Treatment Strategies in Elderly and PS2 Patients Rogerio Lilenbaum, MD, FACP Yale Cancer Center

Chronological Age Does Not Equal Functional Age

Chemotherapy in elderly patients (≥ 65) SEER Database between 1997 and 2002 A First-line n = 21285 B : 2nd line n = 2026 % pts receiving CT : 20.4% in 1997 27.8% in 2002 Distribution by type of chemotherapy, elderly patients with advanced non–small-cell lung cancer. Chemotherapy designated as first line if initiated within 90 days of diagnosis. First-line chemotherapy includes all agents received during the first 30 days of therapy. Second-line chemotherapy designated when a new chemotherapy agent is received after the initial 30-day period. (A) First-line chemotherapy; and (B) second-line chemotherapy (n = 2,026). Source: Surveillance, Epidemiology and End Results–Medicare, 1997-2002. Davidoff A J et al. JCO 2010;28:2191-2197

Elderly Patients with Advanced NSCLC In practice, risk is not systematically assessed, and the decision-making process is based primarily on “gestalt”. Clinicians need an objective, reliable, reproducible, and easy-to-administer “test” of risk that answers: Can I treat this patient? How?

Risk factors for Gr. 3-5 Toxicity Possible score range: 0-25 Predictive Model II Risk factors for Gr. 3-5 Toxicity OR (95% CI) Score Age ≥73 yrs vs. <73 1.8 (1.2-2.7) 2 GI/GU cancer vs. other cancer 2.2 (1.4-3.3) 3 Standard dose vs. Upfront dose reduction 2.1 (1.3-3.5) Polychemotherapy vs. monochemotherapy 1.8 (1.1-2.7) Hemoglobin (male: <11, female: <10) 2.2 (1.1-4.3) Creatinine Clearance (Jelliffe –ideal wt) <34 2.5 (1.2-5.6) 1 or more falls in last 6 months 2.3 (1.3-3.9) Hearing impairment (fair or worse) 1.6 (1.0-2.6) Limited in walking 1 block (MOS) 1.8 (1.1-3.1) Assistance required in medication intake 1.4 (0.6-3.1) 1 Decreased social activity (MOS) 1.3 (0.9-2.0) Possible score range: 0-25 Hurria et al, JCO 2012

Prevalence of Toxicity by Score “High” 83% ( ≥12) 76% 92% ROC: 0.72 “Mid” 53% (6 to 11) 45% 63% 100% 80% “Low” 27% (0 to 5) 31% 21% 60% Grade 3-5 Toxicities 40% 20% 0% 0 to 4 5 6 to 8 9 to 11 12 to 13 ≥14 N=39 N=64 N=123 N=36 N=50 N=161 Total Score

Elderly Selection on Geriatric Index Assessment ESOGIA-GFPC 08-02 Elderly Selection on Geriatric Index Assessment Phase III, randomized, multicenter study comparing in elderly patients (≥70 years) with stage IV NSCL a standard strategy of treatment allocation (carboplatin based bi-therapy or monotherapy with docetaxel) based on PS and age with an experimental strategy allocating the same regimen or BSC according to a comprehensive geriatric assessment Presenting author: R. Corre Co-authors: C. Chouaid, L. Greillier, H. Le Caer, C. Audigier-Valette, N. Baize, H. Bérard, L. Falchero, I. Monnet, E. Dansin, A. Vergnenegre, M. Marcq, C. Decroisette, S. Bota, R.Lamy, B.Massuti, C. Dujon, G. Fraboulet, J. Minguet, C. Plassot, H. Lena Presentation 01503

hepatic, renal functions STUDY DESIGN Non-squamous Carbo-Pemetrexed ≤ 75 and PS 0-1 Carbo-Gemcitabine Squamous R A N D O M I Z T Based on PS and age > 75 and/or PS 2 Docetaxel NSCLC > 70 y PS 0, 1 or 2 Stage IV No prior chemo Adequate hemato, hepatic, renal functions A Carbo-Pemetrexed Non-squamous Fit subjects Carbo-Gemcitabine B Squamous Pre-frailed subjects Based on CGA Docetaxel PS: performance status CGA: comprehensive geriatric assessment BSC: Best supportive care Frailed subjects BSC Primary endpoint: Treatment failure-free survival (TFFS) documented progression, death of any cause, exit for toxicity considered unacceptable, or withdrawal of consent Secondary endpoints: ORR, toxicities, OS, QoL, survival adjusted on QoL Planned sample size: 490 patients for an expected hazard ratio of 1.30, a power of 80%, a two-sided overall type 1 error of 5%, assuming 5% of dropout patients.

TREATMENT FAILURE FREE SURVIVAL (ITT) OVERAL SURVIVAL (ITT) Arm A: median OS 6.5 months (95% CI 4.93; 7.7) Arm B: median OS 6.2 months (95% CI 4.9; 7.8) p=0.7784 Arm A: median TFF 3.2 months (95% CI 2.91;4.13) Arm B: median TFF 3.2 months (95% CI 2.66;4.43) p=0.7149 Arm A (PS,age) n=241 Arm B (CGA) n=232 C-pem N=62 (25%) C-Gem N=21 (9%) Doc N=158 (66%) N=84 (36%) N=25 (11%) N=73 (32%) BSC N=50 (21%) mTFF (months) 4.4 4.53 3.1 4.9 4.8 2.7 1.3 mOS (months) 8.9 6.3 5.9 10.2 8.4 2.9

Elderly Patients with Advanced NSCLC MILES G V GV Swedish G CG CALGB 9730 P CP Pts 233 233 232 65 56 78 77 ORR (%) 18.5 17.3 20 19 22 21 36 MST (mo) 9.2 7.0 7.8 9.4 11 5.8 8.0 1-Y Surv (%) 41 26 31 32 40 31 35 Gridelli et al. JNCI 2003; Sederholm et al. JCO 2006; Lilenbaum et al. JCO 2005

IFCT Study Schema R A N D O M NSCLC Stage III-IV Age 70-89 years PS 0-2 n = 451 R A N D O M Vinorelbine or Gemcitabine* Erlotinib** 150 mg/d Carboplatin + Paclitaxel 451 patients with advanced NSCLC aged between 70 and 89 years and a PS of 0 to 2 ,were randomised 1 to 1 between single agent therapy with either vinorelbine or gemcitabine and the doublet of carboplatin and paclitaxel. At progression or in case of excessive toxicity, both arms were switched to erlotinib 150 mg/d. Stratification by centre, PS 0-1 vs. 2, age ≤80 vs. >80 and stage III vs. IV *Choice of the center at the beginning of the study; ** In case of PD or excessive toxicity Quoix E et al: Lancet. 2011 Sep 17;378(9796):1079-88. 11

Patients characteristics All Patients (N=451) Single Arm (N=226) Doublet Arm (N=225) p-value Sex 0.272 Male 333 (73.8) 172 (76.1) 161 (71.6) Age 0.588 Median 77.1 76.9 77.4 Range 70.0 - 88.8 70.1 - 88.8 70.0 - 86.3 Performance status 0.916 0-1 327 (72.7) 163 (72.4) 164 (72.9) 2-3 123 (27.3) 62 (27.6) 61 (27.1) Stage 0.703 IV 364 (80.7) 184 (81.4) 180 (80) Histology 0.910 Squamous 151 (33.5) 74 (32.7) 77 (34.2) ADC 229 (50.8) 115 (50.9) 114 (50.7) Other 71 (15.7) 37 (16.4) 34 (15.1) Smoking status 0.487 Never smoker 94 (20.9) 50 (22.2) 44 (19.6) Patients characteristics were well balanced between the two arms ; almost three quarters were males, median age was 77. More than seventy percent of the patients had a PS of 0 or 1 and 80% had stage IV disease. A third of the patients had squamous cell histology and 50% adenocarcinoma. As usual in elderly patients neversmokers represented as many as 20% of the patients

Overall survival Doublet Single agent Doublet Single p o b t y MST = 10.3 months (95% CI 8.3-13.3 1-year survival 45.1% (95% CI 38.2-51.8) Doublet Single agent MST = 6.2 months (95% CI 5.3-7.4) 1-year survival 26.9% (95% CI 21-33.1) p= 0.00004 Doublet Single This improvement in PFS is reflected in the overall survival with a benefit of 4 months in median overall survival time for the doublet arm, with 45% vs 27% of patients surviving 1 year. As you can see, median overall survival time and one year survival time in the single agent arm were near those predicted by previous studies in elderly patients whereas the median survival time and one year survival in the doublet arm are at least as one would expect in a general population of ‘any age’, with advanced NSCLC and a PS 0 to 2. Months 6 12 18 24 30 36 42 Single 226 112 45 11 4 1 Doublet 225 150 78 46 14 7 13

PointBreak Randomized, open-label, phase III superiority study conducted in US Pemetrexed 500 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg Paclitaxel 200 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg Induction Phase 4 cycles, q21d Maintenance Phase q21d until PD Inclusion: - No prior systemic therapy for lung cancer - ECOG PS 0/1 - Stage IIIB-IV NS-NSCLC - Stable treated brain mets allowed Exclusion: Peripheral neuropathy ≥Grade 1 - Uncontrolled pleural effusions Pemetrexed + (folic acid & vitamin B12 ) Carboplatin + Bevacizumab Pemetrexed + (folic acid & vitamin B12 ) Bevacizumab R 1:1 450 patients each Paclitaxel + Carboplatin + Bevacizumab Bevacizumab Primary Endpoint: Overall Survival Socinski M, et al. ASCO 2013

Progression-Free and Overall Survival Pem+ Cb+Bev Pac+ Cb+Bev OS median (mo) 12.6 13.4 HR (95% CI); P value 1.00 (0.86, 1.16); P=0.949 Survival rate (%) 1-year 52.7 54.1 2-year 24.4 21.2 Pem+ Cb+Bev Pac+ Cb+Bev PFS median (mo) 6.0 5.6 HR (95% CI); P value 0.83 (0.71, 0.96); P=0.012 ORR (%) 34.1 33.0 Time from Induction (months) Time from Induction (months)

Overall Survival in Age Subgroups Median Survival Time (months) Pem+Cb+Bev Pac+Cb+Bev ≤70 12.55 (95% CI: 11.10, 14.03) 14.26 (95% CI: 12.42, 15.21) >70 12.65 (95% CI: 10.41, 16.85) 11.47 (95% CI: 8.05, 14.29) >75 11.83 (95% CI: 7.16, 16.10) 8.94 (95% CI: 7.03, 14.29) ─ Pem+Cb+Bev ≤70 ─ Pem+Cb+Bev >70 ─ Pem+Cb+Bev >75 ▪▪▪ Pac+Cb+Bev ≤70 ▪▪▪ Pac+Cb+Bev >70 ▪▪▪ Pac+Cb+Bev >75

Efficacy and Safety of Paclitaxel and Carboplatin With Bevacizumab for the First-Line Treatment of Patients With Nonsquamous Non–Small Cell Lung Cancer (NSCLC): Analyses Based on Age in the Phase III E4599 and PointBreak Trials CJ Langer,1 MA Socinski,2 JD Patel,3 AB Sandler,4 JH Schiller,5 L Leon,4 SJ Hazard,4 SS Ramalingam6 1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 2University of Pittsburgh Medical Center, UPMC Cancer Pavilion, Pittsburgh, PA; 3Feinberg School of Medicine, Northwestern University, Chicago, IL; 4Genentech, Inc., South San Francisco, CA; 5Harold C. Simmons Cancer Center, University of Texas Southwestern, Dallas, TX; 6Winship Cancer Institute of Emory University, Atlanta, GA

Results: OS and PFS in the Pooled Population vs E4599 OS for pts treated with PC + Bev vs PC alone in the (A) pooled population of E4599 and PointBreak and in the (B) E4599 trial only PFS for pts treated with PC + Bev vs PC alone in the (A) pooled population of E4599 and PointBreak and in the (B) E4599 trial only A. B. Age Group n HR 95% CI <65 735 0.75 0.62–0.89 65–74 453 0.80 0.64–1.00 70–74 203 0.68 0.48–0.96 <75 1188 0.78 0.68–0.89 ≥75 157 1.05 0.70–1.57 Age Group n HR 95% CI <65 499 0.76 0.62–0.92 65–74 277 0.80 0.61–1.05 70–74 129 0.62 0.40–0.96 <75 776 0.78 0.66–0.92 ≥75 102 1.18 0.76–1.83 0.4 0.6 0.8 1.0 1.2 1.4 1.6 0.4 0.6 0.8 1.0 1.2 1.4 1.6 A. B. Age Group n HR 95% CI <65 735 0.71 0.60–0.85 65–74 453 0.62 0.49–0.78 70–74 203 0.57 0.40–0.81 <75 1188 0.69 0.60–0.79 ≥75 157 0.95 0.62–1.44 Age Group n HR 95% CI <65 499 0.66 0.54–0.80 65–74 277 0.55 0.41–0.73 70–74 129 0.54 0.35–0.84 <75 776 0.63 0.54–0.74 ≥75 102 0.91 0.57–1.43 0.4 0.6 0.8 1.0 1.2 1.4 1.6 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Bev, bevacizumab; CI, confidence interval; E4599, Eastern Cooperative Oncology Group 4599 ; HR, hazard ratio; OS, overall survival; PC, paclitaxel + carboplatin.

Results: Safety in E4599 Incidence of gr 3–5 AEs was significantly higher for PCB vs PC alone Rates for discontinuations due to AEs also higher for PC + Bev vs PC alone Age PC + Bev PC Grade 3–5 toxicitya <75 years 63% 48% Grade 3–5 toxicitya ≥75 years 81% 56% Grade 5 toxicity ≥75 years 8% 2% aP <.005 Age PC + Bev PC <75 years 17% (65/375) 12% (49/401) ≥75 years 29% (17/59) 19% (8/43)

ECOG PS in NSCLC patients at presentation > 200,000 new cases diagnosed in US in 2008 according to ACS estimates After D. Cella from BIOQOL/Q-SCORE database (n=493)

SWOG Phase II Trial of Sequential Vinorelbine + Docetaxel in Elderly or Poor PS Patients with Advanced NSCLC Hesketh et al. JTO 2006

Erlotinib vs. Chemotherapy in PS 2 Patients D O M I Z E 1:1 Erlotinib 150 mg daily Stratified by: Center Age (< 70 vs > 70) Extent of Disease (Stage IIIB vs IV) Carboplatin AUC 6 + Paclitaxel 200 mg/m2 Day 1 q 21 days x 4 cycles Optional Cross-over to Erlotinib Lilenbaum et al. JCO 2008

Erlotinib vs. Chemotherapy in PS2 Patients Arm E = 52 CP = 51 OOR (%) 4 12 SD (%) 37 43 PD (%) 44 20 PFS (mo) 1.9 3.5 MST (mo) 6.6 9.5 1y OS (%) 21 45 Lilenbaum et al. JCO 2008

Phase III Randomized Trial Pemetrexed vs Phase III Randomized Trial Pemetrexed vs. Carboplatin and Pemetrexed in Patients with Advanced NSCLC and PS of 2 Pemetrexed 500 mg/m2 IV Q3W Arm A Eligibility: Stage IIIB/IV NSCLC (malignant effusion) ECOG PS 2 No prior chemotherapy Stable CNS disease Measurable disease Adequate organ function (including GFR≥ 45 ml/min) Signed informed consent R A N D O M I Z A T I O N 1:1 Stratification factors: Stage: IIIB vs IV Age: ≥70 vs <70 Wt loss: ≥5% vs <5% X 4 cycles Pemetrexed 500 mg/m2 IV Q3W + Carboplatin AUC 5 IV Q3W n=137* Arm B Primary endpoint: Overall Survival PD Secondary endpoints: Progression-free survival Overall response rate Safety Pre-medications: Vitamin B12: 1mg IM Injection Folic Acid: 350-1,000mcg po daily Dexamethasone 4mg po BID the day before, the day of, and the day after Lilenbaum et al. ASCO 2012 5 24

Patient Characteristics CP (n=103) Median age (range) ≥70 y (%) 65 (40-86) (35.2) 65 (41-90) (36.8) Male / Female (%) 58.8 / 41.2 63.1 / 36.9 Stage IIIB / IV (%) 4.9 / 95.1 5.8 / 94.2 ≥5% Weight loss (%) 53.9 51.4 Histology (%) Adenocarcinoma Squamous cell Unknown 80.4 10.8 4.9 81.6 2.9 5.8 Smoking Status (%) Current Former Never 66.7 22.5 17.5 60.2 22.3 Co-Morbidities (%) Hypertension COPD Diabetes Mellitus 45.1 17.6 7.8 44.7 11.7 12.6 p=0.123 25

OVERALL SURVIVAL P CP Median, months 5.6 9.1 OS at 6 months, % 50 65 18 43 HR=0.57 (0.41–0.79); p=0.001 CP P

PS 2 Elderly Quoix et al Lilenbaum et al P CP Median, months 5.6 9.1 OS at 6 months, % 50 65 OS at 12 months, % 18 43 MST = 10.3 months 1-year survival 45.1% MST = 6.2 months 1-year survival 26.9%

Bev in PS 2 Advanced NSCLC: TOPPS Pemetrexed 500 mg/m2 IV q 21 days R A N D O M I Z E Chemotherapy-naive patients with stage IIIB (with pleural effusion) or IV NSCLC and ECOG PS 2 Pemetrexed 500 mg/m2 IV q 21 days Bevacizumab 15 mg/kg IV q 21 days Carboplatin AUC=5 IV q 21 days Pemetrexed 500 mg/m2 IV q 21 days Bevacizumab 15mg/kg IV q 21 days Primary Objective: PFS Secondary Objectives: ORR Toxicity OS Spigel, Lilenbaum, et al. 28

Bevacizumab-Related Toxicity (N=106) Number of Patients (%) G1 G2 G3 G4   ARM 2 ARM 3 Thromboembolic event 0.0% 3 5.8% 5.6% 4 7.7% 1 1.9% 2 3.8% Hypertension 3.7% 7.4% Hemorrhage 10 19.2% 2% Proteinuria 7 13.0% Wound-healing complication Osteonecrosis of the Jaw Perforation Fistula CHF

Progression Free Survival (N=163) Arm 1 (N=48) Arm 2 (N=59) Arm 3 (N=56) Pem Only Pem + Bev Pem + Bev+ Carbo Median PFS (95% CI) 2.6 (1.5, 5.1) 3.5 (2.4, 5.1) 4.1 (3.0, 6.4) 12-month PFS (95% CI) 0.05 (0.01, 0.16) 0.10 (0.03, 0.22) 0.16 (0.06, 0.29)

Elderly and PS2 Patients Assessment of risk in elderly patients can be done objectively by reproducible instruments At this time, it does not appear that a CGA-directed treatment algorithm is superior to MD choice (based on age and PS) For elderly and PS 2 patients, a carboplatin doublet leads to an improvement in survival compared to single agent therapy at the cost of increased toxicity Targeted agents are best used in patients selected by molecular criteria Bevacizumab can be safely used in PS 2 patients but not in the “old elderly”