Afatinib versus cisplatin plus gemcitabine for first-line treatment of Chinese patients with advanced non-small-cell lung cancer harboring EGFR mutations: subgroup analysis of the LUX-Lung 6 trial  Yi-Long Wu,1 Chong-Rui Xu,1 Cheng-Ping Hu,2 Jifeng Feng,3 Shun Lu,4 Yunchao Huang,5 Wei Li,6 Mei Hou,7 Jian Hua Shi,8 Angela Märten,9 Jean Fan,10 Barbara Peil,11 Caicun Zhou12 1Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; 2Department of Pulmonary Medicine, Xiangya Hospital, Central South University, Changsha, China; 3Department of Internal Medicine, Jiangsu Provincial Tumor Hospital, Nanjing, Jiangsu, China; 4Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; 5Yunnan Tumor Hospital (The Third Affiliated Hospital of Kunming Medical University), Kunming, Yunnan Province, China; 6CancerCenter, First Hospital of Jilin University, Changchun, China; 7West China Hospital, Sichuan University, Chengdu, Sichuan, China; 8Lin Yi Tumor Hospital, Linyi, Shandong Province, China; 9Boehringer Ingelheim GmbH, Ingelheim, Germany; 10Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 11Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 12Shanghai Pulmonary Hospital, Yangpu District, Shanghai, China

Introduction The reversible EGFR TKIs, erlotinib and gefitinib, and the irreversible ERBB family blocker, afatinib, are approved globally for the first-line treatment of advanced EGFR-mutation positive NSCLC1–4 There are few data to guide treatment choice In the Phase III LUX-Lung 3 (LL3) and LL6 studies, afatinib significantly improved PFS and several PROs versus chemotherapy5,6 In a prespecified analysis of Del19+ patients, afatinib also significantly prolonged OS versus chemotherapy7 Del19 is the most common mutation found among Chinese patients with EGFR-mutation positive NSCLC (~50%)8 Here, we report a post-hoc subgroup analysis of the efficacy and safety of afatinib versus chemotherapy in Chinese patients participating in LL6 EGFR, epidermal growth factor receptor; PFS, progression-free survival; PROs, patient-reported outcomes; OS, overall survival; TKI, tyrosine kinase inhibitor 1. Novello S, et al. Ann Oncol 2016;27:v1–v27; 2. Masters GA, et al. J Clin Oncol 2015;33:3488–515; 3. Zhi X-Y, et al. Cancer 2015;121:3165–81; 4. BI press release. http://www.Boehringer- Ingelheim.com/press-release/afatinib-approved-lung-cancer-china. Accessed September 2017; 5. Sequist LV, et al. J Clin Oncol 2013;31:3327–34; 6. Wu Y-L, et al. Lancet Oncol 2014;15:213–22 7. Yang JC, et al. Lancet Oncol 2015;16:141–51; 8. Shi Y, et al. PLoS One 2015;10:e0143515

LUX-Lung 6 study design and trial endpoints Phase III study conducted in China, Thailand, and South Korea Phase III Gemcitabine/cisplatin (G/C) (≤6 cycles) Afatinib 40 mg QD* PFS† Randomized, open-label, multicenter ORR, DCR, OS, duration of response and disease control, PROs, safety EGFR mutation in the tumor tissue‡ No prior treatment for advanced/ metastatic disease ECOG PS 0/1 Primary endpoints Key secondary endpoints Stage IIIb/IV adenocarcinoma of the lung Patients LL6 Inclusion R 2:1 Stratified by: Mutation type (Del19/L858R/other) Treatment until PD or unacceptable AEs *Dose modification to 50, 30, or 20 mg QD permitted in line with prescribing information †Independent review ‡Assessed at central laboratory AE, adverse event; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; G/C, gemcitabine/cisplatin; ORR, objective response rate; PD, progressive disease; QD, once daily; R, randomized

Overall LL6 population (N=364) Baseline demographics/characteristics were comparable between the Chinese subgroup and the overall LL6 population   Overall LL6 population (N=364) Chinese patients (N=327) Characteristic Afatinib (n=242) G/C (n=122) Afatinib (n=217) G/C (n=110) Sex, n (%) Female/ Male 155 (64.0)/ 87 (36.0) 83 (68.0)/ 39 (32.0) 136 (62.7)/ 81 (37.3) 76 (69.1)/ 34 (30.9) Median age, years (range) 58 (29–79) 58 (27–76) 58 (30–78) 58 (27–75) Race/ethnicity,* n (%) Southeast Asian South Korean Chinese 14 (5.8) 11 (4.5) 217 (89.7) 10 (8.2) 2 (1.6) 110 (90.2) 217 (100) 110 (100) ECOG PS, n (%) 0/ 1 48 (19.8)/ 194 (80.2) 41 (33.6)/ 81 (66.4) 44 (20.3)/ 173 (79.7) 40 (36.4)/ 70 (63.6) Smoking status, n (%) Never smoked Other current or ex-smoker <15 pack-years and stopped >1 year ago 181 (74.8) 53 (21.9) 8 (3.3) 99 (81.1) 19 (15.6) 4 (3.3) 159 (73.3) 50 (23.0) 8 (3.7) 92 (83.6) 15 (13.6) 3 (2.7) Adenocarcinoma stage, n (%) IIIB IV 16 (6.6) 226 (93.4) 6 (4.9) 116 (95.1) 13 (6.0) 204 (94.0) 6 (5.5) 104 (94.5) Number of metastatic sites, n (%) 1 2 ≥3 5 (2.1) 72 (29.8) 91 (37.6) 74 (30.6) 1 (0.8) 52 (42.6) 36 (29.5) 33 (27.0) 3 (1.4) 65 (30.0) 84 (38.7) 1 (0.9) 48 (43.6) 30 (27.3) 31 (28.2) EGFR mutation, n (%) Common mutations Del19 L858R Uncommon mutations‡ 216 (89.3) 124 (51.2) 92 (38.0)† 26 (10.7) 108 (88.5) 62 (50.8) 46 (37.7) 14 (11.5) 193 (88.9) 111 (51.2) 82 (37.8)† 24 (11.1) 97 (88.2) 55 (50.0) 42 (38.2) 13 (11.8) In LL6, 327/364 (90%) patients randomized in LL6 were from mainland China The treated sets comprised 214 patients for afatinib and 103 for G/C Median (range) of treatment duration was 389.5 days (3–1,256) and 86 days (1–154) with afatinib and G/C, respectively *Available categories within Asian race included Indian subcontinent Asian, Southeast Asian, Japanese, Korean, Taiwanese or Chinese, Asian – Other; †Including 4 patients with both L858R and Del19 mutation. ‡Including T790M, exon 20 insertions, G719X, S768I, and L861Q, alone or as complex mutations in 2 or more exons.

Dose adjustments among Chinese patients who were long-term responders Dose adjustments among Chinese patients who were long-term responders* to afatinib At time of analysis, there were 20 Chinese afatinib LTRs*, with a median treatment duration of 56.8 months (range 37.3–68.2) Dose adjustment did not appear to impact long-term responses *Patients who remained on afatinib treatment for ≥36 months

Estimated PFS probability PFS was longer with afatinib than G/C, including across specific subgroups of interest A PFS advantage with afatinib versus G/C was observed in patients with common EGFR (Del19 or L858R) mutations (median 11.0 vs 5.6 months; HR=0.26 [95% CI: 0.18–0.37]; p<0.0001) 217 185 146 110 82 58 46 35 28 22 18 10 1 62 21 7 Afatinib G/C Number at risk 0.2 0.4 0.6 0.8 1.0 Estimated PFS probability 3 6 9 12 15 24 27 30 33 36 39 Time (months) Afatinib G/C Median, months 11.0 5.6 HR (95% CI) 0.30 (0.21–0.43) p value <0.0001 CI, confidence interval; HR, hazard ratio

OS was improved with afatinib versus G/C in Del19+ patients Overall, OS was not different for afatinib and G/C (median 23.1 vs 23.2 months; HR=0.96 [95% CI: 0.73–1.27]; p=0.7765) However, afatinib improved OS versus G/C in Del19+ patients OS in Del19+ Chinese patients Afatinib G/C Number at risk 111 109 105 102 95 89 81 73 66 63 57 37 16 8 1 55 52 48 44 39 30 25 23 21 19 18 11 4 3 Estimated OS probability 45 6 9 12 15 24 27 33 36 42 Time (months) 0.2 0.4 0.6 0.8 1.0 Afatinib G/C Median, months 31.6 16.3 HR (95% CI) 0.61 (0.41–0.91) p value 0.0146

Tumor response in LL6 Chinese subgroup 67% (all Chinese) 78% (Del19+) Afatinib 24% (all Chinese) 27% (Del19+) G/C 92% (all Chinese) 94% (Del19+) 77% (all Chinese) 76% (Del19+) DCR ORR and DCR were both higher with afatinib compared with G/C ORR: odds ratio (OR)=6.94 (95% CI: 4.05–11.88); p<0.0001 DCR: OR=3.45 (95% CI: 1.77–6.71); p=0.0003 The improvement in ORR with afatinib versus G/C was more pronounced among Del19+ patients (OR=9.17 [95% CI: 4.37–19.26]; p<0.0001)

Safety/tolerability findings with afatinib in the Chinese subgroup were consistent with those in the overall LL6 population1 Treatment-related AEs occurring in >20% of Chinese patients in either treatment group – treated set Patients with AEs, n (%) Afatinib (n=214)a Gem/Cis (n=103)a All Grade 3 Grade 4 Any related AE 211 (98.6) 76 (35.5) 2 (0.9) 102 (99.0) 35 (35.9) 22 (21.4) Diarrhea 187 (87.4) 12 (5.6) 10 (9.7) Rash/acneb 173 (80.8) 34 (15.9) 1 (0.5) Stomatitisb 105 (49.1) 13 (6.1) 3 (2.9) Vomiting 19 (8.9) 85 (82.5) 15 (14.6) 4 (3.9) Nausea 16 (7.5) 82 (79.6) 8 (7.8) 1 (1.0) Neutropenia 6 (2.8) 60 (58.3) 19 (18.4) Leukopenia 8 (3.7) 58 (56.3) 2 (1.9) Nail effectb 65 (30.4) Decreased appetite 21 (9.8) 43 (41.7) ALT increased 45 (21.0) 16 (5.5) Fatigueb 39 (37.9) Anemia 11 (5.1) 28 (27.2) White blood cell count decreased 27 (26.2) 7 (6.8) Neutrophil count decreased 25 (24.3) 5 (4.9) Similar proportions of patients experienced grade 3 TRAEs in each arm, but substantially more patients in the G/C group experienced grade 4 treatment-related AEs 1. Wu Y-L, et al. Lancet Oncol 2014;15:213–22 ALT, alanine transaminase; TRAE, treatment-related AE

The tolerability of afatinib was considerably less severe than that experienced with G/C No patients in the afatinib group discontinued treatment due to diarrhea The most common reason for discontinuation was rash (5/12 patients) The most common reasons for discontinuing G/C were vomiting (15/43; 35%), nausea (11/43; 26%), and neutropenia (10/43; 23%) Afatinib G/C 42% Percentage of patients who discontinued study drug due to TRAEs Serious TRAEs were reported in 6% of patients in the afatinib group and 5% in the G/C group Two deaths were considered possibly related to treatment: sudden death in the afatinib group and cardiac failure in the G/C group

PK data suggest that individual tolerability-driven dose modification is effective at reducing excessive afatinib levels Afatinib trough plasma concentrations showed high variability (gCV 47.1% to 90.3%) for all dose groups and over all PK visits However, mean trough plasma concentrations at the last PK observation on day 43 were at a similar level for all dose groups, by which time most patients would have received any required dose adjustments Visit Afatinib 30 mg Afatinib 40 mg Afatinib 50 mg N gMean, ng/mL gCV, % gMean, ng/mL Course 2 Visit 1 (day 22) – 187 22.6 60.9 Course 2 Visit 2 (day 29) 6 19.5 90.3 143 23.5 63.0 33 23.3 60.6 Course 3 Visit 1 (day 43) 17 20.6 47.1 140 21.5 63.5 34 61.5 gCV, geometric coefficient of variation; PK, pharmacokinetics

Substantial improvements in health-related quality of life were reported with afatinib Significantly greater proportions of patients in the afatinib group had improvements in cough, dyspnea, and pain versus the G/C group Significant improvements were observed in all items related to cough, dyspnea, and pain except ‘dyspnea rested’ and ‘pain in arm/shoulder’, suggesting that the beneficial effects of afatinib outweigh its AEs Cancer Quality of Life Questionnaire C30 (QLQ-C30) and its lung cancer-specific module QLQ-LC13

Key findings and conclusions Afatinib improved PFS and ORR versus G/C in Chinese patients An improvement in OS was also observed versus G/C in Chinese patients with an EGFR Del19 mutation The improvement in efficacy with afatinib versus G/C was reflected in a delayed time to deterioration of PROs for the symptoms most important to patients with NSCLC: cough, dyspnea, and pain There were no unexpected safety findings with afatinib in Chinese patients, and discontinuation due to TRAEs was uncommon Afatinib should therefore be considered as a first-line treatment option for Chinese patients with EGFR-mutation positive NSCLC

References Acknowledgments Novello S, et al. Ann Oncol 2016;27:v1–v27 Masters GA, et al. J Clin Oncol 2015;33:3488–515 Zhi X-Y, et al. Cancer 2015;121:3165–81 BI press release. http://www.Boehringer-Ingelheim.com/press-release/afatinib-approved-lung-cancer-china. Accessed September 2017 Sequist LV, et al. J Clin Oncol 2013;31:3327–34 Wu Y-L, et al. Lancet Oncol 2014;15:213–22 Yang JC, et al. Lancet Oncol 2015;16:141–51 Shi Y, et al. PLoS One 2015;10:e0143515 Acknowledgments This study was funded by Boehringer Ingelheim. 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. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Lynn Pritchard of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of the manuscript and accompanying slide set These materials are for personal use only and may not be reproduced without written permission of the authors and the appropriate copyright permissions