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Afatinib as First-line Treatment of Older Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Subgroup Analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 Trials

Open AccessPublished:March 16, 2018DOI:https://doi.org/10.1016/j.cllc.2018.03.009

      Abstract

      Background

      Afatinib is approved in the US, Europe, and several other regions for first-line treatment for epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC).

      Patients and Methods

      Treatment-naive patients with advanced EGFRm+ NSCLC were randomized to afatinib (40 mg/d) versus cisplatin/pemetrexed (LUX-Lung 3 [LL3]) or cisplatin/gemcitabine (LUX-Lung 6 [LL6]), or versus gefitinib (250 mg/d; LUX-Lung 7 [LL7]). We report subgroup analyses according to age, including 65 years or older versus younger than 65 years (preplanned; LL3/LL6) and additional cutoffs up to 75 years and older (exploratory; LL7). Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated.

      Results

      Among the 134 of 345 (39%) and 86 of 364 (24%) patients aged 65 years and older in LL3 and LL6, median PFS was improved with afatinib versus chemotherapy (LL3: hazard ratio [HR], 0.64 [95% confidence interval (CI), 0.39-1.03]; LL6: HR, 0.16 [95% CI, 0.07-0.39]). Afatinib significantly improved OS versus chemotherapy in elderly patients with Del19+ NSCLC in LL3 (HR, 0.39 [95% CI, 0.19-0.80]). Among the 40 of 319 patients (13%) aged 75 years or older in LL7, median PFS (HR, 0.69 [95% CI, 0.33-1.44]) favored afatinib, consistent with the overall population. Afatinib-associated AEs in older patients were consistent with the overall populations.

      Conclusions

      Subgroup analyses of the LL3, LL6, and LL7 trials show that afatinib is an effective and tolerable treatment for patients with EGFRm+ NSCLC, independent of age.

      Keywords

      Introduction

      Lung cancer remains the most common malignancy worldwide, most frequently diagnosed in patients aged 65 to 74 years.
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      First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non–small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study.
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      Overall survival analyses of first-line erlotinib versus chemotherapy in the EURTAC study population controlling for the use of post-study therapy.
      have shown superior progression-free survival (PFS) versus platinum-doublet chemotherapy in patients with EGFR mutation-positive (EGFRm+) NSCLC and is approved in the US, Europe and subsequently other regions. In prespecified analyses of the LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6) trials, afatinib also showed superior overall survival (OS) versus chemotherapy in patients with tumors harboring EGFR Del19 mutations.
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      Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non–small-cell lung cancer (OPTIMAL, CTONG-0802).
      The recent head-to-head randomized trials, LUX-Lung 7 (LL7),
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      Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non–small-cell lung cancer in Asia (IPASS).
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      have shown that afatinib, dacomitinib, and osimertinib are more active than first-generation EGFR TKIs in a first-line setting. Although data from small early-phase studies, retrospective analyses, and subgroup analyses suggest that all approved, and emerging, EGFR TKIs might be similarly effective and well tolerated in older and younger populations,
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      Are EGFR tyrosine kinase inhibitors effective in elderly patients with EGFR-mutated non–small-cell lung cancer?.
      there have been no prospective phase III trials specifically conducted in elderly patients (ie, 65 years or older) in this setting to help drive therapeutic decisions in this subset of patients.
      • Minuti G.
      • D’Incecco A.
      • Cappuzzo F.
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      To evaluate the effect of advancing age on clinical outcomes and tolerability with first-line afatinib in patients with EGFRm+ NSCLC, preplanned subgroup analyses of patients aged years and older and younger than 65 years in LL3 and LL6 were conducted. Additional exploratory analyses on the basis of age cutoffs up to 75 years and older in LL7 were also performed, with a primary focus on the older age subgroup.

      Patients and Methods

      Patients and Study Designs

      Study design and eligibility criteria for the phase III LL3 (NCT00949650) and LL6 (NCT01121393), and phase IIb LL7 (NCT01466660), studies have been published.
      • Sequist L.V.
      • Yang J.C.
      • Yamamoto N.
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      • Park K.
      • Tan E.H.
      • O'Byrne K.
      • et al.
      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.
      • Wu Y.L.
      • Zhou C.
      • Hu C.P.
      • et al.
      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.
      Each study enrolled treatment-naive patients with confirmed EGFRm+ (Del19 or L858R in all 3 trials; uncommon EGFR mutations were also included in LL3/LL6), stage IIIB/IV NSCLC. In LL3/LL6, patients were randomized (2:1) to oral afatinib (40 mg/d) or up to 6 cycles of chemotherapy (LL3: cisplatin/pemetrexed; LL6: cisplatin/gemcitabine; full dosing and schedules previously reported), stratified according to EGFR mutation type (Del19 vs. L858R vs. other “uncommon” mutations) and race (LL3 only; Asian vs. non-Asian). In LL7, patients were randomized (1:1) to afatinib (40 mg/d) or gefitinib (250 mg/d), stratified according to EGFR mutation type (Del19 vs. L858R) and baseline brain metastases (presence vs. absence).
      The primary end point of LL3/LL6 was PFS (independent central review); OS was a key secondary end point. LL7 had 3 co-primary end points: PFS (independent central review), time to treatment failure, and OS. The primary analyses for each of these end points have been published.
      • Sequist L.V.
      • Yang J.C.
      • Yamamoto N.
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      • Park K.
      • Tan E.H.
      • O'Byrne K.
      • et al.
      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.
      • Wu Y.L.
      • Zhou C.
      • Hu C.P.
      • et al.
      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.
      • Paz-Ares L.
      • Tan E.H.
      • O’Byrne K.
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non–small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.
      • Yang J.C.
      • Wu Y.L.
      • Schuler M.
      • et al.
      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.
      All studies were conducted in accordance with the Declaration of Helsinki and guidelines on Good Clinical Practice. Study protocols were approved by local ethics committees at each participating center. All patients provided written informed consent for trial participation.

      Subgroup Analyses

      All treated patients were included in the analyses. In LL3/LL6, analyses on the basis of an age cutoff of younger than 65 years and 65 years of age and older were prespecified; analyses according to age within mutation subgroups were post hoc. Prespecified analyses on the basis of a 65-year old age cutoff were also conducted in LL7 and have been reported.
      • Park K.
      • Tan E.H.
      • O'Byrne K.
      • et al.
      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.
      • Paz-Ares L.
      • Tan E.H.
      • O’Byrne K.
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non–small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.
      Additional exploratory analyses using age cutoffs of younger than 60, younger than 70, 75 years and older, and younger than 75 years were conducted in LL7 and are reported herein, with a focus on the 75 years of age and older subgroup, representing the largest cohort of afatinib-treated patients in any LUX-Lung trial in this older age group (Figure 1). Because of different comparators and randomization schemes for LL3, LL6, and LL7 (Figure 1), combined study analyses for age groups were not conducted; findings from each study are reported separately.
      Figure thumbnail gr1
      Figure 1Patient Disposition by Age Subgroup in the LUX-Lung 3, LUX-Lung 6 and LUX-Lung 7 Trialsa
      Abbreviations: Cis/Gem = cisplatin/gemcitabine; Cis/Pem = cisplatin/pemetrexed; EGFR = epidermal growth factor receptor; NSCLC = non-small-cell lung cancer. aPatient data from the LL3, LL6, and LL7 trials could not be combined in 1 analysis due to different comparators and randomization schemes.
      Data cutoffs for PFS were at the time of primary PFS analysis for each study (LL3: January 11, 2012; LL6: October 29, 2012; LL7: August 21, 2015)
      • Sequist L.V.
      • Yang J.C.
      • Yamamoto N.
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      • Park K.
      • Tan E.H.
      • O'Byrne K.
      • et al.
      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.
      • Wu Y.L.
      • Zhou C.
      • Hu C.P.
      • et al.
      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.
      ; data cutoffs for OS and safety analyses were at the time of primary OS analysis for each study (LL3: November 14, 2013; LL6: December 27, 2013; LL7: April 8, 2016).
      • Paz-Ares L.
      • Tan E.H.
      • O’Byrne K.
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non–small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.
      • Yang J.C.
      • Wu Y.L.
      • Schuler M.
      • et al.
      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.
      Kaplan–Meier estimates were used to construct survival curves and calculate median PFS and OS. A Cox proportional hazards model was used to derive hazard ratios (HRs) and 95% confidence intervals (CIs); treatment groups were compared using a log rank test. Statistical analyses were performed with SAS (version 9.2 or later; SAS Institute Inc).

      Results

      Patients

      Of the 345 and 364 patients randomized in LL3 and LL6, 134 (39%) and 86 (24%), respectively, were aged 65 years or older (Figure 1; see Supplemental Figure 1 in the online version), hereafter described as the “elderly” subgroup. Whereas only 3% to 4% (13 and 12 patients, respectively) in LL3/LL6 were aged 75 years or older, LL7 enrolled the largest cohort of afatinib-treated patients within this age group (13% [n = 40] of the study population; Figure 1; see Supplemental Figure 1 in the online version). Thus, additional exploratory analyses with a focus on this “older” subgroup of LL7 were conducted.
      In each study, baseline demographic and disease characteristics were generally well balanced between treatments within each age subgroup (Table 1). Of note, frequencies of EGFR Del19 versus L858R mutations were similar in the elderly subgroups of LL3 and LL6, whereas a higher frequency of L858R versus Del19 mutation was observed in afatinib-treated patients aged 75 years or older in LL7 (63% vs. 37%, compared with similar frequencies observed in gefitinib-treated patients [52% vs. 48%]). A higher frequency of Del19 versus L858R mutations was observed for the younger subgroup in each study.
      Table 1Baseline Demographic and Disease Characteristics
      CharacteristicLUX-Lung 3LUX-Lung 6LUX-Lung 7
      ≥65 Years<65 Years≥65 Years<65 Years≥75 years<75 years
      Afatinib (n = 90)Cis/Pem (n = 44)Afatinib (n = 140)Cis/Pem (n = 71)Afatinib (n = 66)Cis/Gem (n = 20)Afatinib (n = 176)Cis/Gem (n = 102)Afatinib (n = 19)Gefitinib (n = 21)Afatinib (n = 141)Gefitinib (n = 138)
      Sex, n (%)
       Female56 (62)29 (66)91 (65)48 (68)46 (70)13 (65)109 (62)70 (69)14 (74)14 (67)77 (55)92 (67)
       Male34 (38)15 (34)49 (35)23 (32)20 (30)7 (35)67 (38)32 (31)5 (26)7 (33)64 (45)46 (33)
      Median Age (Range), Years70 (65-86)69 (65-83)56 (28-64)56 (31-64)69 (65-79)68 (65-76)53 (29-64)56 (27-64)79 (75-86)79 (75-89)61 (30-74)62 (32-74)
      Age Category, n (%)
       <75 years81 (90)40 (91)140 (100)71 (100)56 (85)18 (90)176 (100)102 (100)0 (0)0 (0)141 (100)138 (100)
       ≥75 years9 (10)4 (9)0 (0)0 (0)10 (15)2 (10)0 (0)0 (0)19 (100)21 (100)0 (0)0 (0)
      Race/Ethnicity, n (%)
       Asian61 (68)31 (70)105 (75)52 (73)66 (100)20 (100)176 (100)102 (100)9 (47)9 (43)85 (60)79 (57)
       Non-Asian
      Including American Indian/Alaska Native, Black/African American, Hawaiian/Pacific Islander and White.
      29 (32)13 (30)35 (25)19 (27)0 (0)0 (0)0 (0)0 (0)7 (37)9 (43)42 (30)45 (33)
       Missing
      Patients recruited at French sites did not have their race/ethnicity reported.
      0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)3 (16)3 (14)14 (10)14 (10)
      ECOG PS, n (%)
       042 (47)16 (36)50 (36)25 (35)10 (15)4 (20)38 (22)37 (36)3 (16)4 (19)48 (34)43 (31)
       148 (53)28 (64)90 (64)46 (65)
      Includes 1 patient with an ECOG PS of 2.
      56 (85)16 (80)138 (78)65 (64)16 (84)17 (81)93 (66)95 (69)
      Smoking Status, n (%)
       Never56 (62)33 (75)99 (71)48 (68)48 (73)18 (90)133 (76)81 (79)13 (68)14 (67)93 (66)92 (67)
       Former34 (38)10 (23)36 (26)22 (31)14 (21)2 (10)30 (17)11 (11)6 (32)6 (29)42 (30)44 (32)
       Current0 (0)1 (2)5 (4)1 (1)4 (6)0 (0)13 (7)10 (10)0 (0)1 (5)6 (4)2 (1)
      Adenocarcinoma Stage, n (%)
       IIIB11 (12)8 (18)9 (6)9 (13)3 (5)0 (0)13 (7)6 (6)1 (5)2 (10)7 (5)1 (1)
       IV79 (88)36 (82)131 (94)62 (87)63 (95)20 (100)163 (93)96 (94)18 (95)19 (90)134 (95)137 (99)
      Number of Metastatic Sites, n (%)
       03 (3)1 (2)2 (1)1 (1)2 (3)0 (0)3 (2)1 (1)1 (5)2 (10)4 (3)2 (1)
       130 (33)11 (25)30 (21)23 (32)21 (32)7 (35)51 (29)45 (44)7 (37)5 (24)32 (23)31 (22)
       218 (20)12 (27)41 (29)18 (25)24 (36)7 (35)67 (38)29 (28)3 (16)7 (33)47 (33)45 (33)
       ≥339 (43)20 (45)67 (48)29 (41)19 (29)6 (30)55 (31)27 (26)8 (42)7 (33)58 (41)60 (43)
      EGFR Mutation, n (%)
       Common mutations81 (90)37 (84)122 (87)67 (94)59 (89)19 (95)157 (89)89 (87)19 (100)21 (100)140 (99)138 (100)
      Del1940 (44)21 (48)72 (51)36 (51)27 (41)12 (60)97 (55)50 (49)7 (37)10 (48)85 (60)83 (60)
      L858R41 (46)16 (36)50 (36)31 (44)32 (48)7 (35)60 (34)39 (38)12 (63)11 (52)55 (39)55 (40)
      Including 1 patient with both L858R and Del19 mutation.
       Uncommon mutations
      Including T790M, exon 20 insertions, G719X, S768I and L861Q, alone or as complex mutations in 2 or more exons.
      ,
      Including 1 patient in LL3 and 1 patient in LL7 with wild-type EGFR who were randomly assigned in error. For LL7 analyses, the patient reported with wild-type EGFR was included in the Del19 stratum (as randomized).
      9 (10)7 (16)18 (13)4 (6)7 (11)1 (5)19 (11)13 (13)0 (0)0 (0)1 (1)0 (0)
      Abbreviations: Cis/Gem = cisplatin/gemcitabine; Cis/Pem = cisplatin/pemetrexed; ECOG PS = Eastern Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor.
      a Including American Indian/Alaska Native, Black/African American, Hawaiian/Pacific Islander and White.
      b Patients recruited at French sites did not have their race/ethnicity reported.
      c Includes 1 patient with an ECOG PS of 2.
      d Including T790M, exon 20 insertions, G719X, S768I and L861Q, alone or as complex mutations in 2 or more exons.
      e Including 1 patient in LL3 and 1 patient in LL7 with wild-type EGFR who were randomly assigned in error. For LL7 analyses, the patient reported with wild-type EGFR was included in the Del19 stratum (as randomized).
      f Including 1 patient with both L858R and Del19 mutation.

      Treatment Exposure

      In LL3 and LL6, median treatment exposure was longer with afatinib than chemotherapy in elderly (65 years or older; LL3: 9.4 vs. 3.0 months; LL6: 13.9 vs. 2.0 months) and younger patients (LL3: 11.4 vs. 3.4 months; LL6: 12.5 vs. 3.0 months). In LL7, median treatment durations with afatinib versus gefitinib were generally similar in older (75 years and older; 11.9 vs. 12.0 months) and younger patients (14.4 vs. 11.3 months).

      Survival Outcomes

      Progression-free survival and OS outcomes according to age subgroup for the overall study populations and according to EGFR mutation type in LL3 and LL6 are shown in Supplemental Table 1 in the online version. Median PFS was improved with afatinib versus chemotherapy in elderly patients (LL3: 11.3 vs. 8.2 months, HR, 0.64 [95% CI, 0.39-1.03]; LL6: 13.7 vs. 4.1 months, HR, 0.16 [95% CI, 0.07-0.39]) and younger patients (11.0 vs. 5.8 months, HR, 0.53 [95% CI, 0.36-0.76]; LL6: 11.0 vs. 5.6 months, HR, 0.30 [95% CI, 0.21-0.43]) in the overall EGFRm+ population, as well as those with tumors harboring common EGFR mutations (Figure 2A). Analysis of patients from LL7 using the 65-year cutoff were in line with LL3/LL6 analyses, showing a median PFS of 11.0 months with afatinib in each age subgroup (younger than 65 years and 65 years and over).
      • Park K.
      • Tan E.H.
      • O'Byrne K.
      • et al.
      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.
      Figure thumbnail gr2
      Figure 2PFS (A) and OS (B) in Patients Aged 65 Years or Older With NSCLC Harboring Common EGFR Mutations (Del19/L858R), and OS (C) in Patients Aged 65 Years and Older With Del19+ Disease in LUX-Lung 3 and LUX-Lung 6
      Abbreviations: Cis/Gem = cisplatin/gemcitabine; Cis/Pem = cisplatin/pemetrexed; EGFR = epidermal growth factor receptor; HR = hazard ratio; OS = overall survival; PFS = progression-free survival.
      A trend toward improved OS with afatinib was observed in elderly patients in the overall study population of LL6 (22.7 vs. 18.0 months, HR, 0.59 [95% CI, 0.33-1.05]), and those with tumors harboring common EGFR mutations in LL3 (31.6 vs. 24.9 months, HR, 0.73 [95% CI, 0.43-1.21]) as well as LL6 (23.2 vs. 19.0 months, HR, 0.60 [95% CI, 0.33-1.10]; Figure 2B). In elderly patients with Del19+ NSCLC, OS was significantly improved with afatinib versus chemotherapy in LL3 (41.5 vs. 14.3 months, HR, 0.39 [95% CI, 0.19-0.80]), with a trend toward improved OS in LL6 (34.1 vs. 21.1 months, HR, 0.57 [95% CI, 0.24-1.36]; Figure 2C). A trend toward OS improvement with afatinib was also observed in elderly patients with L858R+ NSCLC in LL6 (19.8 vs. 16.0 months, HR, 0.43 [95% CI, 0.18-1.04]).
      In exploratory analyses of patients aged 75 years or older in LL7, a trend toward improved median PFS was observed with afatinib versus gefitinib (14.7 vs. 10.8 months, HR, 0.69 [95% CI, 0.33-1.44]; Figure 3A), consistent with the overall population and younger subgroup. Median OS with afatinib versus gefitinib was 27.9 versus 19.7 months (HR, 1.05 [95% CI, 0.50-2.21]) in patients aged 75 years or older, and 28.9 versus 25.2 months (HR, 0.85 [95% CI, 0.64-1.12]) in patients aged younger than 75 years (Figure 4A). PFS and OS with afatinib were generally consistent across other exploratory age cutoffs in LL7, with notable improvements versus gefitinib observed in patients aged younger than 70 years (Figures 3B and 4B).
      Figure thumbnail gr3
      Figure 3PFS Based on the 75 Years of Age and Older Versus Participants Younger Than 75-Years (A) and Across Additional Age Cut-offs (B) in Patients With NSCLC Harbouring Common EGFR Mutations (Del19/L858R) in LUX-Lung 7
      Abbreviations: EGFR = epidermal growth factor receptor; HR = hazard ratio; PFS = progression-free survival.
      Figure thumbnail gr4
      Figure 4Estimated OS Probability in (A) Participants 75 Years of Age and Older Versus Participants Younger Than 75 Years and Across Additional Age Cut-offs (B) in Patients With NSCLC Harboring Common EGFR Mutations (Del19/L858R) in LUX-Lung 7
      Abbreviations: EGFR = epidermal growth factor receptor; HR = hazard ratio; OS = overall survival.

      Safety

      The overall safety profiles of afatinib and chemotherapy were similar in the elderly and younger subgroups of LL3/LL6, with slightly greater incidences of Grade 3/4 treatment-related adverse events (AEs) observed in elderly patients irrespective of treatment (Table 2; see Supplemental Tables 2 and 3 in the online version). The most frequent treatment-related AEs with afatinib, irrespective of age, were diarrhea, rash/acne, stomatitis, and nail effects. The most frequent treatment-related AEs with chemotherapy were nausea, vomiting, fatigue, decreased appetite, and hematological AEs (eg, anemia, neutropenia, and leukopenia). Afatinib was associated with a higher incidence of treatment-related AEs leading to dose reduction compared with chemotherapy in elderly (LL3: 64% vs. 20%; LL6: 42% vs. 17%) as well as younger patients (LL3: 53% vs. 12%; LL6: 29% vs. 28%; see Supplemental Table 2 in the online version). However, fewer discontinuations due to treatment-related AEs were observed with afatinib versus chemotherapy irrespective of age (elderly LL3: 14% vs. 16%; LL6: 9% vs. 72%; younger LL3: 4% vs. 9%; LL6: 5% vs. 34%). The incidence of treatment-related serious AEs was similar across treatment groups in LL3/LL6, and slightly higher in elderly patients, with few deaths, independent of treatment.
      Table 2Frequent Treatment-Related AEs in Patients Aged ≥ 65 Years in LUX-Lung 3 and LUX-Lung 6, and ≥ 75 Years in LUX-Lung 7 (≥ 20% All Grade in Any Treatment Group)
      LUX-Lung 3 (≥65 Years)LUX-Lung 6 (≥65 Years)LUX-Lung 7 (≥75 Years)
      Afatinib (n = 90)Cis/Pem (n = 44)Afatinib (n = 64)Cis/Gem (n = 18)Afatinib (n = 19)Gefitinib (n = 21)
      AllG3/4
      In patients aged ≥ 65 years, Grade 5 AEs considered potentially related to treatment by the investigators were reported in 3 patients treated with afatinib (dyspnoea, sepsis and unknown) in LL3, and in 1 patient each treated with afatinib (sudden death) or cis/gem (cardiac failure) in LL6. In LL 7, no patients aged ≥ 75 years experienced a treatment-related Grade 5 AE.
      AllG3/4AllG3/4
      In patients aged ≥ 65 years, Grade 5 AEs considered potentially related to treatment by the investigators were reported in 3 patients treated with afatinib (dyspnoea, sepsis and unknown) in LL3, and in 1 patient each treated with afatinib (sudden death) or cis/gem (cardiac failure) in LL6. In LL 7, no patients aged ≥ 75 years experienced a treatment-related Grade 5 AE.
      AllG3/4
      In patients aged ≥ 65 years, Grade 5 AEs considered potentially related to treatment by the investigators were reported in 3 patients treated with afatinib (dyspnoea, sepsis and unknown) in LL3, and in 1 patient each treated with afatinib (sudden death) or cis/gem (cardiac failure) in LL6. In LL 7, no patients aged ≥ 75 years experienced a treatment-related Grade 5 AE.
      AllG3/4AllG3/4
      Any AE90 (100)53 (59)43 (98)25 (57)64 (100)27 (42)18 (100)12 (67)17 (89)8 (42)20 (95)6 (29)
      Diarrhea85 (94)19 (21)7 (16)0 (0)59 (92)5 (8)2 (11)0 (0)17 (89)4 (21)12 (57)2 (10)
      Rash/Acne
      Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      79 (88)17 (19)3 (7)0 (0)50 (78)6 (9)1 (6)0 (0)15 (79)1 (5)13 (62)0 (0)
      Stomatitis
      Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      63 (70)9 (10)9 (20)0 (0)37 (58)2 (3)1 (6)0 (0)8 (42)2 (11)5 (24)0 (0)
      Nail Effect/Paronychia
      Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      55 (61)14 (16)0 (0)0 (0)23 (36)0 (0)0 (0)0 (0)5 (26)0 (0)5 (24)1 (5)
      Dry Skin34 (38)0 (0)2 (5)0 (0)6 (9)0 (0)1 (6)0 (0)7 (37)0 (0)9 (43)0 (0)
      Decreased Appetite26 (29)5 (6)24 (55)2 (5)13 (20)2 (3)7 (39)0 (0)6 (32)0 (0)6 (29)0 (0)
      Pruritus18 (20)1 (1)1 (2)0 (0)10 (16)1 (2)0 (0)0 (0)5 (26)0 (0)2 (10)0 (0)
      Vomiting16 (18)3 (3)16 (36)2 (5)9 (14)1 (2)16 (89)6 (33)2 (11)0 (0)3 (14)1 (5)
      Nausea15 (17)0 (0)28 (64)3 (7)7 (11)0 (0)13 (72)3 (17)4 (21)0 (0)4 (19)0 (0)
      Fatigue
      Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      13 (14)1 (1)21 (48)8 (18)11 (17)0 (0)4 (22)0 (0)6 (32)2 (11)4 (19)0 (0)
      Anemia4 (4)0 (0)15 (34)1 (2)4 (6)1 (2)5 (28)1 (6)0 (0)0 (0)0 (0)0 (0)
      Constipation4 (4)0 (0)13 (30)0 (0)2 (3)0 (0)2 (11)0 (0)0 (0)0 (0)0 (0)0 (0)
      Leukopenia3 (3)1 (1)11 (25)4 (9)3 (5)1 (2)5 (28)2 (11)0 (0)0 (0)0 (0)0 (0)
      Neutropenia1 (1)1 (1)17 (39)8 (18)3 (5)1 (2)8 (44)5 (28)0 (0)0 (0)0 (0)0 (0)
      Thrombocytopenia0 (0)0 (0)5 (11)2 (5)2 (3)1 (2)4 (22)2 (11)0 (0)0 (0)0 (0)0 (0)
      Neutrophil Count Decreased0 (0)0 (0)1 (2)1 (2)0 (0)0 (0)4 (22)0 (0)0 (0)0 (0)0 (0)0 (0)
      Data are presented as n (%).
      Abbreviations: AE = adverse event; Cis/Gem = cisplatin/gemcitabine; Cis/Pem = cisplatin/pemetrexed.
      a In patients aged ≥ 65 years, Grade 5 AEs considered potentially related to treatment by the investigators were reported in 3 patients treated with afatinib (dyspnoea, sepsis and unknown) in LL3, and in 1 patient each treated with afatinib (sudden death) or cis/gem (cardiac failure) in LL6. In LL 7, no patients aged ≥ 75 years experienced a treatment-related Grade 5 AE.
      b Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      No new or unexpected AEs with afatinib were observed in patients aged 75 years or older in LL7 (Table 2; see Supplemental Tables 2 and 3 in the online version). The incidence of treatment-related Grade 3/4 AEs was slightly higher with afatinib and gefitinib in older (42% and 29%) versus younger patients (30% and 17%). Discontinuation rates due to treatment-related AEs were also similar between afatinib and gefitinib, and higher in older (16% and 14%) versus younger patients (5% each). Most treatment-related serious AEs with afatinib in the older subgroup were due to diarrhea (5 of 6 patients); interstitial lung disease was the most common treatment-related serious AE with gefitinib (2 of 3 patients). No treatment-related deaths occurred with afatinib in LL7; 1 patient died from treatment-related hepatic and renal failure with gefitinib.

      Discussion

      Consistent with the overall populations of LL3 and LL6,
      • Sequist L.V.
      • Yang J.C.
      • Yamamoto N.
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      • Wu Y.L.
      • Zhou C.
      • Hu C.P.
      • et al.
      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.
      • Yang J.C.
      • Wu Y.L.
      • Schuler M.
      • et al.
      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.
      afatinib conferred substantial clinical benefit versus chemotherapy in subgroup analyses of patients aged 65 years or older. PFS was improved with afatinib in elderly EGFRm+ NSCLC patients harboring common EGFR mutations in both trials, with a trend toward improved OS observed in the overall population of elderly EGFRm+ NSCLC patients, as well as those harboring common EGFR mutations. OS was significantly improved with afatinib in patients with EGFR Del19+ NSCLC in LL3, with a trend toward improved OS observed in patients with Del19+ or L858R+ NSCLC in LL6. Further, in exploratory analyses of patients across different age subgroups in LL7, including the older subgroup (75 years or older), PFS and OS findings were consistent with the overall study population,
      • Park K.
      • Tan E.H.
      • O'Byrne K.
      • et al.
      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.
      • Paz-Ares L.
      • Tan E.H.
      • O’Byrne K.
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non–small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.
      indicating that afatinib is an effective treatment for older patients with EGFRm+ NSCLC.
      The incidence of treatment-related AEs, including serious AEs, and discontinuations due to AEs was slightly higher in the older versus younger subgroups in all 3 studies, independent of treatment. However, the overall safety profile observed with afatinib in older patients was as expected and consistent with the younger subgroup, with diarrhea, rash/acne, stomatitis, and nail effects as the most common treatment-related AEs. Dose reductions due to treatment-related AEs were common with afatinib irrespective of age, reflecting afatinib’s well defined dose optimization protocol,
      • Yang J.C.
      • Sequist L.V.
      • Zhou C.
      • et al.
      Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials.
      and ultimately resulting in few treatment discontinuations. Overall, these findings suggest that afatinib is associated with a predictable and manageable safety profile irrespective of patient age.
      Most phase III trials evaluating EGFR-targeted agents in NSCLC included patient subgroup analyses on the basis of a 65 years of age or older cutoff, whereas smaller phase II trials and retrospective analyses have explored cutoffs of 70 years or older and younger than 75 years,
      • Minuti G.
      • D’Incecco A.
      • Cappuzzo F.
      Current and emerging options in the management of EGFR mutation-positive non–small-cell lung cancer: considerations in the elderly.
      • Hohenforst-Schmidt W.
      • Zarogoulidis P.
      • Steinheimer M.
      • et al.
      Tyrosine kinase inhibitors for the elderly.
      reflecting the variable definition of “older” cancer patients. The current literature describes 65 years and older as “older,” with subcategories of 65 to 75 years (“young old”), 76 to 85 years (“old”), and older than 85 years (“oldest old”).
      • Hurria A.
      • Wildes T.
      • Blair S.L.
      • et al.
      Senior adult oncology, version 2.2014: clinical practice guidelines in oncology.
      In the context of lung cancer treatment, 75 years and older has been identified as a relevant cutoff when considering chemotherapy and the age at which more effective therapies with improved tolerability are needed.
      • Hohenforst-Schmidt W.
      • Zarogoulidis P.
      • Steinheimer M.
      • et al.
      Tyrosine kinase inhibitors for the elderly.
      Similar to other phase III trials in this setting, LL3 and LL6 included prespecified subgroup analyses on the basis of a 65 years or older cutoff, including 39% and 24% of the study populations, respectively. Although these proportions are relatively small and represent a limitation to the analysis, they are consistent with most oncology trials (25%-30% of patients aged 65 years or older),
      • Minuti G.
      • D’Incecco A.
      • Cappuzzo F.
      Current and emerging options in the management of EGFR mutation-positive non–small-cell lung cancer: considerations in the elderly.
      reflecting routine trial eligibility criteria, which often limits inclusion of older patients (eg, Eastern Cooperative Oncology Group performance status [ECOG PS] < 2; no significant comorbidities). Although the small number of patients aged 75 years or older in LL3/LL6 prevented further analysis of this older population, a larger cohort of patients aged 75 years or older was enrolled in LL7, allowing for a more meaningful analysis of this older age group. LL7 provided the best available comparison of afatinib with gefitinib in older patients; a head-to-head assessment of EGFR-targeted agents has not been previously reported. Experts agree that chronological age alone should not determine treatment choice in older patients, and that biological age, which takes into account age-related factors such as functional status and comorbidity burden, provides the most relevant information for predicting treatment outcomes and tolerability.
      • Blanco R.
      • Maestu I.
      • de la Torre M.G.
      • et al.
      A review of the management of elderly patients with non–small-cell lung cancer.
      • Minuti G.
      • D’Incecco A.
      • Cappuzzo F.
      Current and emerging options in the management of EGFR mutation-positive non–small-cell lung cancer: considerations in the elderly.
      • Pallis A.G.
      • Gridelli C.
      • Wedding U.
      • et al.
      Management of elderly patients with NSCLC; updated expert’s opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology.
      The older subgroups of the LUX-Lung studies might be considered relatively “fit,” because of eligibility criteria that excluded patients with poor functional status (ie, ECOG PS ≥ 2) and significant comorbidities (eg, cardiovascular abnormalities). However, previously published subgroup analyses in LL3, LL6, and LL7 have shown significant improvements in PFS, and a trend toward improved OS, with afatinib versus comparators in patients with an ECOG PS of 1, similar to the overall study populations.
      • Sequist L.V.
      • Yang J.C.
      • Yamamoto N.
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      • Park K.
      • Tan E.H.
      • O'Byrne K.
      • et al.
      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.
      • Wu Y.L.
      • Zhou C.
      • Hu C.P.
      • et al.
      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.
      • Paz-Ares L.
      • Tan E.H.
      • O’Byrne K.
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non–small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.
      • Yang J.C.
      • Wu Y.L.
      • Schuler M.
      • et al.
      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.
      One advantage of afatinib treatment for patients who are receiving multiple medications for comorbidities (as is often observed in elderly patients) is the low occurrence of drug–drug interactions. This is aided by the fact that only a small fraction of afatinib is exposed to hepatic metabolism and excretion, compared with other EGFR TKIs that undergo extensive hepatic metabolism by cytochrome P450-dependent enzymes.
      • Schnell D.
      • Buschke S.
      • Fuchs H.
      • et al.
      Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment.
      Further analyses to determine the effect of poorer functional status and other key factors associated with advancing biological age, such as comorbidities and polypharmacy, on clinical outcomes with afatinib are warranted. Of note, there are some ongoing studies in advanced NSCLC patients currently evaluating the utility of standardized Comprehensive Geriatric Assessment in guiding treatment decisions in older cancer patients
      • Corre R.
      • Greillier L.
      • Le Caer H.
      • et al.
      Use of a comprehensive geriatric assessment for the management of elderly patients with advanced non–small-cell lung cancer: the phase III randomized ESOGIA-GFPC-GECP 08-02 study.
      ; however, to the best of our knowledge, there are no such trials including EGFR-targeted agents, and these types of assessments are not routinely used in the clinic.

      Conclusion

      In summary, subgroup analyses of treatment-naive patients with EGFRm+ advanced NSCLC in the LUX-Lung trials showed that advancing age alone did not adversely affect the clinical benefits observed with afatinib versus chemotherapy (LL3/LL6) or gefitinib (LL7). Of note, exploratory analyses across different age cutoffs in LL7 showed that efficacy outcomes with afatinib were consistent independent of age, with notable improvements over gefitinib in patients aged younger than 70 years. Further, afatinib was associated with a predictable and manageable safety profile irrespective of age in all studies. Taken together, these findings show that afatinib can provide an effective and tolerable treatment for older patients with EGFRm+ NSCLC.

      Clinical Practice Points

      • There are limited data on the efficacy of EGFR TKIs in older patients.
      • These subanalyses show that first-line afatinib can provide effective and tolerable treatment for patients with EGFRm+ NSCLC, and is superior to platinum-doublet chemotherapy or gefitinib in this clinical setting; therefore, afatinib is an appropriate treatment choice to consider in older patients.
      • These data are relevant to day-to-day clinical practice because of the aging population and increased incidence of EGFRm+ NSCLC in older patients.
      • However, chronological age alone should not determine treatment choice; clinicians should consider physiological age and take into account age-related factors such as functional status and comorbidity burden when considering treatment choice. These provide more information for predicting treatment outcomes and tolerability.
      • Afatinib might be an advantageous treatment choice for elderly patients who are receiving multiple medications for comorbidities because drug–drug interactions are less likely than with other EGFR TKIs.
      • Clinicians should exercise judgement when prescribing afatinib in all older patients and decisions should be made on a case-by-case basis.

      Disclosure

      Dr Wu reports receiving honoraria from AstraZeneca, Roche, Eli Lilly, Pfizer, and Sanofi. Dr Sequist has received advisory board fees from AstraZeneca, Genentech, Bristol-Myers Squibb (BMS), and Ariad, and has provided unpaid consulting for Clovis, Boehringer Ingelheim (BI), and Merrimack. Dr Geater has participated on boards for Novartis and BI, and has conducted corporate-sponsored research for AstraZeneca, Novartis, BI, and Roche. Dr Zhang is on the board of directors for the Multinational Association of Supportive Care in Cancer, and has conducted corporate-sponsored research for BMS and Pfizer. Dr Kato has received honoraria and conducted corporate-sponsored research for BI. Dr Barrios reports conducting corporate-sponsored research for Pfizer, Novartis, Amgen, AstraZeneca, BI, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, BioMarin, BMS, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Daiichi Sankyo, Exelixis, ImClone Systems, LEO Pharma, and Millennium, participating on advisory boards for BI, GlaxoSmithKline, Novartis, Pfizer, Roche/Genentech, and Eisai, and has received honoraria from BI, GlaxoSmithKline, Novartis, Pfizer, Roche/Genentech, and Eisai. Dr Schuler reports participating on advisory boards for AstraZeneca, BI, BMS, Celgene, Eli Lilly, Novartis, and Roche, conducting corporate-sponsored research for BI, BMS, and Novartis, receiving honoraria from Alexion, BI, BMS, Celgene, Eli Lilly, MSD, Novartis, AstraZeneca, and Roche; and holds patents with University Duisburg-Essen. Dr Hirsh has received honoraria and participated on advisory boards for BI, AstraZeneca, Roche, Amgen, Pfizer, Eli Lilly, and BMS. Dr Yamamoto has received honoraria and participated on advisory boards for AstraZeneca, BI, Chugai, Eli Lilly, MSD, Novartis, Ono Pharmaceutical Co. Ltd, and Taiho, and has conducted corporate-sponsored research for BI, Chugai, Eli Lilly, and MSD. Dr O’Byrne has received honoraria and participated on advisory boards for MSD, BMS, BI, Roche, Lilly, Novartis, AstraZeneca, and Pfizer, and is a shareholder in CARP Pharmaceuticals. Dr Boyer has participated on advisory boards for Pfizer, AstraZeneca, Merck and BMS, and has conducted corporate-sponsored research for Pfizer, AstraZeneca, Merck, BMS, Amgen, BI, and Roche/Genentech. Dr Mok has participated on advisory boards for AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Clovis Oncology, Merck Serono, MSD, Novartis, SFJ Pharmaceuticals Group, and BMS, received lecture fees from AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Novartis, BMS, and Taiho, and owns stock in Sanomics Ltd. Dr Peil is an employee of BI. Dr Märten is an employee of BI. Dr Yang has received honoraria and participated on advisory boards for BI, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceutical Co. Ltd, Daiichi Sankyo, and AstraZeneca. Dr Park has participated on advisory boards for Astellas, AstraZeneca, BI, Clovis, Eli Lilly, Hanmi, Loxo Oncology, MSD, Novartis, Ono Pharmaceutical Co. Ltd, and Roche. The remaining authors have stated that they have no conflicts of interest.

      Acknowledgments

      The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Katie Dean, PhD, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version.
      We thank the patients, their families, and all of the investigators who participated in these studies.

      Supplemental Data

      Figure thumbnail fx1
      Supplemental Figure 1Patient Disposition by Age Subgroup in LUX-Lung 3, LUX-Lung 6 (A) and LUX-Lung 7 (B)
      Abbreviations: Cis/Pem = cisplatin/pemetrexed; EGFR = epidermal growth factor receptor. aReasons for exclusion prior to randomization included did not meet inclusion criteria (n = 58), withdrew consent (n = 24), AEs (n = 5), lost to follow-up (n = 5) and other reason (n = 15) in LL3, and did not meet inclusion criteria (n = 51), withdrew consent (n = 38), AEs (n = 1) and other reason (n = 17) in LL6. bSafety analyses included randomized patients who received at least 1 dose of study drug. Following randomization in LL3, 1 patient did not receive afatinib and 4 patients did not receive chemotherapy. In LL6, 3 patients did not receive afatinib and 9 patients did not receive chemotherapy. All patients randomized in LL7 received treatment. cReasons for exclusion prior to randomization included did not meet inclusion criteria (n = 233), withdrew consent (n = 12), AEs (n = 3) and other reason (n = 4).
      Supplemental Table 1Survival Outcomes by Age Subgroup in LUX-Lung 3 and LUX-Lung 6
      OutcomeLUX-Lung 3LUX-Lung 6
      ≥ 65 years<65 years≥ 65 years<65 years
      AfatinibCis/PemAfatinibCis/PemAfatinibCis/GemAfatinibCis/Gem
      Overall Population, n9044140716620176102
       Median PFS, Months11.38.2115.813.74.1115.6
      HR (95% CI)0.64 (0.39-1.03)0.53 (0.36-0.76)0.16 (0.07-0.39)0.30 (0.21-0.43)
      P.0636.0006<.0001<.0001
       Median OS, Months27.629.129.426.222.71823.124.7
      HR (95% CI)0.94 (0.58-1.51)0.84 (0.59-1.19)0.59 (0.33-1.05)0.95 (0.70-1.28)
      P.7861.3206.0676.7251
      Common EGFR Mutations, n813712267591915789
       Median PFS, months13.78.211.85.813.74.1115.6
      HR (95% CI)0.45 (0.26-0.78)0.48 (0.32-0.71)0.15 (0.06-0.38)0.27 (0.19-0.40)
       Median OS, months31.624.931.528.623.21924.224.5
      HR (95% CI)0.73 (0.43-1.21)0.82 (0.57-1.19)0.60 (0.33-1.10)0.87 (0.64-1.20)
      Del194021723627129750
       Median OS, months41.514.331.625.634.121.130.417.5
      HR (95% CI)0.39 (0.19-0.80)0.64 (0.40-1.03)0.57 (0.24-1.36)0.65 (0.42-0.99)
      L858R411650313276039
       Median OS, months27.243.23129.519.81619.325.4
      HR (95% CI)1.40 (0.63-3.12)1.25 (0.67-2.31)0.43 (0.18-1.04)1.50 (0.94-2.40)
      Abbreviations: Cis/Gem = cisplatin/gemcitabine; Cis/Pem = cisplatin/pemetrexed; HR = hazard ratio; OS = overall survival; PFS = progression-free survival.
      Supplemental Table 2Overall Safety Summary by Age Subgroup in LUX-Lung 3, LUX-Lung 6 and LUX-Lung 7
      LUX-Lung 3LUX-Lung 6LUX-Lung 7
      ≥65 Years<65 Years≥65 Years<65 Years≥75 Years<75 Years
      Afatinib (n = 90)Cis/Pem (n = 44)Afatinib (n = 139)Cis/Pem (n = 67)Afatinib (n = 64)Cis/Gem (n = 18)Afatinib (n = 175)Cis/Gem (n = 95)Afatinib (n = 19)Gefitinib (n = 21)Afatinib (n = 141)Gefitinib (n = 138)
      Any AE90 (100)44 (100)139 (100)65 (97)64 (100)18 (100)175 (100)94 (99)18 (95)21 (100)140 (99)138 (100)
      Treatment-Related AEs90 (100)43 (98)138 (99)63 (94)64 (100)18 (100)172 (98)94 (99)17 (89)20 (95)139 (99)133 (96)
      Leading to Dose Reduction58 (64)9 (20)74 (53)8 (12)27 (42)3 (17)51 (29)27 (28)10 (53)1 (5)56 (40)2 (1)
      Leading to Discontinuation13 (14)7 (16)6 (4)6 (9)6 (9)13 (72)9 (5)32 (34)3 (16)3 (14)7 (5)7 (5)
      Treatment-Related Serious AEs17 (19)8 (18)16 (12)7 (10)7 (11)2 (11)8 (5)7 (7)6 (32)3 (14)11 (8)6 (4)
      Treatment-Related Deaths3 (3)
      Death, dyspnea and sepsis.
      0 (0)1 (1)
      Acute respiratory distress syndrome.
      0 (0)1 (2)
      Sudden death.
      1 (6)
      Cardiac failure.
      0 (0)0 (0)0 (0)0 (0)0 (0)1 (1)
      Hepatic failure and renal failure.
      Data are presented as n (%).
      Abbreviation: AE = adverse event.
      a Death, dyspnea and sepsis.
      b Acute respiratory distress syndrome.
      c Sudden death.
      d Cardiac failure.
      e Hepatic failure and renal failure.
      Supplemental Table 3Frequent Treatment-Related AEs in Patients Younger Than 65 Years in LUX-Lung 3 and LUX-Lung 6, and Younger Than 75 Years in LUX-Lung 7 (Occurrence of 20% or More Across All Grade in Any Treatment Group)
      LUX-Lung 3 (<65 years)LUX-Lung 6 (<65 years)LUX-Lung 7 (<75 years)
      Afatinib (n = 139)Cis/Pem (n = 67)Afatinib (n = 175)Cis/Gem (n = 95)Afatinib (n = 141)Gefitinib (n = 138)
      AllG3/4
      In patients aged < 65 years, Grade 5 AEs considered potentially related to treatment by the investigators were reported in 1 patient treated with afatinib (acute respiratory distress syndrome) in LL3, and no patients in LL6. In patients aged < 75 years in LL7, 1 patient treated with gefitinib had a treatment-related Grade 5 AE (hepatic and renal failure).
      AllG3/4AllG3/4
      In patients aged < 65 years, Grade 5 AEs considered potentially related to treatment by the investigators were reported in 1 patient treated with afatinib (acute respiratory distress syndrome) in LL3, and no patients in LL6. In patients aged < 75 years in LL7, 1 patient treated with gefitinib had a treatment-related Grade 5 AE (hepatic and renal failure).
      AllG3/4
      In patients aged < 65 years, Grade 5 AEs considered potentially related to treatment by the investigators were reported in 1 patient treated with afatinib (acute respiratory distress syndrome) in LL3, and no patients in LL6. In patients aged < 75 years in LL7, 1 patient treated with gefitinib had a treatment-related Grade 5 AE (hepatic and renal failure).
      AllG3/4AllG3/4
      In patients aged < 65 years, Grade 5 AEs considered potentially related to treatment by the investigators were reported in 1 patient treated with afatinib (acute respiratory distress syndrome) in LL3, and no patients in LL6. In patients aged < 75 years in LL7, 1 patient treated with gefitinib had a treatment-related Grade 5 AE (hepatic and renal failure).
      Any AE138 (99)57 (41)63 (94)27 (40)172 (98)59 (34)94 (99)55 (58)139 (99)42 (30)133 (96)24 (17)
      Diarrhea133 (96)15 (11)10 (15)0 (0)153 (87)8 (5)10 (11)0 (0)127 (90)17 (12)85 (62)0 (0)
      Rash/Acne
      Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      126 (91)20 (14)4 (6)0 (0)144 (82)30 (17)9 (9)0 (0)127 (90)14 (10)116 (84)5 (4)
      Stomatitis
      Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      104 (75)11 (8)8 (12)1 (1)88 (50)11 (6)5 (5)0 (0)95 (67)5 (4)33 (24)0 (0)
      Nail Effect/Paronychia
      Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      88 (63)15 (11)0 (0)0 (0)60 (34)0 (0)0 (0)0 (0)85 (60)3 (2)23 (17)0 (0)
      Dry Skin35 (25)1 (1)0 (0)0 (0)8 (5)0 (0)0 (0)0 (0)45 (32)0 (0)50 (36)0 (0)
      Ocular Effect/Conjunctivitis
      Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      29 (21)0 (0)0 (0)0 (0)10 (6)0 (0)0 (0)0 (0)8 (6)0 (0)10 (7)1 (1)
      Fatigue
      Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.
      28 (20)2 (1)31 (46)6 (9)14 (8)1 (1)37 (39)1 (1)27 (19)7 (5)19 (14)0 (0)
      Nausea28 (20)2 (1)45 (67)1 (1)11 (6)0 (0)72 (76)6 (6)22 (16)2 (1)18 (13)0 (0)
      Pruritus28 (20)0 (0)0 (0)0 (0)16 (9)0 (0)0 (0)0 (0)32 (23)0 (0)34 (25)0 (0)
      Vomiting26 (19)4 (3)31 (46)1 (1)14 (8)1 (1)75 (79)16 (17)15 (11)0 (0)3 (2)0 (0)
      Decreased Appetite23 (17)2 (1)35 (52)1 (1)11 (6)1 (1)39 (41)2 (2)20 (14)1 (1)13 (9)0 (0)
      ALT Increased17 (12)1 (1)2 (3)0 (0)39 (22)2 (1)16 (17)3 (3)15 (11)0 (0)36 (26)11 (8)
      AST Increased13 (9)0 (0)2 (3)1 (1)32 (18)1 (1)10 (11)2 (2)10 (7)0 (0)31 (22)3 (2)
      Anemia5 (4)1 (1)16 (24)6 (9)9 (5)0 (0)26 (27)9 (9)3 (2)0 (0)1 (1)0 (0)
      Neutropenia1 (1)0 (0)18 (27)12 (18)3 (2)0 (0)53 (56)25 (26)3 (2)1 (1)1 (1)0 (0)
      Leukopenia1 (1)0 (0)10 (15)5 (7)5 (3)0 (0)53 (56)15 (16)1 (1)0 (0)0 (0)0 (0)
      Neutrophil Count Decreased1 (1)1 (1)7 (10)3 (4)2 (1)0 (0)25 (26)11 (12)0 (0)0 (0)0 (0)0 (0)
      WBC Count Decreased0 (0)0 (0)2 (3)0 (0)1 (1)0 (0)24 (25)7 (7)0 (0)0 (0)0 (0)0 (0)
      Data are presented as n (%).
      Abbreviations: AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; Cis/Gem = cisplatin/gemcitabine; Cis/Pem = cisplatin/pemetrexed; G3/4 = Grade 3 or 4; WBC = white blood cell.
      a In patients aged < 65 years, Grade 5 AEs considered potentially related to treatment by the investigators were reported in 1 patient treated with afatinib (acute respiratory distress syndrome) in LL3, and no patients in LL6. In patients aged < 75 years in LL7, 1 patient treated with gefitinib had a treatment-related Grade 5 AE (hepatic and renal failure).
      b Grouped term. Note that the names and definitions of some grouped terms may have changed based on the MedDRA versions used for the different LUX-Lung trials.

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