TÓM TẮT LÝ LỊCH TRÍCH NGANG GS SUMITRA THONGPRASERT -Nơi công tác hiện tai: Trường Đại Học Chiang Mai, Thái Lan. -Chuyên ngành: ung thư. -GS là chủ tịch hội ung thư Thái Lan và là đại diện khu vực Đông Á của hiệp hội Ung Thư Châu Âu ( ESMO). -Từ năm 2011: GS là thành viên trong ban chủ tịch của hiệp hội nghiên cứu ung thư phổi thế giới ( IASLC). -Ngoài ra GS hiện đang là thành viên của nhiều tổ chức- hiệp hội về ung thư khác như: Hiệp hội ung thư Châu Á ( ACOS) và hiệp hội ung thư Hoa Kỳ ( ASCO)

SUMITRA THONGPRASERT MAHARAJ NAKORN CHIANG MAI HOSPITAL, CHIANG MAI UNIVERSITY, THAILAND New Treatment Paradigm for EGFR-positive NSCLC The 6 th National Conference on Lung Health Da Nang, Vietnam, Aug 2015

Cure Cure still possible Quality of life  Survival  Surgery ± adjuvant therapy Localised Disease Local Advanced Disease Metastatic Disease (Neoadjuvant) chemotherapy ± radiation Systemic therapy ± palliative locoregional therapies (radiation, laser, stent, brachytherapy, palliative surgery) Surgery (if possible) ± adjuvant therapy Schmidt, Wiewrodt et al. Klinikarzt. 2011;40: Therapeutic Algorithm for NSCLC

Incidence of Single Driver Mutations Johnson, et al. ASCO 2013 (abstract 8019) Barlesi, et al. ASCO 2013 (Abstract 8000) Lung Cancer Mutation Consortium: Mutations found in 64% of cases of lung adenocarcinoma French platforms network: Mutations found in 46% of cases of NSCLC

EGFR Mutations: Validated Predictive Biomarker Guidelines recommend testing for EGFR mutation and ALK rearrangement NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for Non-Small Cell Lung Cancer V Lindeman et al. J Thorac Oncol. 2013;8: Peters et al. Ann Oncol ;23 Suppl 7:vii For all advanced NSCLC with an adenocarcinoma component regardless of sex, race, smoking history, or other clinical risk factors For all advanced NSCLC with nonsquamous histology & for squamous cell carcinoma in never/former light smokers For all advanced NSCLC with nonsquamous histology & for squamous cell carcinoma in never smokers and small biopsy specimens

NCCN Clinical Practice Guidelines in Oncology ® NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for Non-Small Cell Lung Cancer V

NCCN Clinical Practice Guidelines in Oncology® (cont’d) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for Non-Small Cell Lung Cancer V

Afatinib: An Irreversible ErbB Family Blocker Targeting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 EGFR = epidermal growth factor receptor; HER = human epidermal growth factor receptor. Sharma SV, et al. Nature Rev Cancer 2007;7;169 ∙ Ji H, et al. Proc Natl Acad Sci USA 2006;103;7817 ∙ Stephens P, et al. Nature 2004;431:525 ∙ Maheswaran S, et al. N Engl J Med 2008;359:366–377 ∙ Perera SA, et al. PNAS 2009;106:474–479 ∙ BI data on File Afatinib is not yet approved in Vietnam. Afaninib not yet has been approved in Viet Nam

Afatinib: Structure and Binding Afatinib was designed to covalently bind, and therefore irreversibly block the ErbB Family O N N N F Cl O N O N N S O N S O N N N F O O N O N Afatinib Afatinib covalently bound to EGFR, HER2 or ErbB4 Afatinib irreversibly blocks EGFR, HER2 and ErbB4 Li D, et al. Oncogene 2008;27:4702–11; Solca F, et al. J Pharmacol Exp Ther Epub ahead of print.

RESULTS OF LUX-LUNG 3 & 6 TRIALS

Gemcitabine/Cisplatin 1000 mg/m 2 D1, D mg/m 2 IV q21 days, up to 6 cycles LUX-Lung 3 & 6: Study Design Afatinib 40 mg/day † Cisplatin/Pemetrexed 75 mg/m mg/m 2 IV q21 days, up to 6 cycles Stage IIIB (wet)/IV lung adenocarcinoma EGFR mutation in tumour (central lab testing; Therascreen EGFR29* RGQ PCR) *EGFR29: 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I. † Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10-mg decrements in case of related G3 or prolonged G2 AE. ‡ Tumour assessments: q6 weeks until Week 48 and q12 weeks thereafter until progression/start of new therapy. § Patient-reported outcomes: EQ-5D, EORTC QLQ-C30 and LC 13 at randomisation and q3 weeks until progression or new anti-cancer therapy. 1. Sequist LV, et al. J Clin Oncol. 2013;31: Wu Y-L, et al. Abstract Poster presented at ASCO LUX-Lung 3 1 LUX-Lung 6 2 (Asian pts) Randomisation 2:1 Stratified by: EGFR mutation (Del19/L858R/other) Primary endpoint: PFS (RECIST 1.1, independent review) ‡ Secondary endpoints: ORR, DCR, DoR, tumour shrinkage, OS, PRO §, safety

LUX-Lung 3 & 6: Patient Demographics Phase III Studies in the First-line Setting 1.Sequist LV, et al. J Clin Oncol Wu YL, et al. J Clin Oncol. 31, 2013 (suppl;abstr 8016). LUX-Lung 3LUX-Lung 6 Afatinib (n=230) Cis/Pem (n=115) Afatinib (n=242) Gem/Cis (n=122) Gender, n (%)Male83 (36)38 (33)87 (36)39 (32) Female147 (64)77 (67)155 (64)83 (68) Median age, years (range)62 (28–86)61 (31–83)58 (29-79)58 (27-76) Race, n (%)Caucasian61 (27)30 (26) Asian165 (72)83 (72) 242 (100)122 (100) Other4 (1)2 (2) Smoking status, n (%)Never smoked155 (67)81 (70)181 (75)99 (81) Ex-smoker70 (30)32 (28)44 (18)13 (11) Current smoker5 (2)2 (2)17 (7)10 (8) Stage (AJCC 6.0), n (%)IIIB (wet)20 (9)17 (15)16 (7)6 (5) IV210 (91)98 (85)226 (93)116 (95) ECOG PS, n (%)092 (40)41 (36)48 (20)41 (34) 1138 (60)73 (64)194 (80)81 (66) 201 (1) EGFR mutation, n (%)Del19113 (49)57 (49)124 (51)62 (51) L858R91 (40)47 (41)92 (38)46 (38) Other26 (11)11 (10)26 (11)14 (11)

LUX-Lung 3 and 6: Primary Endpoint LUX-Lung 3, 1 n=345 (A vs Cis/Pem) LUX-Lung 6, 2 n=364 (A vs Gem/Cis) Median PFS11.1 vs vs 5.6 HR for PFS0.58 P< P< month PFS47% vs 22%47% vs 2% Independent Review ‒ All Randomised Patients Number at risk Afatinib (LL3) Pem/cis (LL3) Afatinib (LL6) Gem/cis (LL6) Progression-free survival (probability) Progression-free survival (months) 0 Afatinib LUX-Lung 3 Pem/cis LUX-Lung 3 47% 2% Afatinib LUX-Lung 6 Gem/cis LUX-Lung Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213.

. Time of progression free survival (months) Estimated PFS probability Afatinib LUX-Lung 3 Cis/Pem LUX-Lung 3 Afatinib LUX-Lung 6 Cis/Gem LUX-Lung 6 No. at risk: LL3 Afatinib LL3 Cis/Pem LL6 Afatinib LL6 Cis/Gem PFS in overall population LUX-Lung 3 1 (n=308) Afatinib vs Cis/Pem LUX-Lung 6 2,3 (n=324) Afatinib vs Cis/Gem Median PFS13.6 mo vs 6.9 mo11.0 mo vs 5.6 mo HR for PFS0.47, P< , P< *Exon 19 deletions or exon 21 [L858R] substitutions PFS = progression-free survival. 1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213; 3. Data on file. Boehringer Ingelheim LUX-Lung 3 and LUX-Lung 6: Primary End Point PFS in Patients With Common Mutations by Independent Review

LUX-Lung 3 and 6: PFS in Del19 Subgroup 1,2 LUX-Lung 3 No. at risk: Afatinib Cis/Pem Time of progression-free survival (months) Estimated PFS probability Afatinib Cis/Pem 1. Giotrif ® (afatinib) prescribing information, 2013; 2. Data on file. Boehringer Ingelheim. LUX-Lung 6 No. at risk: Afatinib Cis/Gem Time of progression free survival (months) Estimated PFS probability Afatinib Cis/Gem LUX-Lung 3LUX-Lung 6 Afatinib n=113 Cis/Pem n= 57 Afatinib n=124 Cis/Gem n=62 Median, months HR (95% CI), P value0.28 ( ), P< ( ), P<0.01

LUX-Lung 3 and 6: PFS in L858R Subgroup 1,2 LUX-Lung 3 No. at risk: Afatinib Cis/Pem Time of progression-free survival (months) Estimated PFS probability Afatinib Cis/Pem LUX-Lung 6 No at risk: Afatinib Cis/Gem Time of progression free survival (months) Estimated PFS probability Afatinib Cis/Gem LUX-Lung 3LUX-Lung 6 Afatinib n=91 Cis/Pem n=47 Afatinib n=92 Cis/Gem n=46 Median, months HR (95% CI), P value 0.73 ( ), P= ( ), P< Giotrif ® (afatinib) prescribing information, 2013; 2. Data on file. Boehringer Ingelheim.

LUX-Lung 3—All patients 1,2 LUX-Lung 3 and LUX-Lung 6: P<0.001 ORR (%) ORR = objective response rate. 1.Sequist et al. J Clin Oncol. 2013;31:3327; 2. Data on file. Boehringer Ingelheim; 3. Wu et al. Lancet Oncol. 2014;15:213. LUX-Lung 3—Common mutations (Del19/L858R) 1,2 P<0.001 P< LUX-Lung 6—All patients 2,3 P<0.001 ORR (%) LUX-Lung 6—Common mutations (Del19/L858R) 3 P<0.001 P< ORR (%) Afatinib Improved Rates of Response vs Chemotherapy

Clinically Relevant Symptom Improvement 1. Yang et al. J Clin Oncol. 2013;31: Wu et al. Lancet Oncol. 2014;15:213. LUX-Lung 6 2 LUX-Lung 3 1 Afatinib (n=230) Cisplatin/pemetrexed (n=115) Afatinib (n=242) Cisplatin/gemcitabine (n=122) Cough (Q1 from QLQ-LC13) Dyspnoea (Q3-5 from QLQ-LC13) Dyspnoea rested (Q3 from QLQ-LC13) Dyspnoea walked (Q4 from QLQ-LC13) Dyspnoea climbed stairs (Q5 from QLQ-LC13) Short of breath (Q8 from QLQ-C30) Pain (Q9, Q19 from QLQ-C30) Have pain (Q9 from QLQ-C30) Pain affecting daily activities (Q19 from QLQ-C30) Pain in chest (Q10 from QLQ-LC13) Pain in arm/shoulder (Q11 from QLQ-LC13) Pain in other parts (Q12 from QLQ-LC13) P < Patients (%) Cough Dyspnoea (rested) Short of breath Pain Pain in chest Pain in arm or shoulder Pain in other parts < P Patients (%) Dyspnoea Dyspnoea (walked) Dyspnoea (climbed stairs) Pain affecting daily activities Have pain <

Time to Deterioration (Worsening) of Symptoms CoughDyspnoeaPain LUX-Lung 3 1 LUX-Lung Sequist LV, et al. J Clin Oncol Wu YL, et al. J Clin Oncol. 31, 2013 (suppl;abstr 8016).

Difference in Mean Scores Over Time for Global Health Status/QoL and Functional Scales LUX-Lung 3 1 LUX-Lung 6 2 Mean Treatment Difference (95% CI) P Value Global health status Global health status/QoL (QLQ-C30: Q29– 30) –3.18 (–5.75 to – 0.61) Functional scales Physical (QLQ-C30: Q1–5) –4.80 (–7.47 to – 2.13) <0.001 Role (QLQ-C30: Q6–7) –4.40 (–7.40 to – 1.40) Emotional (QLQ-C30: Q21–24) –0.87 (–3.20 to 1.46) Cognitive (QLQ-C30: Q20 and 25) –3.16 (–5.47 to – 0.85) Social (QLQ-C30: Q26–27) –1.11 (–3.94 to 1.72) Favours afatinib Favours cisplatin-pemetrexed –10–8–6–4– No. Patients Mean treatment difference (95% CI) Factors Global health status Global health status/QoL (QLQ-C30: Q29– 30) 354–8.78 (–11.19 to –6.36) Functional scores Physical (QLQ-C30: Q1–5)354–9.35 (–11.55 to –7.14) Role (QLQ-C30: Q6–7)354–8.08 (–10.76 to –5.40) Emotional (QLQ-C30: Q21–24)354–5.61 (–7.83 to –3.39) Cognitive (QLQ-C30: Q20 and 25)354–5.91 (–8.18 to –3.64) Social (QLQ-C30: Q25–27)354–10.48 (–13.35 to –7.61) –18–13–8–327 Favours afatinibFavours gemcitabine/cisplatin CI = confidence interval. 1. Yang et al. J Clin Oncol. 2013;31:3342; 2. Geater et al. ASCO Abstract 8061.

LUX-Lung 3 LUX-Lung 3 & 6: OS in Common Mutations Estimated OS probability Time (months) Afatinib Cis/Pem No of patients PFS in overall population Afatinib (n=203) Cis/Pem (n=104) Median, months HR (95% CI), P value 0.78 ( ), P= Afatinib Cis/Pem Estimated OS probability Time (months) Afatinib Cis/Gem No of patients PFS in overall population Afatinib (n=216) Cis/Gem (n=108) Median, months HR (95% CI), P value 0.83 ( ), P= LUX-Lung 6 Afatinib Cis/Gem Yang et al. Lancer Oncol. 2015;16(2):

Overall Survival in Common Mutations: Subgroups PatientsHR Total Gender Male Female Age (years) < ≥ EGFR mutation Del L858R Baseline ECOG score Smoking history Never smoker yr ago Other current/ex-smoker Race Non-Asian Asian PatientsHR Favours Afatinib Favours Cis/Pem Favours Afatinib Favours Cis/Gem LUX-Lung 3LUX-Lung /4 1/ /4 1/16 16 Yang et al. Lancer Oncol. 2015;16(2):

LUX-Lung 3 LUX-Lung 3 & 6: OS in Del19 Subgroup Afatinib Cis/Pem No. of patients: Estimated OS probability Time (months) PFS in overall population Afatinib (n=112) Cis/Pem (n=57) Median, months HR (95% CI) P value 0.54 (0.36–0.79) P= Afatinib Cis/Pem LUX-Lung Estimated OS probability Time (months) Afatinib Cis/Gem No. of patients: PFS in overall population Afatinib (n=124) Cis/Gem (n=62) Median, months HR (95% CI) P value 0.64 (0.44–0.94) P= Afatinib Cis/Gem Yang et al. Lancer Oncol. 2015;16(2):

Common mutations Afatinib (n=419) Chemo (n=212) Median, months HR (95% CI) P value 0.81 ( ) P= Common mutations (Del19/L858R) (n=631) Time of overall survival (months) Estimated OS probability No. at risk: Afatinib Chemotherapy Afatinib Chemotherapy Yang et al. Lancer Oncol. 2015;16(2): LUX-Lung 3 & 6 Post-hoc Combined OS Analysis: Subgroup With Common Mutations

Treatment After 1st Line In Patients With Common Mutations LUX-Lung 3LUX-Lung 6 Afatinib (n=203) Cis/Pem (n=104) Afatinib (n=216) Cis/Gem (n=108) Discontinued treatment, n (%)184 (100)104 (100)194 (100)108 (100) Subsequent systemic therapy, n (%) a 144 (78)88 (85)123 (63)70 (65) Chemotherapy, n (%)131 (71)49 (47)114 (59)29 (27) EGFR TKI, n (%) Erlotinib Gefitinib Afatinib AZD9291 Dacomitinib Icotinib EGFR TKI combinations 81 (44) 61 (33) 28 (15) 2 (1) – 5 (3) 78 (75) 46 (42) 44 (42) 7 (7) 1 (1) – 9 (9) 50 (26) 21 (11) 19 (10) – 11 (6) 5 (3) 61 (56) 22 (20) 39 (36) – 3 (3) Other systemic therapy b, n (%)5 (3)2 (2) 3 (2)4 (4) Radiotherapy, n (%)32 (17)21 (20) 4 (2)0 (0) a Collection of data on subsequent therapies still ongoing. b Includes investigational agents, monoclonal antibodies, non-EGFR targeting protein kinase inhibitors etc. Yang et al. Lancer Oncol. 2015;16(2):

Impact Of Subsequent EGFR TKIs On OS: Exploratory Analyses By Category Of EGFR TKI Reimbursement Policy In Country Of Residence* Poplation % received TKI after 1 st line chemo HR (95% CI) Common mutations HR (95% CI) Del19 HR (95% CI) L858R Combined LL-3/6 population (n=631) 66% 0.81 (0.66–0.99) 0.59 (0.45–0.77) 1.25 (0.92–1.71) Countries with reimbursement** (n=219) 91% 0.71 (0.49–1.02) 0.50 (0.31–0.81) 1.14 (0.64–2.03) Countries without reimbursement*** (n=412) 52% 0.85 (0.66–1.08) 0.59 (0.42–0.82) 1.32 (0.91–1.92) Japan (n=77) 100% 0.57 (0.29–1.12) 0.34 (0.13–0.87) 1.13 (0.40–3.21) *Determined by presence or absence of a national reimbursement policy in effect throughout the period of trial conduct: **Main countries contributing : Japan, Taiwan, Korea, Germany, France, Australia, UK, Belgium, Ireland ***Main countries contributing : China, Thailand, Russia, the Philippines, Malaysia Yang et al. Lancer Oncol. 2015;16(2):

Afatinib is the first drug proving an overall survival benefit in EGFR mutated NSCLC Yang et al. ASCO Abstract Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213; 3. Mok et al. N Engl J Med. 2009;361:947; 4. Fukuoka et al. J Clin Oncol. 2011;29:2866; 5. Yang et al. Eur J Cancer. 2011;(suppl 1):S633; 6. Maemondo et al. N Engl J Med. 2010;362:2380; 7. Inoue et al. Ann Oncol. 2013;24:54; 8. Mitsudomi et al. Lancet Oncol. 2010;11:121; 9. Rosell et al. Lancet Oncol. 2012;13:239; 10. TARCEVA ® (erlotinib) prescribing information, 2013; 11. Zhou et al. Lancet Oncol. 2011;12:735; 12. Wu et al. J Thorac Oncol. 2013;8(suppl 2):P Trial PFS HR (95% CI) LUX-Lung 3 1 Del (0.18–0.44) L858R0.73 (0.46–1.17) LUX-Lung 6 2 Del (0.13–0.33) L858R0.32 (0.19–0.52) IPASS 3–5 Del (0.26–0.56) L858R0.55 (0.35–0.87) NEJ002 6,7 Del (0.23–0.52) L858R0.32 (0.20–0.50) WJTOG Del (0.27–0.77) L858R0.51 (0.29–0.90) EURTAC 9,10 Del (0.18–0.50) L858R0.55 (0.29–1.02) OPTIMAL 11 Del (0.07–0.25) L858R0.26 (0.14–0.49) ENSURE 12 Del (0.12–0.33) L858R0.54 (0.32–0.90) Favours ChemotherapyFavours TKI Favours ChemotherapyFavours TKI OS HR (95% CI) 0.54 (0.36–0.79) 1.30 (0.80–2.11) 0.64 (0.44–0.94) 1.22 (0.81–1.83) 0.79 (0.54–1.15) 1.44 (0.90–2.30) 0.83 (0.52–1.34) 0.82 (0.49–1.38) NA 0.94 (0.57–1.54) 0.99 (0.56–1.76) NA

Meta-analysis: No OS difference with 1231 patients in 6 major randomized trials comparing 1 st Gen TKIs vs CTs Lee et al. ASCO Abstract Study Name n†n† Treatment Comparison NEJ002218*Gefitinib vs CP WJTOG Gefitinib vs CisD OPTIMAL154Erlotinib vs CG EURTAC173 Erlotinib vs Platinum-G or Platinum-D IPASS298*Gefitinib vs CP ENSURE216Erlotinib vs CisG * Contains patients with both Exon 19 deletion and Exon 21 L858R substitution mutation of the epidermal growth factor receptor gene (NEJ002, n = 3; IPASS, n = 6). † Includes only patients with common mutation of the epidermal growth factor receptor gene CisG = cisplatin-gemcitabine; CisD = cisplatin- docetaxel; CP = carboplatin-paclitaxel; CG = carboplatin-gemcitabine

Meta-analysis: No OS difference with type of EGFR mutation, smoking and gender subgroups comparing 1 st Gen TKIs vs Chemotherapies 029 Lee et al. ASCO Abstract 8072.

LUX-Lung 3 1,2 / LUX-Lung 6 2,3, % Afatinib LL3 (n=229) / LL6 (n =239 )Cis/Pem (n=111) / Cis/Gem (n=113) All GradesGrade 3Grade 4All GradesGrade 3Grade 4 Rash/acne a 89.1 / / / / Diarrhoea95.2 / / / Paronychia/nail effect a 56.8 / / / 000 Stomatitis/mucositis a 72.1 / / / / / 0.00 Decreased appetite20.5 / / / / 1.80 Vomiting17.0 / / / / / 3.5 Fatigue a 17.5 / / / / 0.90 Nausea17.9 / / / / /0.9 Dry skin/pruritus b 29.3 / / / Neutropenia0.9 / / / / / 8.8 Anaemia3.1 / / / / / 1.8 Leukopenia1.7 / / / / / 1.8 ALT increase7.4 / / / / / 0.9 AST increase5.2 / / / / 1.80 Most Frequent Treatment-Related Adverse Events (>20% Difference Between Treatment Arms) a Grouped term for closely related AEs. b In LUX-Lung 3, the incidence for dry skin and pruritus were reported separately as 29.3% and 18.8%, respectively, for all grades and 0.4% each for grade ≥3 in afatinib arm. ALT = alanine aminotransferase; AST = aspartate aminotransferase. 1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Data on file. Boehringer Ingelheim; 3. Wu et al. Lancet Oncol. 2014;15:213.

LUX-Lung 3 and LUX-Lung 6: Summary of Adverse Events a Includes 3 patients (1%) who discontinued due to diarrhoea, no discontinuations for rash. b Includes 3 patients (1%) with ILD-like events (1 grade 1, 1 grade 3; 1 grade 5). c Including 1 patient with ILD. d Preferred terms: dyspnoea, sepsis, ARDS, death (unknown cause). e Sudden death (afatinib) and cardiac failure (Cis/Gem). SAE = serious adverse event; ILD = interstitial lung disease; ARDS = acute respiratory distress syndrome. 1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Data on file. Boehringer Ingelheim; 3. Wu et al. Lancet Oncol. 2014;15:213. % of Patients LUX-Lung 3 1,2 LUX-Lung 6 2,3 Afatinib (n=229) Cis/Pem (n=111) Afatinib (n=239) Cis/Gem (n=113) Drug-related AEs Drug-related AE grade ≥ Drug-related AEs leading to discontinuation 8 a,b 126c6c 40 Discontinuation due to rash002.1 (5 pts)0 Discontinuation due to diarrhoea1.3 (3 pts)000 Drug-related SAE14 57 Related SAE leading to death1.7 (4 pts) d 00.4 (1 pt) e 0.9 (1 pt) e

Conclusions: LUX-Lung 3 & 6 Trial Data LUX-Lung 3 and LUX-Lung 6 are the largest and most robust prospective randomised trials in EGFR mutation–positive NSCLC LUX-Lung 3 met its primary end point of PFS (independent review) –Median PFS of 11.1 months for afatinib vs 6.9 months for chemotherapy in overall study population; HR=0.58 (95% CI, ); P<0.001 –Consistent efficacy in all relevant subgroups –Significant improvement in response rates and disease control rates LUX-Lung 6 consistently confirmed the results of LUX-Lung 3 and met its primary end point of PFS (independent review) –Median PFS of 11.0 months for afatinib vs 5.9 months for chemotherapy in overall study population; HR=0.28 (95% CI, ); P< –Consistent efficacy in all relevant subgroups –Significant improvement in response rates and disease control rates PFS improvement with first-line afatinib was associated with a significant improvement in patient-reported outcomes and the QoL in both trials –Afatinib demonstrated a significant delay in time to deterioration for cough and dyspnoea in both LUX-Lung 3 and 6 trials and also delayed pain in LUX-Lung 6 trial

Conclusions: LUX-Lung 3 & 6 Trial Data (cont‘d) First-line afatinib significantly improved OS vs chemotherapy in EGFR Del19 patients in two randomized trials –LUX-Lung 3: median 33.3 vs 21.1 months, HR=0.54, p= –LUX-Lung 6: median 31.4 vs 18.4 months, HR=0.64, p= No significant difference in OS of patients with L858R mutations, individually, or in exploratory combined analysis –Benefit in PFS, ORR and PRO previously shown Del19 and L858R patients are two distinct populations and should be studied separately in the future An OS benefit with afatinib in patients with common mutations (Del19/L858R) in the exploratory combined analysis Diarrhoea and rash were the most frequent AEs; manageable with low treatment discontinuation rate First-line afatinib should be the standard of care for EGFR Del19 patients and remains a treatment option for EGFR L858R patients