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until tumour progression until tumour progression LUX Lung 7 Clinical Trial LUX-Lung 7 is a randomised, open-label, phase IIb trial of afatinib versus gefitinib as a first-line treatment of patients with EGFR M+ advanced adenocarcinoma of the lung. afatinib 40 mg oral once daily until tumour progression Adenocarcinoma of the lung Stage IIIb/IV EGFR mutation (Del19 and/or L858R) in the tumour tissue No prior treatment for advanced/metastatic disease ECOG PS 0-1 1:1 randomisation N=319 gefitinib 250 mg once daily until tumour progression Median follow-up: 27.4 months

Secondary endpoints included LUX Lung 7 Study Endpoints Primary endpoints Progression-free survival (PFS) by independent review Time to treatment failure (TTF): the time from randomisation to discontinuation for any reason, allowing continuation of treatment if physicians consider patients to be receiving clinical benefit Overall survival (OS) Secondary endpoints included Objective response rate (ORR) Time to and duration of response Duration of disease control Tumour shrinkage Health related quality of life (HRQoL), as reported by EQ-5D patient questionnaires

LUX Lung 7: 64 sites in 14 countries Recruitment: Dec 2011-Aug 2013 Canada 31 China 48 Hong Kong 6 Taiwan 22 Korea 56 Singapore 27 Germany 14 Spain 25 France 34 Norway 3 Sweden UK 7 Ireland 9 Australia 19

Patient demographics and characteristics were well balanced between the 2 treatment arms Afatinib 160, N (%) Gefitinib 159, N (%) Total 319, N (%) Age, median yrs (min-max) 63 (30-86) 63 (32-89) 63 (30-89) Gender Female 91 (56.9) 106 (66.7) 197(61.8) Male 69 (43.1) 53 (33.3) 122 (38.2) Race Asian 94 (58.8) 88 (55.3) 182 (57.1) Non-Asian* 66 (41.2) 71 (44.7) 137 (42.9) Brain mets 26 (16.3) 25 (15.7) 51 (16.0) Never smoker 106 (66.3) 212 (66.5) Baseline ECOG 51 (31.9) 47 (29.6) 98 (30.7) 1 109 (68.1) 112 (70.4) 221 (69.3) NSCLC stage IIIB 8 (5.0) 3 (1.9) 11 (3.5) IV 152 (95.0) 156 ( 98.1) 308 (96.6) EGFR mutation Del19# 93 (58.1) 93 (58.4) 186 (58.3) L858R 67 (41.9) 66 (41.6) 133 (41.7)

LUX-LUNG 7 Efficacy

Progression-free survival by independent review (primary endpoint) Afatinib demonstrated a 27% reduction in relative risk of death or progression compared to gefitinib Progression-free survival by independent review (primary endpoint) Estimated PFS probability 0.2 0.4 0.6 0.8 1.0 0.0 Median (months) Afatinib® (n=160) 11.0 Gefitinib (n=159) 10.9 Hazard ratio 0.73 (95% CI, 0.57-0.95) P=0.0165 27% vs 15% 18% vs 8% 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time of progression free survival (months) Patients twice as likely to be alive and progression free at 2 years with afatinib vs gefitinib (18% vs 8%, respectively) Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Afatinib – PFS benefit consistent across subgroups, including EGFR mutation type Progression-free survival by independent review (primary endpoint) prespecified subgroups Factors Number of patients Hazard ratio (95% Cl) Total 319 0.732 (0.566, 0.947) EGFR mutation L858R 133 0.708 (0.475, 1.055) Del19 186 0.764 (0.549, 1.063) Brain métastasés Absent 268 0.739 (0.560, 0.976) Present 51 0.764(0.405, 1.439) Baseline ECOG score 98 0.892 (0.542, 1.469) 1 221 0.705 (0.524, 0.948) Gender Maie 122 0.876 (0.585, 1.312) Female 197 0.653 (0.469, 0.910) Age group <65 years 177 0.681 (0.479, 0.968) >65 years 142 0.845 (0.585, 1.221) Race Non-Asian 137 0.717 (0.487, 1.056) Asian 182 0.756 (0.539, 1.060) Smoking hïstory Never smoked 212 0.801 (0.584, 1.097) <15 pack years + stopped >1 year before 40 1.094 (0.559, 2.140) Other current or ex-smokers 67 0.477 (0.270, 0.845) 1/4 1 4 16 1/16 Favours afatinib Favours gefitinib Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Time to treatment failure (primary endpoint) Patients remained on treatment significantly longer with afatinib than with gefitinib Time to treatment failure (primary endpoint) Estimated probability of being free of treatment failure 0.2 0.4 0.6 0.8 1.0 0.0 Median (months) Afatinib® (n=160) 13.7 Gefitinib (n=159) 11.5 Hazard ratio 0.73 (95% CI, 0.58-0.92) P=0.0073 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time to treatment failure (months) 27% significant reduction in relative risk of treatment failure vs gefitinib (P=0.0073) Overall survival data not yet mature TTF is the time from randomisation to discontinuation for any reason, allowing continuation of treatment if physicians consider patients to be receiving clinical benefit Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Objective response by independent review (secondary endpoint) Afatinib demonstrated significantly improved response rates vs gefitinib Objective response by independent review (secondary endpoint) P=0.0083 Afatinib Gefitinib Improved objective response and disease control rates vs gefitinib (ORR: 70% vs 56%, P=0.0083; DCR: 91.3% vs 87.4%) Longer duration of response vs gefitinib (10.1 vs 8.4 months, respectively) Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Tumour shrinkage by independent review (secondary endpoint) Greater tumour shrinkage in all mutations with afatinib versus gefitinib Tumour shrinkage by independent review (secondary endpoint) All mutations Afatinib Gefitinib Based on maximum percentage decrease from baseline in the sum of target lesion diameters. Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Tumour shrinkage by independent review (secondary endpoint) Greater tumour shrinkage in Del19 mutation patients with afatinib versus gefitinib Tumour shrinkage by independent review (secondary endpoint) Del19 mutations Afatinib Gefitinib ≥20% increase >0 - <30% decrease ≥50% decrease ≥0 - <20% increase ≥30 - <50% decrease Based on maximum percentage decrease from baseline in the sum of target lesion diameters. Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Tumour shrinkage by independent review (secondary endpoint) Greater tumour shrinkage in L858R mutation patients with afatinib versus gefitinib Tumour shrinkage by independent review (secondary endpoint) L858R mutations Afatinib Gefitinib ≥20% increase >0 - <30% decrease ≥50% decrease ≥0 - <20% increase ≥30 - <50% decrease Based on maximum percentage decrease from baseline in the sum of target lesion diameters. Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

LUX-LUNG 7 Adverse events

Pattern of AEs consistent with the known profiles of both agents Equally low rates of AE-related discontinuation (6.3% vs 6.3%) with differing causes; skin-related, diarrhoea and fatigue for GIOTRIF®, liver enzyme elevation and ILD for gefitinib The most common AEs were predictable and generally manageable through supportive care and dose reduction AE-related discontinuation 6.3% 6.3% Afatinib Gefitinib AE=adverse event; ILD=interstitial lung disease. Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Pattern of AEs consistent with the known profiles of both agents Related Aes occuring in >10% patients, n(%) Afatinib Gefitinib All Grades Grade 3 Diarrhoea 144 (90.0) 19 (11.9) 97 (61.0) 2 (1.3) Rash/Acne* 142 (88.8) 15 (9.4) 129 (81.1) 5 (3.1) Stomatitis* 103 (64.4) 7 (4.4) 38 (23.9) Paronychia* 89 (55.6) 3 (1.9) 27 (17.0) 1 (0.6) Dry skin 52 (32.5) 59 (37.1) Pruritus 37 (23.1) 36 (22.6) Fatigue* 33 (20.6) 9 (5.6) 23 (14.5) Decreased appetite 26 (16.3) Nausea 22 (13.8) Alopecia 17 (10.6) 24 (15.1) Vomiting 6 (3.8) ALT increase 12 (7.5) AST increase 10 (6.3) 33 (20.8) 4 (2.5) *Preferred terms of AEs. 4 cases of ILD with gefitinib, 3 of them ≥ grade 3, no case of ILD with GIOTRIFR. 1 case of grade 4 diarrhoea with GIOTRIF®, 1 case of grade 4 ALT with gefitinib. ALT=alanine aminotransferase; AST=aspartate transaminase; ILD=interstitial lung disease. Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.