Targeting angiogenesis in NSCLC: Clinical trial update Martin Reck Lung Clinic Grosshansdorf Grosshansdorf, Germany

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1 Targeting angiogenesis in NSCLC: Clinical trial update Martin Reck Lung Clinic Grosshansdorf Grosshansdorf, Germany This presentation was selected by the 15 th World Conference on Lung Cancer Program Committee as an independent activity held in conjunction with the 15 th World Conference on Lung Cancer. This presentation is not sponsored or endorsed by IASLC.

2 Bevacizumab: Meta-analysis of efficacy data from first-line RCTs Trial HR HR (95% CI) AVF-757g ( )* AVF-757g ( )* ECOG (.69.93) AVAiL ( ) AVAiL ( ) JO ( ) Total Meta-analysis confirmed that both OS and PFS in NSCLC patients primarily of non-squamous histology are significantly improved by bevacizumab treatment OS.9 (.81.99) p=.3 PFS Favours bevacizumab Favours control Test for heterogeneity p=.44 For *AVF-757g trial: direction of OS HR unknown, worst scenario chosen. RCTs = randomized controlled trials; OS = overall survival; PFS = progression-free survival; HR = hazard ratio; CI = confidence interval. Soria JC, et al. Ann Oncol 213;24:2 3. HR Favours bevacizumab Favours control Test for heterogeneity p=.17 HR (95% CI).76 ( ).52 ( ).66 (.57.77).75 (.63.9).85 ( ).55 (.38.79).72 (.66.79) p<.1

3 Bevacizumab: Meta-analysis of safety data from first-line RCTs Tolerability of bevacizumab in NSCLC patients primarily of non-squamous histology Grade 3 toxicity (%) Category Bevacizumab Control Odds ratio OR (95% CI) Proteinuria ( ) Hypertension ( ) Thrombosis ( ) Haemorrhagic events ( ) Neuropathy ( ) Neutropenia ( ) Febrile neutropenia ( ) Thrombocytopenia ( ) Anaemia ( ) RCTs = randomized controlled trials; OR = odds ratio; CI = confidence interval. Soria JC, et al. Ann Oncol 213;24:2 3. Favours bevacizumab Favours control

4 However, numerous antiangiogenic agents have failed to show a survival benefit in advanced NSCLC First line Second line Study Intervention Target PFS, months OS, months ESCAPE 1 (n=926) NExUS 2 (n=772) ZEAL 3 (n=534) ZODIAC 4 (n=1391) SUN187 5 (n=96)* VITAL 6 (n=913) BETA 7 (n=636) CB/PTX/placebo CB/PTX/sorafenib VEGFR-2, -3, CIS/GEM/placebo CIS/GEM/sorafenib Pemetrexed/placebo Pemetrexed/vandetanib Docetaxel/placebo Docetaxel/vandetanib Erlotinib/placebo Erlotinib/sunitinib Docetaxel/placebo Docetaxel/aflibercept Erlotinib/placebo Erlotinib/bevacizumab PDGFR-ß, Flt-3, b-raf, c-kit VEGFR, EGFR, RET VEGFR-1, -2, -3, PDGFR-ɑ, -ß, Flt-3, c-kit VEGF-A, -B, PIGF VEGF-A HR:.99 ( ) HR:.83 (.71.97) HR:.86 ( ) HR:.79 (.7.9) HR:.81 (.7.94) HR:.82 (.72.94) HR:.62 (.52.75) HR: 1.15 ( ) HR:.98 ( ) HR:.86 ( ) HR:.91 ( ) HR:.92 (.8 1.7) HR: 1.1 ( ) HR:.97 ( ) Primary endpoint OS OS PFS PFS OS OS OS *28 patients received >1 prior treatment lines. CB = carboplatin; PTX = paclitaxel; CIS = cisplatin; GEM = gemcitabine; OS = overall survival; PFS = progression-free survival; HR = hazard ratio; VEGF = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor; RAF = rapidly accelerated fibrosarcoma; PIGF = placental growth factor receptor. 1. Scagliotti G, et al. J Clin Oncol 21;28: ; 2. Paz-Ares LG, et al. J Clin Oncol 212;3:384 92; 3. de Boer R, et al. J Clin Oncol 211;29:167 74; 4. Herbst R, et al. Lancet Oncol 21;11:619 26; 5. Scagliotti GV, et al. J Clin Oncol 212;3:27 8; 6. Ramlau R, et al. J Clin Oncol 212;3:364 7; 7. Herbst R, et al. Lancet Oncol 211;377:

5 Ramucirumab a monoclonal antibody targeting VEGFR-2 Key Phase II/III studies in advanced NSCLC Trial Therapy line (patient selection) Regimens Primary endpoint(s) Secondary endpoint(s) Status NCT (I4T-IE-JVBJ) 1 Phase II First line Ramucirumab + paclitaxel + carboplatin PFS: 7.85 months ORR: 55% Final results presented at ESMO 212 NCT (I4T-IE-JVBL) 2,3 Phase II First line (recurrent or advanced NSCLC) Ramucirumab + pemetrexed + carboplatin + cisplatin versus pemetrexed + carboplatin + cisplatin Ramucirumab + gemcitabine + carboplatin + cisplatin versus gemcitabine + carboplatin + cisplatin PFS: 6.3 months (interim data) PFS: 4.3 months (interim data) Not reported ORR Safety Not reported Interim results presented at ESMO 212 REVEL NCT (I4T-MC-JVBA) 4 Phase III Second line (Stage IV NSCLC) Ramucirumab + Docetaxel + placebo OS PFS ORR Estimated primary completion date: Jan 214 VEGFR = vascular endothelial growth factor receptor; PFS = progression-free survival; OS = overall survival; ORR = overall response rate. 1. Camidge DR, et al. Ann Oncol 212;23(Suppl. 9):Abstract 2147; 2. NCT116744: 3. Doebele R, et al. Ann Oncol 212;23(Suppl. 9):Abstract 1245P; 4. NCT :

6 Nintedanib* a triple angiokinase inhibitor Oral triple angiokinase inhibitor targeting:1,2 VEGFR 1 3 FGFR 1 3 PDGFR α/β RET Manageable safety profile in combination with: Docetaxel3 Pemetrexed4 Paclitaxel/carboplatin5 Gemcitabine/cisplatin6 Afatinib7 *Nintedanib is an investigational agent and it is not yet approved; its efficacy and safety have not yet been fully established. VEGF = vascular endothelial growth factor receptor; FGFR = fibroblast growth factor receptor; PDGFR = platelet-derived growth factor receptor. 1. Hilberg F, et al. Cancer Res 28;68:4774 8; 2. Boehringer Ingelheim Data on file; 3. Bousquet G, et al. Br J Cancer 211;15:164 5; 4. Ellis PM, et al. Clin Cancer Res 21;16:2881 9; 5. Doebele RC, et al. Ann Oncol 212;23:294 12; 6. Boehringer Ingelheim. Data on file; 7. Soria J-C, et al. Ann Oncol 212;23(Suppl.9):Abstract 979.

7 LUME-Lung 1: Study design Stage IIIB/IV recurrent NSCLC patients after first-line chemotherapy (all histologies) R A N D O M IZ E 1:1 Nintedanib 2mg BID p.o., Days mg/m 2 IV, Day 1, 21-day cycles (n=655) Placebo BID p.o., Days 2 21, + 75mg/m 2 IV, Day 1, 21-day cycles (n=659) PD PD N=1314 Number of cycles not restricted Monotherapy allowed after 4 cycles of combination therapy Primary endpoint: PFS (independent central review) Key secondary endpoint: OS (pre-planned analyses of adenocarcinoma and ITT population) Stratification: ECOG PS ( vs. 1) Prior bevacizumab (yes vs. no) Histology (squamous vs. non-squamous) Brain metastases (yes vs. no) Regions: Europe/Asia/South Africa Accrual: 23 Dec 28 to 9 Feb 211 BID = twice daily; p.o. = by mouth; IV = intravenous; PD = progressive disease; PFS = progression-free survival; OS = overall survival; ITT = intent-to-treat; ECOG PS = Eastern Cooperative Oncology Group pefermance status. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation.

8 LUME-Lung 1: Baseline demographics and oncological history Nintedanib + (n=655) Placebo + (n=659) 1 Patients (%) ECOG PS = Eastern Cooperative Oncology Group pefermance status. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation.

9 LUME-Lung 1: Progression-free survival Independent central review in all patients Probability of PFS (%) Time (months) No. at risk: Nintedanib Placebo Nintedanib + Placebo + Median, mo HR (95% CI).79 (.68.92) p value PFS = progression-free survival; mo = months; HR = hazard ratio; CI = confidence interval. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation.

10 LUME-Lung 1: Progression-free survival Independent central review in major histologies Adenocarcinoma Squamous-cell carcinoma 1 Nintedanib + Placebo + 1 Nintedanib + Placebo + Probability of PFS (%) Median, mo HR (95% CI).77 (.62.96) p value.193 Probability of PFS (%) Median, mo HR (95% CI).77 (.62.96) p value.2 No. at risk: Nintedanib Placebo Time (months) No. at risk: Nintedanib Placebo Time (months) PFS = progression-free survival; mo = months; HR = hazard ratio; CI = confidence interval. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation.

11 LUME-Lung 1: Progression-free survival All patients Characteristic Hazard ratio (95% CI) Int. p value Overall.79 (.68.92) Sex.8413 Female.87 ( ) Male.79 (.66.94) Age class.5789 <65 years.76 (.64.91) 65 years.86 ( ) Ethnic origin.7752 Asian.87 ( ) Non-Asian.79 (.67.93) Smoking status.129 Current smoker/ex-smoker.86 ( ) Never smoker.64 (.46.89) Tumour histology.47 Adenocarcinoma.77 (.62.96) Squamous-cell carcinoma.77 (.62.96) Other.96 ( ) ECOG PS (.6 1.8) 1.78 (.66.93) Brain metastases.4612 No.79 (.68.93) Yes.71 ( ) Prior bevacizumab.572 No.8 (.68.93) Yes.64 ( ) Time since start of first-line.2333 <9 months.72 (.6.87) 9 months.87 ( ) Best response to first-line.657 CR/PR/SD.8 (.67.97) PD.73 (.54.97) Favours nintedanib Favours placebo ECOG PS = Eastern Cooperative Oncology Group perfomance status; CR = complete response; PR = partial reponse; SD = stable disease; PD = progressive disease; CI = confidence interval. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation.

12 LUME-Lung 1: Overall survival All patients Probability of survival (%) Nintedanib + Placebo + Median, mo HR (95% CI).94 ( ) p value No. at risk: Nintedanib Placebo Time (months) mo = months; HR = hazard ratio; CI = confidence interval. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation.

13 LUME-Lung 1: Overall survival Patients with adenocarcinoma histology Probability of survival (%) No. at risk: Nintedanib Placebo % 44.7% 25.7% 19.1% Nintedanib + Placebo + Median, mo HR (95% CI).83 (.7.99) p value Time (months) mo = months; HR = hazard ratio; CI = confidence interval. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation.

14 LUME-Lung 1: Overall survival Patients with adenocarcinoma histology Characteristic Hazard ratio (95% CI) Overall.83 (.7.99) Sex.794 Female.84 ( ) Male.84 ( ) Age class.756 <65 years.83 ( ) 65 years.82 ( ) Ethnic origin.532 Asian.89 ( ) Non-Asian.81 (.67.98) Smoking status.511 Current smoker/ex-smoker.86 ( ) Never smoker.81 (.6 1.9) ECOG PS ( ) 1.85 (.7 1.4) Brain metastases.125 No.8 (.67.96) Yes 1.27 ( ) Prior bevacizumab.241 No.85 ( ) Yes.61 ( ) Time since start of first line.419 <9 months.75 (.6.92) 9 months.89 ( ) Best response to first line.189 CR/PR/SD.9 ( ) PD.62 (.41.94) Favours nintedanib Favours placebo ECOG PS = Eastern Cooperative Oncology Group perfomance status; CR = complete response; PR = partial reponse; SD = stable disease; PD = progressive disease; CI = confidence interval. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation. Int. p value

15 LUME-Lung 1: Overall survival in patients with adenocarcinoma and PD as best response to first-line chemotherapy Probability of survival (%) No. at risk: Nintedanib Placebo Nintedanib + Placebo + Median, mo HR (95% CI).62 (.41.94) p value Time (months) mo = months; HR = hazard ratio; CI = confidence interval. Mellemgaard A, et al. Eur J Cancer 213;49(Suppl. 2):Abstract 349 and oral presentation.

16 LUME-Lung 1: HR as a function of time since start of first-line therapy in adenocarcinoma patients 4. OS, final analysis from LUME-Lung 1 HR (95% CI) Time since start of first-line therapy (months) The shorter the time from start of first-line therapy to randomization, the better the treatment effect from nintedanib HR = hazard ratio; CI = confidence interval; OS = overall survival. Kaiser R, et al. Eur J Cancer 213;49(Suppl. 2):Abstract 3479 and poster presentation.

17 LUME-Lung 1: Met its primary endpoint Nintedanib in combination with significantly prolonged PFS for all patients, regardless of histology (HR:.79, p=.19) A significant improvement in OS was demonstrated in patients with adenocarcinoma (HR:.83, p=.359, median 1.3 to 12.6 months) Indications of increased efficacy in patients with fast-progressing adenocarcinoma PFS = progression-free survival; HR = hazard ratio; OS = overall survival. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation.

18 LUME-Lung 2: Study design Study stopped, as per IDMC recommendation, after interim futility analysis of investigator-assessed PFS Stage IIIB/IV or recurrent NSCLC Non-squamous histology only Relapsed or failed 1 prior line of CTX Measurable lesion ECOG PS or 1 Non-active brain metastases permitted N=1116 n=713 R 1:1 Nintedanib 2 mg BID p.o., Days 2 21, + pemetrexed 5 mg/m 2 IV, Day 1 21-day cycles (n=353) Placebo 2 mg BID p.o., Days 2 21, + pemetrexed 5 mg/m 2 IV, Day 1 21-day cycles (n=36) Monotherapy with nintedanib/placebo or pemetrexed allowed after 4 cycles PD PD Primary endpoint: PFS (independent central review) Secondary endpoints: OS, PFS (investigator assessment), ORR, safety Regions: Asia, North and South America, Europe IDMC = independent data monitoring committee; PFS = progression-free survival; CTX = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group performance status; BID = twice daily; p.o. = by mouth; IV = intravenous; OS = overall survival; ORR = overall response rate; PD = progressive disease. Hanna NH, et al. J Clin Oncol 213;31(Suppl.):Abstract 834 and poster presentation.

19 LUME-Lung 2: Baseline demographics and oncological history Nintedanib + pemetrexed (n=353) Placebo + pemetrexed (n=36) 1 8 Patients (%) ECOG PS = Eastern Cooperative Oncology Group performance status. Hanna NH, et al. J Clin Oncol 213;31(Suppl.):Abstract 834 and poster presentation.

20 LUME-Lung 2: Stopped after interim futility analysis Based on a pre-planned futility analysis of investigator-assessed PFS performed by the IDMC, enrolment was halted after 713/13 planned patients had entered the study The analysis suggested that the study was futile and that the primary endpoint of centrally assessed PFS would likely not be met Ongoing patients were unblinded and follow-up was continued per protocol Analysis of the primary endpoint (PFS) was conducted by independent central review after 498 events had occurred IDMC = independent data monitoring committee; PFS = progression-free survival. Hanna NH, et al. J Clin Oncol 213;31(Suppl.):Abstract 834 and poster presentation.

21 LUME-Lung 2: Met its primary endpoint, even though the study was stopped prematurely Centrally reviewed PFS Probability of PFS (%) No. at risk: Nintedanib Placebo Nintedanib + Placebo + Median, mo HR (95% CI).83 (.7.99) p value Time (months) Includes patients entered after 18 June 211 (all events up to 9 July 212). PFS = progression-free survival; mo = months; HR = hazard ratio; CI = confidence interval. Hanna NH, et al. J Clin Oncol 213;31(Suppl.):Abstract 834 and poster presentation.

22 LUME-Lung 1 LUME-Lung 1 and 2: Nintedanib had a manageable, expected safety profile with or pemetrexed Nintedanib + Placebo Non-haematological AEs All CTCAE grades (%) 15% incidence CTCAE Grade 3 (%) 1% incidence LUME-Lung 2 Nintedanib + pemetrexed Placebo + pemetrexed Red text indicates AEs for which the frequency for nintedanib is twice that of placebo. LUME-Lung 2 AEs are listed in the same order as LUME-Lung 1 AEs AEs = adverse events; AST = aspartate aminotransferase; ALT = alanine aminotransferase. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation; Hanna NH, et al. J Clin Oncol 213;31(Suppl.):Abstract 834 and poster.

23 LUME-Lung 1: Low frequency of VEGF/VEGFR inhibitorassociated adverse events following nintedanib treatment 2 All CTCAE grades (%) 2 CTCAE Grade 3 (%) Patients (%) Nintedanib + Placebo Nintedanib + Placebo + Incidence rates of characteristic adverse events were comparable in LUME-Lung 2 VEGF(R) = vascular endothelial growth factor (receptor); CTCAE = Common Terminology Criteria for Adverse Events; GI = gastrointestinal; VTE = venous thromboembolism; ATE = arterial thromboembolism. Reck M, et al. J Clin Oncol 213;31(Suppl.):Abstract LBA811 and oral presentation; Hanna NH, et al. J Clin Oncol 213;31(Suppl.):Abstract 834 and poster presentation.

24 Targeting angiogenesis in NSCLC Recent data with nintedanib in the second-line setting is encouraging for patients with advanced NSCLC Significant improvement of centrally reviewed PFS with nintedanib plus chemotherapy in two Phase III trials (LUME-Lung 1 and LUME-Lung 2) First agent to show significant prolongation of survival in combination with versus alone in patients with pretreated adenocarcinoma (median survival 12.6 vs. 1.4 months; p=.359) Manageable safety profile with no unexpected findings Further investigations are warranted to identify molecular and clinical determinants of benefit for nintedanib in NSCLC Data from ongoing trials are eagerly awaited to further define the role of angiogenic inhibition in NSCLC PFS = progression-free survival.

25 Questions and answers This presentation was selected by the 15 th World Conference on Lung Cancer Program Committee as an independent activity held in conjunction with the 15 th World Conference on Lung Cancer. This presentation is not sponsored or endorsed by IASLC.