LUX-Lung 3 clinical trial LUX-Lung 3 is a multi-national, prospective, randomised, phase III trial of afatinib vs cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations Treatment-naïve Advanced NSCLC stage IIIB/IV adenocarcinoma EGFR M+ ECOG 0 or 1 Afatinib 40 mg oral once daily n=230 Pemetrexed/cisplatin 75 mg/m2 / 500 mg/m2 IV d1, q3w up to 6 cycles n=115 Median follow-up: For PFS: 16.4 months For OS: 41 months 2:1 randomisation ECOG=Eastern Cooperative Oncology Group. Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.

LUX-Lung 3 study endpoints Primary endpoint Progression-free survival (PFS) by independent review Secondary endpoints included Overall survival (OS) Objective response rate Disease control rate Duration of response Patient-reported outcomes, including symptom control and health-related quality of life as measured through EORTC questionnaires EORTC=European Organisation for Research and Treatment of Cancer. Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.

Patient demographics and characteristics were well balanced between the 2 treatment arms Afatinib (n=230) Pem/cis (n=115) Sex, n (%) Male 83 (36.1) 38 (33.0) Female 147 (63.9) 77 (67.0) Age, years, median (range) 61.5 (28-86) 61.0 (31-83) Race, n (%) White 61 (26.5) 30 (26.1) Eastern Asian 165 (71.7) 83 (72.2) Other 4 (1.7) 2 (1.7) Smoking status, n (%) Never 155 (67.4) 81 (70.4) Former 70 (30.4) 32 (27.8) Current 5 (2.2) ECOG PS, n (%) 92 (40.0) 41 (35.7) 1 138 (60.0) 73 (63.5) 2 0.0 1 (0.9) Adenocarcinoma stage*, n (%) IIIB (with pleural effusion) 20 (8.7) 17 (14.8) IV 210 (91.3) 98 (85.2) EGFR mutation, n (%) Exon 19 deletion 113 (49.1) 57 (49.6) L858R 91 (39.6) 47 (40.9) 26 (11.3) 11 (9.6) * By American Joint Committee on Cancer, sixth edition. Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.

LUX-LUNG 3 Efficacy

Afatinib significantly increased first-line PFS vs pemetrexed/cisplatin in common mutations (del19/L858R) Del9/L858R mutations Progression-free survival (primary endpoint) LUX-Lung 3 preplanned subgroup analysis PFS rate (%) 0.2 0.4 0.6 0.8 1.0 0.0 Afatinib (n=204) 13.6 months Pemetrexed/cisplatin (n=104) Hazard ratio 0.47 (95% CI, 0.34-0.65) P<0.001 6.9 months 3 6 9 12 15 18 21 24 27 Time (months) 53% reduction in relative risk of death or tumour progression in patients with common mutations (HR 0.47; P<0.001) In ITT population, median PFS was 11.1 and 6.9 months for afatinib and pemetrexed/ cisplatin, respectively (HR: 0.58; 95% CI, 0.43-0.78; P<0.001) ITT=intent to treat; PFS=progression-free survival. Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.

reduction in relative risk of death Afatinib achieved over 1 year extended OS vs pemetrexed/cisplatin in subgroup of del19 patients Del19 mutations Overall survival (secondary endpoint) LUX-Lung 3 preplanned subgroup analysis Afatinib (n=112) Estimated OS probability 0.2 0.4 0.6 0.8 1.0 0.0 Pemetrexed/cisplatin (n=57) 33.3 months Hazard ratio 0.54 (95% CI, 0.36-0.79) P=0.0015 >12 months increase median OS >12 months increase median OS 21.1 months 46% reduction in relative risk of death 3 6 9 18 21 30 36 39 45 12 15 24 27 33 42 48 51 Time of overall survival (months) 46% reduction in relative risk of death in del19 patients (HR 0.54; P=0.0015) OS in ITT population (N=345) was 28.2 and 28.2 months for afatinib vs pemetrexed/cisplatin, respectively (HR 0.88; P=0.39) ITT=intent to treat; OS=overall survival. Yang JC et al. Lancet Oncol. 2015;16(2):141-51.

Patient-reported outcomes LUX-LUNG 3 Patient-reported outcomes

Afatinib significantly improved dyspnoea and some pain symptoms compared with pemetrexed/cisplatin Patients with improvement in symptoms (EORTC scores improved by ≥10 points)1* >97% questionnaire completion >97% questionnaire completion * Improvement=a linear transformation was applied to standardise the raw score to a range from 0 to 100. A 10-point change is accepted as the threshold for being clinically meaningful2 Yang JC et al. J Clin Oncol. 2013;31(27):3342-3350. Osoba D et al. J Clin Oncol. 1998;16(1):139-44.)

Afatinib delayed time to worsening of clinically relevant symptoms vs pemetrexed/cisplatin Median TTD of symptoms (EORTC QoL QLQ-C30 and QLQ LC-13)1,2 >97% questionnaire completion 27.0 months Cough 8.0 P=0.006 10.4 months Dyspnoea 2.9 Afatinib (n=230) P=0.013 Pem/cis (n=115) 4.2 months Pain 3.1 P=0.188 >97% questionnaire completion Median TTD (months) TTD=time to deterioration, the time from randomisation to first appearance of a score ≥10 points lower than the baseline score. EORTC=European Organisation for Research and Treatment of Cancer. Yang JC et al. J Clin Oncol. 2013;31(27):3342-3350. Wu YL et al. Annals of Oncology (2014) 25 (suppl_4): iv426-iv470. 10.1093/annonc/mdu349.

Afatinib significantly improved quality of life (QoL) vs pemetrexed/cisplatin EORTC QLQ-C30 questionnaire scores Favours afatinib Favours pem/cis Significant difference favouring afatinib Favours pem/cis Global health status/QoL Physical functioning Role functioning Cognitive functioning Emotional functioning Social functioning >97% questionnaire completion >97% questionnaire completion 10 5 -5 Differences in mean scores (95% confidence intervals) Yang JC et al. J Clin Oncol. 2013;31(27):3342-3350.

LUX-LUNG 3 Adverse events

Manageable adverse event profile in LUX-Lung 3 The most common AEs with afatinib were diarrhoea, stomatitis, rash, acne, and paronychia The most common adverse events with afatinib were generally manageable through supportive care Treatment-related discontinuation due to any AE was low (8% vs 12% for pemetrexed/cisplatin) Discontinuation due to diarrhoea and rash/acne with afatinib was 1.3% and 0%, respectively AE=adverse event. Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.

Manageable adverse event profile in LUX-Lung 3   Afatinib (n=229) Pem/cis (n=111) All grades (%) ≥ grade 3 (%) Diarrhoea 218 (95.2) 33 (14.4) 17 (15.3) 0 (0.0) Rash/acne† 204 (89.1) 37 (16.2) 7 (6.3) Stomatitis/mucositis† 165 (72.1) 20 (8.7) 17(15.3) 1 (0.9) Paronychia 130 (56.8) 26 (11.4) Dry skin 67 (29.3) 1 (0.4) 2 (1.8) Decreased appetite 47 (20.5) 7 (3.1) 59 (53.2) 3 (2.7) Pruritis 43 (18.8) Nausea 41 (17.9) 2 (0.9) 73 (65.8) 4 (3.6) Fatigue† 40(17.5) 3 (1.3) 52 (46.8) 14 (12.6) Vomiting 39 (17.0) 47 (42.3) Epistaxis 30 (13.1) Cheilitis 28 (12.2) Anaemia‡ 31 (27.9) Constipation 6 (2.6) 21 (18.9) Leukopenia‡ 4 (1.7) 9 (8.1) Neutropenia‡ 35 (31.5) 20 (18.0) Events are included if reported in more than 10% of patients in either of the treatment groups and if there was at least 10% difference between the groups. Events are listed according to the incidence in the afatinib group. † Group term. ‡ Numbers are based on the AEs reported by the investigator and not derived from the laboratory data. Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.