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Elderly and PS 2 Patients With Advanced NSCLC Winter Lung Cancer Conference 2012 Rogerio Lilenbaum, MD, FACP Cleveland Clinic Florida Weston, FL

Elderly and PS 2 Patients With Advanced NSCLC Combination vs. Single Agent Therapy Bevacizumab with chemotherapy Targeted agents in unselected patients

IFCT Study Schema *Choice of the center at the beginning of the study; ** In case of PD or excessive toxicity NSCLC Stage III-IV Age years PS 0-2 n = 451 Vinorelbine or Gemcitabine * Carboplatin + paclitaxel Erlotinib** 150 mg/d RANDOMRANDOM Stratification by center, PS 0-1 vs. 2, age ≤80 vs. >80 and stage III vs. IV Ref: Quoix E, Zalcman G, Oster JP, et al; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet Sep 17;378(9796):

PFS (ITT) Quoix et al Doublet chemotherapy Median PFS: 6.1 months (95% CI ) 1-year PFS: 15.4% (95% CI ) Monotherapy Median PFS: 3.0 months (95% CI ) 1-year PFS: 2.3% (95% CI ) p < 10 -6

Overall survival (ITT) Quoix et al Doublet chemotherapy MST = 10.3 months (95% CI ) 1-year survival 45.1% (95% CI ) Monotherapy MST = 6.2 months (95% CI ) 1-year survival 26.9% (95% CI ) p =

Exploratory Sub-group analysis "Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC."

Brazilian PS2 NSCLC: Trial Design Chemotherapy-naive patients with stage IIIB (with pleural effusion) or IV NSCLC and ECOG PS 2 N= 208 Chemotherapy-naive patients with stage IIIB (with pleural effusion) or IV NSCLC and ECOG PS 2 N= 208 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE Pemetrexed 500 mg/m 2 IV q 21 days (max 4 cycles) Pemetrexed 500 mg/m 2 IV q 21 days (max 4 cycles) Carboplatin AUC=5 IV q 21 days Pemetrexed 500 mg/m 2 IV q 21 days (max 4 cycles) Carboplatin AUC=5 IV q 21 days Pemetrexed 500 mg/m 2 IV q 21 days (max 4 cycles) Primary Objective: OS Trial closed – submitted to ASCO 2012

Elderly and PS 2 Patients With Advanced NSCLC Combination vs. Single Agent Therapy –Elderly: Yes –PS 2: TBD Bevacizumab with chemotherapy Targeted agents in unselected patients

Elderly and PS 2 Patients With Advanced NSCLC Combination vs. Single Agent Therapy Bevacizumab with chemotherapy Targeted agents in unselected patients

Outcomes for Elderly Advanced NSCLC Patients Treated with Bevacizumab in Combination with Carboplatin and Paclitaxel: Analysis of ECOG 4599 Study Elderly (≥ 70)*Non-Elderly (< 70) PCPCBPCPCB CR+PR17%29%14%36% SD50%39%50%39% Median PFS4.9 m 5.9 m P= m 6.2 m P< Yr Survival50%46%42%53% Median survival 12.1 m 11.3 m P = m 12.8 m P = Ramalingan et al. JCO 2008 *Median Age “Elderly”: 74

Toxicity on PCB Arm: Elderly vs. Non-Elderly Grade 3/4> 70 yrs < 70 yrsP Neutropenia (Gr 4) 34%22%0.02 Melena/GI Bleed 3.5%0.9%0.005 Proteinuria7.9%1.3%0.001 Motor neuropathy 3.5%0.6%0.05 Worst Grade87%70%< TRDs6.3%2.6%0.08

Outcomes for Elderly Patients Treated With Bevacizumab in Combination with Cisplatin and Gemcitabine: Analysis of the AVAIL Study CG N=112 CGB – 7.5 N=89 CGB – 15 N=103 CG N-235 CGB – 7.5 N=256 CGB – 15 N=248 ORR30%40%29%24%41%44% PFS OS Leighl et al. JCO 2008 *Median Age Elderly Group: 68 (36% 70 or older) Elderly Group ≥ 65 * Younger Group < 65 Results reported in HR

Elderly Patients : Toxicity Analysis of the AVAIL Study Only Gr≥3 PLT more frequent with Bev. Post Hoc analysis of ≥ 70 vs. 70 similar to age 65 cutoff

Bev in PS 2 Advanced NSCLC: TOPPS Chemotherapy-naive patients with stage IIIB (with pleural effusion) or IV NSCLC and ECOG PS 2 Chemotherapy-naive patients with stage IIIB (with pleural effusion) or IV NSCLC and ECOG PS 2 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE Pemetrexed 500 mg/m 2 IV q 21 days Carboplatin AUC=5 IV q 21 days Pemetrexed 500 mg/m 2 IV q 21 days Bevacizumab 15 mg/kg IV q 21 days Carboplatin AUC=5 IV q 21 days Pemetrexed 500 mg/m 2 IV q 21 days Bevacizumab 15 mg/kg IV q 21 days Primary Objective: PFS Secondary Objectives: ORR Toxicity OS Pemetrexed 500 mg/m 2 IV q 21 days Bevacizumab 15 mg/kg IV q 21 days

Elderly and PS 2 Patients With Advanced NSCLC Combination vs. Single Agent Therapy Bevacizumab with chemotherapy –Age alone is not a contraindication to Bev –Exercise caution with very old patients and/or those with significant co-morbidities or compromised PS Targeted agents in unselected patients

Elderly and PS 2 Patients With Advanced NSCLC Combination vs. Single Agent Therapy Bevacizumab with chemotherapy Targeted agents in unselected patients

Erlotinib or Chemotherapy in PS2 Patients ArmE = 52CP = 51 OOR (%)412 SD (%)3743 PD (%)4420 PFS (mo) MST (mo) y OS (%)2145 Lilenbaum et al. JCO 2008

TOPICAL Erlotinib* (150mg/day) to PD Placebo* to PD 1:1 randomization Inclusion criteria Histologically/cytologically confirmed NSCLC Measurable stage IIIB/IV disease and ≥ 18 yrs Chemo-naive and unsuitable for chemotherapy: – ECOG PS 2–3 or – PS 0–1 with impaired renal function CC<60ml/min Life expectancy ≥8 weeks Primary Overall survival (OS) Secondary Progression-free survival (PFS) Objective response rate Quality of life (QoL) Disease-related symptoms Safety and tolerability Translational Biomarker analyses – EGFR mutation – proteomic/genomic markers Endpoints *+/- palliative XRT Lee SM et al ASCO 2010

Erlotinib (n=350) Placebo (n=320) Age, median (range), years77.4 (42–91)77.2 (45–91) Male / female, %61 / 39 Stage IIIB / IV, %36 / 6433 / 67 ECOG PS 0–1 / 2 / 3, %16 / 55 / 2916 / 56 / 28 Adeno / squamous cell / large cell / other, %38 / 38 / 4 / 2038 / 40 / 5 / 17 Caucasian / Asian / other, %96 / 2 / 298 / 1 / 1 Current / ex- / never smoker, %36 / 59 / 537 / 57 / 6 Pack-years (current/ex-smoker), median (range)40 (1–220)38 (1–130) Median time since cessation (ex-smoker), years1817 Baseline characteristics *Asian = East, Southeast, South Asia; other = African-Caribbean

TOPICAL Trial ArmE = 350P = 320 PFS (m)2.8 mo2.7 mo PFS (6mo)22%13% PFS (1y)9%4% OS (m)3.8 mo3.6 mo OS (6mo)36%33% OS (1y)16%14% Lee et al. ASCO 2010

OS: planned subgroups Overall, erlotinib plus BSC did not improve OS Clear effect on OS for females

Elderly and PS 2 Patients With Advanced NSCLC Combination vs. Single Agent Therapy Bevacizumab with chemotherapy Targeted agents in unselected patients –First-line use of TKIs should be based on molecular selection –Consider erlotinib in female patients with adenocarcinoma, if the alternative is no therapy

Saturday, February 11, 2012 Hollywood, Florida Faculty Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD