Therapeutic Algorithm for Lung Adenocarcinoma Suresh S. Ramalingam, MD Professor Director of Medical Oncology Emory University Atlanta, USA

Disclosures Advisory board Amgen, Aveo, Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Clovis, Genentech, Lilly, Novartis

Outline Role of systemic chemotherapy Integration of targeted agents Targeted agents with salvage chemotherapy

Treatment Algorithm For Advanced NSCLC Lung Adenocarcinoma Known Oncogenic Driver Targetable (EGFR, ALK, ROS) Targeted Therapy First-line, Maintenance or Salvage No Proven Targeted Therapy (KRAS, HER2, RAF, MET, PIK3CA) Clinical Trial or Chemotherapy Absence of Driver Mutations / Unknown Molecular Status Chemotherapy

First- Line TKI Therapy in EGFR Mutated NSCLC—Randomized Phase III Trials Study N Treatment Arm Control Stage Median PFS OS Indication IPASS (Mok TS, et al. N Engl J Med. 2009;361:947-957.) 1217 Gefitinib Carboplatin/ Placitaxel IIIB/IV 5.7 vs 5.8 months (HR for EGFR mutated pts 0.48; HR for nonmutated pts 2.84) 18.6 vs 17.3 months (P = NS) First-line WJTOG3405 (Mitsudomi T, et al. Lancet Oncol. 2010; 11:121-128.) 177 (M+) Cisplatin, Docetaxel 9.2 vs 6.3 months (P < 0.001) Maemondo M, et al. N Engl J Med. 2010; 362:2380-2388. 230 (M+) Carboplatin, Paclitaxel 10.8 vs 5.4 months (HR 0.3, P < 0.0001) 30.5 vs 23.6 months OPTIMAL (Zhou C, et al. Lancet Oncol. 2011;12:735-742.) 165 (M+) Erlotinib Carboplatin/ Gemcitabine 13.6 vs 4.6 months (HR 0.16, P < 0.0001) EURTAC (Rosell R, et al. Lancet Oncol. Jan 25, 2012 [Epub ahead of print].) 153 (M+) Platinum-based chemotherapy 9.4 vs 5.2 months (HR, 0.42, P < 0.0001) 22.9 vs 18.8 months (P = 0.42) PFS is superior, no survival advantage for first line TKI- effect of cross-over

Afatinib Vs. Chemotherapy Exon 19 Exon 21 Yang et al, Lancet Oncol, 2015

Phase III Study in Chemotherapy Naïve Patients with NSCLC: Study Design Pemetrexed 500 mg/m2 + Cisplatin 75 mg/m2 day 1 Stage IIIB/IV NSCLC PS 0-1 No prior chemo Randomization: gender, PS, stage, histo vs cyto dx, brain mets Primary objective: OS 15% non-inferiority margin (HR 1.17) N = 1700, Power 80% R Gemcitabine 1250 mg/m2 + Cisplatin 75 mg/m2 day 1; Gemcitabine 1250 mg/m2 day 8 B12, folate, and dexamethasone given in both arms Scagliotti GV et al. J Clin Oncol. 2008;26:3543-3551.

Overall Survival: Entire Patient Population and Patients With Non Squamous Histology Median; 95% CI CP 10.3; 9.8, 11.2 CG 10.3; 9.6, 10.9 CP vs CG Adjusted HR; 95% CI 0.94; 0.84, 1.05 Median; 95% CI CP 11.8; 10.4, 13.2 CG 10.4; 9.6, 11.2 CP vs CG Adjusted HR; 95% CI 0.81; 0.70, 0.94 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 6 12 18 24 30 Survival Time (months) in All Patients Survival Probability Survival Time (months) in Patients With Nonsquamous Histology Scagliotti GV et al. J Clin Oncol. 2008;26:3543-3551. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

Docetaxel + Cisplatin versus Pemetrexed + Cisplatin in 1st Line non-squamous NSCLC Study objective To prove the non-inferiority of docetaxel + cisplatin compared with pemetrexed + cisplatin in patients with non-squamous NSCLC Docetaxel 60 mg/m2 + cisplatin 70 mg/m2 q3w, up to 4 cycles (n=76) Key patient inclusion criteria Stage IV non-squamous NSCLC Chemotherapy naïve ECOG PS 0–2 (n=156) Pemetrexed or EGFR-TKI or docetaxel Stratification ECOG PS (0–1 vs. 2) and sex R 1:1 Pemetrexed 500 mg/m2 + cisplatin 70 mg/m2 q3w, up to 4 cycles (n=80) Primary endpoint PFS Secondary endpoints Response rate, ORR and safety Note: the trial was closed early due to slow accrual and, therefore, the results should be interpreted with caution Kim et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA41_PR

PFS & OS Partial remission was observed in 33.3% of patients who received docetaxel + cisplatin, compared with 31.2% who received pemetrexed + cisplatin OS PFS 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 Docetaxel + cisplatin: 28.0 months (95% CI 7.5, 48.5) Pemetrexed + cisplatin: 19.7 months (95% CI 10.8, 28.6) Docetaxel + cisplatin: 4.6 months (95% CI 3.7, 5.6) Pemetrexed + cisplatin: 4.7 months (95% CI 4.4, 5.1) HR 1.016 (95% CI 0.74, 1.40) 0 200 400 600 800 1000 0 100 200 300 400 500 Days Days Kim et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA41_PR

Pemetrexed + cisplatin Toxicity Compared with pemetrexed + cisplatin, significantly higher rates of grade 3/4 neutropenia and febrile neutropenia, as well as a greater number of SAEs were observed with docetaxel + cisplatin Conclusion In patients with non-squamous NSCLC, treatment with docetaxel + cisplatin produced similar PFS and response rate as pemetrexed + cisplatin, but was associated with more SAEs and toxicity Docetaxel + cisplatin (n=72) Pemetrexed + cisplatin (n=77) Neutropenia grade 3/4 10 (13.9%)** 1 (1.3%) Febrile neutropenia 8 (11.1%)* Total number of SAE 42 24 Number of cases with SAE 29 (40.3%)* 17 (22.1%) *p<0.05, **p<0.01 Kim et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA41_PR

No Premedication for hypersensitivity Dexamethasone + Antihistamines Nab-Paclitaxel Albumin-bound paclitaxel 100 mg/m2 d1, 8, 15 Carboplatin AUC 6 d1 21 Day Cycles No Premedication for hypersensitivity Chemo-naive PS 0-1 Stage IIIb/IV NSCLC N = 1,050 1:1 Paclitaxel 200 mg/m2 d1 Carboplatin AUC 6 d1 21 Day Cycles With Premedication of Dexamethasone + Antihistamines Dr Socinski Stratification factors: Stage (IIIb vs IV) Age (<70 vs ≥70) Sex Histology (squamous vs nonsquamous) Geographic region Socinski, MA et al. J Clin Oncol., 2012.

Objective Responses by Histology* ab-P/C showed 67% improvement in response rate over P/C in squamous patients Response ratio = 1.034 P = 0.808 Response ratio = 1.680 P < 0.001 Percent Responses Ab-P/C (n=228) P/C (n=221) Dr Socinski Yellow font: Increased RR in SCCA *Subgroup analyses exploratory in nature; by independent radiologic review

Summary of Efficacy By Histology Population Ab-P/Carbo (ORR, PFS, OS) Paclitaxel/Carbo (ORR, PFS, OS) RR/HR (PFS, OS) P-Value (ORR, PFS, OS) ITT (n=1052) 33% 6.3 mos 12.1 mos 25% 5.8 mos 11.2 mos 1.313 0.902 0.922 0.005 0.214 0.271 Squamous (n=450) 41% 5.6 mos 10.7 mos 24% 5.7 mos 9.5 mos 1.680 0.865 0.890 <0.001 0.245 0.284 Non-Squamous (n=602) 26% 6.9 mos 13.1 mos 6.5 mos 13.0 mos 1.030 0.933 0.950 0.808 0.532 0.611 Dr Socinski

Phase III Trial of Bevacizumab in Non-Squamous NSCLC: ECOG 4599 CbP Paclitaxel 200 mg/m2 Carboplatin AUC = 6 (q3wks) x 6 cycles N = 855 (eligible) Eligibility – Non-squamous NSCLC – No history of hemoptysis – No CNS metastases No crossover to bevacizumab permitted CbP + Bevacizumab CbP x 6 cycles + Bevacizumab (15mg/kg q3wks) to PD Stratification Variables – RT vs. no RT – Stage IIIB or IV vs. recurrent – Weight loss < 5% vs. ≥ 5% – Measurable vs. non-measurable AUC=area under the curve; CbP=carboplatin, bevacizumab, paclitaxel; CNS=central nervous system; PD=progressive disease; RT=radiotherapy. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

Carboplatin/Paclitaxel +/- Bevacizumab RR: 15% for CbP vs. 35% for CbP + Bevacizumab PFS OS 100 CbP 100 CbP CbP + Bevacizumab CbP + Bevacizumab 80 80 p < 0.001; HR = 0.66 Median PFS: 6.2 mos vs. 4.5 mos 6-Mos PFS: 55% vs. 33% 1-Yr PFS: 15% vs. 6% p = 0.003; HR = 0.79 Median OS: 12.3 mos vs. 10.3 mos 1-Yr OS: 51% vs. 44% 2-Yr OS: 23% vs. 15% Patients Surviving (%) 60 60 Patients With PFS (%) 40 40 20 20 6 12 18 24 30 36 6 12 18 24 30 36 Time (mos) Time (mos) CbP=carboplatin, bevacizumab, paclitaxel; PFS=progression-free survival; RR=response rate. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

Are 4–6 Cycles of Chemotherapy Enough? Diagnosis CR/PR/SD First-Line Treatment Platinum Doublet Chemotherapy (4–6 cycles) ‘Watch-and-Wait’ PD Second and Further Lines of Treatment As a result of cumulative toxicity, patients receive a limited number of cycles of chemotherapy ‘Watch-and-Wait’ approach According to ASCO guidelines, those with SD will be observed, with regular follow-up to check for PD Pfister DG, et al. J Clin Oncol 2004;22:330–53 CR = complete response; PR = partial response; SD = stable disease; ASCO = American Society of Clinical Oncology. Pfister DG et al. J Clin Oncol 2004;22:330–353. Azzoli CG et al. J Clin Oncol. 2009;27(36):6251-6266. 17 17

JMEN : Double-blind, Placebo-controlled, Multicenter, Phase III Trial of Maintenance Pemetrexed vs Placebo Patients - Stage IIIB/IV NSCLC - PS 0-1 - 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)* 2:1 Randomization Primary Endpoint = PFS Randomization factors: gender PS stage best tumor response to induction non-platinum induction drug brain mets Placebo (d1, q21d) + BSC (N=222)* *B12, folate, and dexamethasone given in both arms Ciuleanu T et al. Lancet. 2009;374:1432-1440. 18

Pemetrexed: Switch Maintenance Improved overall survival over placebo Pem Placebo PFS OS (ITT Population) Post study therapy: 51% in pem arm and 67% in placebo arm; 18% of placebo patients received post-study pemetrexed Ciuleanu T et al. Lancet. 2009;374:1432-1440.

PARAMOUNT: Study Design Study Treatment Period Progression Induction Therapy (4 cycles) Maintenance Therapy (Until PD) 21 to 42 Days 500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d CR, PR, SD PD Placebo + BSC, d1, q21d 500 mg/m2 Pemetrexed + BSC, d1, q21d 2:1 Randomization Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) Randomized, placebo-controlled, double-blind, phase III study Folic acid and vitamin B12 administered to both arms Paz-Ares LG et al. J Clin Oncol. 2013;31(23):2895-2902.

PFS Paz-Ares LG et al. J Clin Oncol. 2013;31(23):2895-2902.

Outcomes for Subsets Paz-Ares LG et al. J Clin Oncol. 2013;31(23):2895-2902.

SATURN Co-primary endpoints Secondary endpoints Placebo Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n=1,949 4 cycles of 1st-line platinum-based doublet* Non-PD n=889 1:1 Placebo PD Mandatory tumor sampling Co-primary endpoints PFS in all patients PFS in patients with EGFR IHC+ tumors Secondary endpoints Overall survival (OS) in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC– tumors; biomarker analyses; safety; time to symptom progression; quality of life (QoL) Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region 889 is the intention to treat population (ITT) Cappuzzo F et al. Lancet Oncol. 2010;11(6):521-529. 23

Erlotinib as Maintenance Therapy All patients EGFR mt Cappuzzo F et al. Lancet Oncol. 2010;11(6):521-529.

AVAPERL: Bevacizumab ± Pemetrexed Continuation Maintenance Edited JA 8/18/11 1:1 RANDOM I Z E Bevacizumab (7.5mg/kg) q3w (7.5mg/kg) + pemetrexed q3w PD Previously untreated stage IIIB/IV nonsquamous NSCLC Bevacizumab pemetrexed cisplatin q3w 4 cycles of induction therapy (n=373) Maintenance therapy (n=244) Criteria: CR/PR/SD (RECIST) Open-label, randomized, multicenter, phase III study Stratified by: gender, smoking status (never smoker vs past/current smoker), and disease control after 4 cycles Primary endpoint: PFS Secondary endpoint: OS, safety Barlesi F et al. J Clin Oncol. 2013;31(24):3004-3011.

Double Maintenance: PFS From Induction From Randomization Barlesi et al, Ann Oncol 2014

Overall Survival From Induction From Randomization Barlesi et al, Ann Oncol 2014

Primary endpoint Overall Survival ECOG 5508: Schema R A N D O MI Z E Bevacizumab IIIB/IV NSCLC PS0/1 No Prior Tx N=1495 CR PR SD N=897 Carboplatin Paclitaxel Bevacizumab X 4 cycles Pemetrexed Bevacizumab Pemetrexed Stratification Factors: Smoking status, Gender Histology, Best response, Stage Primary endpoint Overall Survival http://clinicaltrials.gov/show/NCT01107626

Salvage Therapy

TKI Vs. Chemotherapy in EGFR-WT Lee et al, JAMA, 2014

Presented By Maurice Perol at 2014 ASCO Annual Meeting REVEL: Study Design Presented By Maurice Perol at 2014 ASCO Annual Meeting

Presented By Maurice Perol at 2014 ASCO Annual Meeting Progression-Free Survival<br />ITT Population, Investigator Assessment Presented By Maurice Perol at 2014 ASCO Annual Meeting

Overall Survival<br />ITT Population Presented By Maurice Perol at 2014 ASCO Annual Meeting

Presented By Maurice Perol at 2014 ASCO Annual Meeting Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm Presented By Maurice Perol at 2014 ASCO Annual Meeting

Characteristics of Nintedanib Oral angiokinase inhibitor targeting VEGFR 1–3, FGFR 1–3, and PDGFR α/β as well as RET1,2 No drug–drug interaction liability via CYP4503 Single-agent nintedanib was active in a phase II trial in recurrent NSCLC8 1. Hilberg F, et al. Cancer Res 2008;68:4774–8; 2. Data on File; 3. Stopfer P, et al. Xenobiotica 2011;41:297–311; 4. Bousquet G, et al. Br J Cancer 2011;105:1640–5; 5. Ellis PM, et al. Clin Cancer Res 2010;16:2881–9; 6. Doebele RC, et al. Ann Oncol 2012;23:2094–102; Data on File (clinicaltrials.gov NCT01346540); 7. Soria J-C, et al. Ann Oncol 2012;23(Suppl.9): abs 979; 8.Reck M, et al. Ann Oncol 2011;22:1374–81.

LUME-Lung 1 Study Design RANDOMIZE Nintedanib 200mg BID p.o., D2–21, + Docetaxel 75mg/m2 IV, D1, 21-day cycles (n=655) PD Stage IIIB/IV or recurrent NSCLC patients after 1st line chemotherapy (all histologies) 1:1 Placebo BID p.o., D2–21, + Docetaxel 75mg/m2 IV, D1, 21-day cycles (n=659) PD N=1314 Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy Stratification: ECOG PS (0 vs 1) Prior bevacizumab (yes vs no) Histology (squamous vs non-squamous) Brain metastases (yes vs no) Regions: Europe / Asia / South Africa Accrual: Dec 23, 2008 to Feb 9, 2011

Overall Survival Patients with Adenocarcinoma Histology 100 Nintedanib + docetaxel Placebo + docetaxel Median, mo 12.6 10.3 HR (95% CI) 0.83 (0.70 to 0.99) p-value 0.0359 80 60 52.7% Probability of survival (%) 40 44.7% 25.7% 20 Analysis of OS in the adenocarcinoma patient subpopulation showed a statistically significant improvement favoring treatment with nintedanib + docetaxel over placebo + docetaxel. Second-line treatment with the nintedanib/docetaxel combination increased median OS to 12.6 months, i.e. more than 1 year, compared with 10.3 months in the placebo + docetaxel arm; a median improvement of 2.3 months. The hazard ratio for the difference was 0.83 and the associated p-value was 0.0359. 19.1% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk Nintedanib Placebo 322 302 263 230 203 180 163 149 131 113 96 87 72 59 46 36 25 22 10 336 312 269 219 184 159 139 119 101 88 73 62 55 46 33 29 15 13 7

Adenocarcinoma histology GALAXY-1 Study Schema Ganetespib + Docetaxel G: 150 mg/m2 days 1,15 q3w D: 75 mg/m2 day 1 q3w Advanced NSCLC 1 prior regimen Adenocarcinoma histology RANDOMIZE 1:1 Docetaxel D: 75 mg/m2 day 1 q3w Stratification Factors ECOG PS (0 vs. 1) Time since diagnosis of advanced disease (≤6 mo vs. >6 mo) Baseline serum LDH (< or > ULN) Smoking status Endpoints Co-primary: PFS in elevated LDH, mKRAS groups Key secondary: PFS and OS in all adenocarcinoma patients Ramalingam SS et al. WCLC. 2013.

Population selected for Phase 3 Summary: PFS, OS Hazard Ratio G+D vs. D (90% CI) Elevated LDH N=76 mKRAS N=63 Chemosensitive (Dx >6m) N=178 ITT N=252 PFS Unadjusted 0.94 (0.57, 1.36) p=0.409 0.83 (0.52, 1.33) p=0.256 0.73 (0.55, 0.96) p=0.031 0.84 (0.67, 1.06) p=0.114 Adjusted 0.69 (0.43, 1.08) p=0.088 0.95 (0.58, 1.54) p=0.427 0.72 (0.53, 0.96) p=0.030 0.84 (0.66, 1.06) p=0.110 OS 0.69 (0.45, 1.05) p=0.073 1.12 (0.67, 1.88) p=0.641 0.75 (0.56, 1.03) p=0.065 0.90 (0.70, 1.17) p=0.217 0.52 (0.33, 0.81) p=0.009 1.22 (0.71, 2.07) p=0.727 0.72 (0.52, 0.98) p=0.040 0.86 (0.66, 1.12) p=0.175 Database lock: Oct 2013 Population selected for Phase 3 All p-values 1-sided. Adjusted: prespecified analysis for hazard ratio after adjusting for other variables in study with Cox Proportional Hazards model (gender, smoking status, LDH, ECOG performance status, interval since diagnosis advanced disease, age, total baseline target lesion size, and geographic region).

PFS: Dx >6 months Population HR, unadjusted 0.73 (0.55,0.96), P = 0.031 HR, adjusted 0.72 (0.53,0.96), P = 0.030 Median G+D vs. D: 5.3 vs. 3.4 months Events: 138 (78%) Docetaxel Ganetespib + Docetaxel Progression-Free Probability Months Ramalingam SS et al. WCLC. 2013.

Conclusions Individualized therapy is a reality for lung adenocarcinoma patients Molecular testing is recommended for newly diagnosed patients regardless of clinical characteristics Systemic chemotherapy continues as the main stay of treatment for majority of lung adenocarcinoma patients