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document
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 . BACKGROUND We aimed 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 , randomised , 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 randomly 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 ClinicalTrials.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 .
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Intervention_Pharmacological
Afatinib
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Intervention_Pharmacological
cisplatin-based chemotherapy
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Intervention_Pharmacological
afatinib
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Intervention_Pharmacological
LUX-Lung
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Intervention_Pharmacological
LUX-Lung 6
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Intervention_Pharmacological
afatinib
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Intervention_Pharmacological
chemotherapy ( pemetrexed-cisplatin [ LUX-Lung 3 ]
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Intervention_Pharmacological
gemcitabine-cisplatin [ LUX-Lung 6 ] )
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Outcome_Mortality
overall survival
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Outcome_Mortality
overall survival
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Outcome_Mortality
overall survival
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Outcome_Mortality
overall survival
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Outcome_Mortality
overall survival
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Outcome_Mortality
overall survival
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Outcome_Mortality
overall survival
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Outcome_Adverse-effects
grade 3-4 adverse events
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Outcome_Adverse-effects
rash or acne
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Outcome_Adverse-effects
diarrhoea
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Outcome_Adverse-effects
paronychia
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Outcome_Adverse-effects
stomatitis or mucositis
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Outcome_Adverse-effects
neutropenia
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Outcome_Adverse-effects
fatigue
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Outcome_Adverse-effects
leucopenia
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Outcome_Adverse-effects
grade 3-4 adverse events
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Outcome_Adverse-effects
neutropenia
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Outcome_Adverse-effects
vomiting
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Outcome_Adverse-effects
leucopenia
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Participant_Condition
EGFR mutation-positive lung adenocarcinoma ( LUX-Lung 3
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Participant_Condition
LUX-Lung 6
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Participant_Condition
patients with EGFR mutation-positive lung adenocarcinoma
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Participant_Condition
adenocarcinoma
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Participant_Sample-size
n=345
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Participant_Sample-size
n=364
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Participant_Sample-size
345
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Participant_Condition
patients with EGFR
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Participant_Sample-size
229 patients
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Participant_Sample-size
239 patients
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Participant_Condition
patients with del19 EGFR mutations
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Participant_Condition
patients with Leu858Arg EGFR mutations