of platinum-based chemotherapy ) . At the end of the run-in phase , 889 patients who did not have progressive disease were entered into the main study , and were r and omly allocated using a 1:1 adaptive r and omisation method through a third-party interactive voice response system to receive erlotinib ( 150 mg/day ; n=438 ) or placebo ( n=451 ) until progression or unacceptable toxicity . Patients were stratified by EGFR immunohistochemistry status , stage , Eastern Cooperative Oncology Group performance status , chemotherapy regimen , smoking history , and region . Co- primary endpoints were progression-free survival ( PFS ) in all analysable patients irrespective of EGFR status , and PFS in patients whose tumours had EGFR protein overexpression , as determined by immunohistochemistry . This study is registered with www . Clinical Trials.gov , number NCT00556712 . FINDINGS 884 patients were analysable for PFS ; 437 in the erlotinib group and 447 in the placebo group . After a median follow-up of 11.4 months for the erlotinib group and 11.5 months for the placebo group , median PFS was significantly longer with erlotinib than with placebo : 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group ( HR 0.71 , 95 % CI 0.62 - 0.82 ; p<0.0001 ) . PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib ( n=307 ) compared with EGFR-positive patients given placebo ( n=311 ; median PFS 12.3 weeks in the erlotinib group vs 11.1 weeks in the placebo group ; HR 0.69 , 0.58 - 0.82 ; p<0.0001 ) . The most common grade 3 or higher adverse events were rash ( 37 [ 9 % ] of 443 patients in the erlotinib group vs none of 445 in the placebo group ) and diarrhoea ( seven [ 2 % ] of 443 patients vs none of 445 ) . Serious adverse events were reported in 47 patients ( 11 % ) on erlotinib compared with 34 patients ( 8 % ) on placebo . The most common serious adverse event was pneumonia ( seven cases [ 2 % ] with erlotinib and four [ < 1 % ] with placebo ) . INTERPRETATION Maintenance therapy with erlotinib for patients with NSCLC is well tolerated and significantly prolongs PFS compared with placebo . First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy . FUNDING F Hoffmann-La Roche 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 Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21 , or both ( ie , common mutations ) . However , a subset of patients ( 10 % ) with mutations in EGFR have tumours that harbour uncommon mutations . There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors . Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations . METHODS In this post-hoc analysis , we used prospect ively collected data from  tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced ( stage IIIb-IV ) lung adenocarcinomas who were given afatinib in a single group phase 2 trial ( LUX-Lung 2 ) , and r and omised phase 3 trials ( LUX-Lung 3 and LUX-Lung 6 ) . Analyses were done in the intention-to-treat population , including all r and omly assigned patients with uncommon EGFR mutations . The type of EGFR mutation ( exon 19 deletion [ del19 ] , Leu858Arg point mutation in exon 21 , or other ) and ethnic origin ( LUX-Lung 3 only ; Asian vs non-Asian ) were pre-specified stratification factors in the r and omised trials . We categorised all uncommon mutations as : point mutations or duplications in exons 18 - 21 ( group 1 ) ; de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations ( group 2 ) ; or exon 20 insertions ( group 3 ) . We also assessed outcomes in patients with the most frequent uncommon mutations , Gly719Xaa , Leu861Gln , and Ser768Ile , alone or in combination with other mutations . Response was established by independent radiological review . These trials are registered with Clinical Trials.gov , numbers NCT00525148 , NCT00949650 , and NCT01121393 . FINDINGS Of 600 patients given afatinib across the three trials , 75 ( 12 % ) patients had uncommon EGFR mutations ( 38 in group 1 , 14 in group 2 , 23 in group 3 ) . 27 ( 71·1 % , 95 % CI 54·1 - 84·6 ) patients in group 1 had objective responses , as did two ( 14·3 % , 1·8 - 42·8 ) in group 2 and two ( 8·7 % , 1·1 - 28·0 ) in group 3 . Median progression-free survival was 10·7 months ( 95 % CI 5·6 - 14·7 ) in group 1 , 2·9 months ( 1·2 - 8·3 ) in group 2 ; and 2·7 months ( 1·8 - 4·2 ) in group 3 . Median overall survival was 19·4 months ( 95 % CI 16·4 - 26·9 ) in group 1 , 14·9 months ( 8·1 - 24·9 ) in group 2 , and 9·2 months ( 4·1 - 14·2 ) in group 3 . For the most frequent uncommon mutations , 14 ( 77·8 % , 95 % CI 52·4 - 93·6 ) patients with Gly719Xaa had an objective response , as did nine ( 56·3 % , 29·9 - 80·2 ) with Leu861Gln , and eight ( 100·0 % , 63·1 - 100·0 ) with Ser768Ile . INTERPRETATION Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations , especially Gly719Xaa , Leu861Gln , and Ser768Ile , but less active in other mutations types . Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations . These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations . FUNDING Boehringer Ingelheim AIMS Retrospective analyses from first-line clinical studies in advanced non-small cell lung cancer ( NSCLC ) have reported conflicting results on progression-free survival ( PFS ) and overall survival benefits with the addition of bevacizumab to chemotherapy in elderly patients . Here we report effectiveness and safety outcomes by age subgroup for patients with NSCLC in the ARIES observational cohort study . MATERIAL S AND METHODS ARIES enrolled patients with advanced non-squamous NSCLC who received first-line bevacizumab-containing treatment per physician 's choice . Kaplan-Meier estimates were used to calculate medians and 95 % confidence intervals for PFS and overall survival for patients aged < 65 , ≥65 , < 75 and ≥75 years . RESULTS In total , 1967 patients receiving first-line treatment with bevacizumab and chemotherapy were enrolled .  The median PFS and overall survival values were 6.4 ( 95 % confidence interval = 6.0 - 6.8 ) and 14.2 ( 95 % confidence interval = 12.7 - 15.2 ) months for patients aged < 65 years , respectively , and 6.8 ( 95 % confidence interval = 6.3 - 7.0 ) and 12.1 ( 95 % confidence interval = 11.4 - 13.1 ) months for patients ≥65 years , respectively . For patients < 75 years , the median PFS and overall survival values were 6.6 ( 95 % confidence interval = 6.3 - 6.9 ) and 13.5 ( 95 % confidence interval = 12.6 - 14.5 ) months , respectively , and 6.6 ( 95 % confidence interval = 5.9 - 7.1 ) and 11.6 ( 95 % confidence interval = 10.0 - 12.5 ) months , respectively , for patients ≥75 years . Incidence proportions of bevacizumab-associated adverse events were generally similar across all age groups . CONCLUSIONS Data from the ARIES study suggest that treatment with bevacizumab in combination with chemotherapy is a viable first-line treatment option for elderly bevacizumab-eligible patients with advanced non-squamous 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
target: We believe that this attempt enables clinicians to choose appropriate treatment easier .
background: According to rapid development of chemotherapy in advanced non-small cell lung cancer ( NSCLC ) , the Japan Lung Cancer Society has been up date d its own guideline annually since 2010 .
  Recently , we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors .
  Thus , the guideline proposes to categorize patients into three entities : ( 1 ) driver oncogene-positive , ( 2 ) PD-L1 ≥ 50 % , and ( 3 ) others .
  Here , we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC , stages IV