Targeted Agents as Maintenance Therapy. Karen Kelly, MD Professor of Medicine UC Davis Cancer Center

Transcription

1 Targeted Agents as Maintenance Therapy Karen Kelly, MD Professor of Medicine UC Davis Cancer Center

2 Disclosures Genentech Advisory Board

3 Maintenance Therapy Defined Treatment Non-Progressing Patients Drug Therapy Until progression Continuation or Switch Molecularly Targeted Agents Are Ideal Candidates Majority have an oral route of administration Modest to low toxicity profile with potential for long term administration

4 SATURN Study Schema Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n=1,949 4 cycles of 1st-line platinumbased doublet* Non-PD n=889 1:1 Placebo PD Mandatory tumour sampling 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 Co-Primary Endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary Endpoints: Overall survival (OS) in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL)

5 SATURN Primary Endpoint Progression-Free Survival ITT EGFR Wild Type Cappuzzo F et al. Lancet Oncol 11: , 2010

6 SATURN Overall Survival ITT EGFR Wild Type

7 SATURN Progression-Free Survival Overall Survival Cappuzzo F et al. Lancet Oncol 11: , 2010

8 SATURN Primary Endpoint Progression-Free Survival EGFR mutated Patients Cappuzzo F et al. Lancet Oncol 11: , 2010

9 SATURN Efficacy by Response Courdert B, et al. Ann Onc epublished May 24, 2011

10 SATURN Efficacy in Patients with Stable Disease Overall Survival

11 SATURN Efficacy in Patients with Stable Disease EGFR Wild Type Courdert B, et al. Ann Onc epublished May 24, 2011

12 INFORM: Study Design Patients Age 18 years Completed 4 cycles of first-line platinumbased chemotherapy without PD or unacceptable toxicity Life expectancy 12 weeks WHO PS 0-2 Measurable Stage IIIB/IV disease Gefitinib (250 mg/day) 1:1 randomization Placebo (once daily) Endpoints Primary Progression-free survival (PFS) Secondary Objective response rate (ORR) Disease control rate (DCR) Overall survival (OS) Quality of life Safety and tolerability Exploratory Biomarkers EGFR mutation Zhang L, et al. J Clin Oncol 29:478s, 2011

13 Probability of PFS (%) Progression-Free Survival (ITT population) Median PFS, months 6-month PFS rate, % 12-month PFS rate, % No. events, n (%) Gefitinib (n=148) (83.8) HR (95% CI) = 0.42 (0.33, 0.55); p< Placebo (n=148) (97.3) Patients at risk : Placebo Gefitinib Estimated using the Kaplan-Meier method Primary Cox analysis with covariates HR <1 implies a lower risk of progression on Gefitinib Time since randomization (weeks)

14 ORR (%) DCR (%) Objective Response Rate and Disease Control Rate (RECIST; ITT population) Odds ratio (95% CI) = 54.1 (7.17, 408); p= Odds ratio (95% CI) = 2.69 (1.62, 4.46); p= (n=148) (n=148) (n=148) (n=148)

15 Overall survival (%) Overall Survival (ITT Population) 100 Gefitinib (n=148) Placebo (n=148) Median OS, months month survival rate, % month OS rate, % 68.8 No. events, n (%) 79 (53.4) (62.8) HR (95% CI) = 0.84 (0.62, 1.14); p= Time (weeks) Patients at risk: Placebo Gefitinib HR <1 implies a lower risk of death on Gefitinib

16 PFS (%) PFS (%) Progression-Free Survival by EGFR Mutation Status 100 EGFR Mutation-Positive Gefitinib (n=15) Median PFS, 16.6 months No. events, 9 (60.0%) Placebo (n=15) Median PFS, 2.8 months No. events, 15 (100.0%) HR (95% CI) = 0.17 (0.07, 0.42) 100 EGFR Mutation-Negative Gefitinib (n=25) Median PFS, 2.7 months No. events, 25 (100.0%) Placebo (n=24) Median PFS, 1.5 months No. events, 24 (100.0%) HR (95% CI) = 0.86 (0.48, 1.51) Time (weeks) No. of patients at risk Placebo Gefitinib Time (weeks) No. of patients at risk Placebo Gefitinib

17 EGFR Mutations and Maintenance EGFR mutations predicts substantial and sustained PFS benefit from EGFR TKI INFORM SATURN

18 IFCT-GFPC 0502 Study Design PD: off A Maintenance treatment Observation PD Progression: 2 nd line Pemetrexed Cisplatin Gemcitabine x 4 cycles N=834 Objective response or stable disease R* N=464 B N=155 Gemcitabine N=154 PD Pemetrexed NSCLC Stage IIIB wet IV PS 0-1, years Asymptomatic brain mets allowed Tumor tissue EGFR IHC EGFR mutation C Erlotinib N=155 Primary endpoint: PFS PD Pemetrexed Induction Chemo: Cisplatin 80mg/m 2 d1 + Gemcitabine 1,250mg/m 2 d1, d8 Arm B: Gemcitabine 1,250mg/m 2 d1, d8 /3 wks Arm C: Erlotinib 150mg daily *Stratification factors: gender histology: adenocarcinoma vs other histology smoking status: non-smokers vs current/former smokers center response vs stabilization to induction chemotherapy Perol, M, et al. J Clin Oncol 28:#7505, 2010

19 PFS by Independent Review Erlotinib versus Observation Probability 1.0 Observation N=152 Erlotinib N= Median PFS, months PFS at 3 months, % PFS at 6 months, % HR=0.82 ( ) Log-rank test, p=0.002 Observation Erlotinib Time (months) PFS is measured from time of randomisation into the maintenance phase

20 Erlotinib versus Observation Subgroup analysis of PFS Factor Obsv. N Erlo. N HR 95% CI All Stable disease Objective response Adenocarcinoma No Adenocarcinoma Smoker Non-smoker Male Female Pemetrexed No Pemetrexed PS PS PS

21 Preliminary Overall Survival Probability Observation Gemcitabine Erlotinib Gemcitabine vs observation HR=0.86 ( ) Erlotinib vs observation HR=0.91 ( ) Time (months) Median follow-up: 21.6 months 324 deaths / 464 randomized patients (69.6%)

22 ATLAS Study Design Advanced NSCLC patients w/ no prior chemotherapy N=1,160 Eligibility: Stage IIIB/IV NSCLC ECOG PS 0-1 Stratification factors: Gender Smoking history ECOG O vs 1 Chemotherapy regimen 4 cycles of 1 st -line chemo + Bevacizumab Non-PD n=768 1:1 Bevacizumab + Erlotinib Bevacizumab + Placebo PD PD Primary endpoint Secondary endpoints Exploratory endpoints Progression-free survival Overall survival, safety Biomarker analyses (IHC, FISH, EGFR, K-Ras) Miller VA, et al. ASCO Abstract 8002.

23 Proportion Without Event ATLAS Progression-Free Survival Bev + Placebo (n=373) Bev + Erlotinib (n=370) Median 4.8 months HR=0.722 ( ) Log-rank P= Median 3.8 months Progression-Free Survival (months) No. of patients at risk: Bev + Placebo Bev + Erlotinib Miller VA, et al. J Clin Oncol 27:407s, 2009

24 ATLAS: OS Results Evaluate Bev 15mg/kg + Erl 150 mg vs Bev + Placebo following Bev + Platinum-based chemotherapy Data cut-off Patients with events, n/n (%) Median OS (months) Bev + Erl vs Bev HR (95% CI) p-value July 18, 2008 (pre-specified) 228/743 (31) 14.4 vs ( ) Jan 28, /768 (46) 14.4 vs ( ) Jun 19, /768 (57) 15.9 vs ( ) Kabbinavar KK, et al, J Clin Oncol, 28:15s 2010 (suppl; abstr 7526)

25 Erlotinib Maintenance R E G I S T E R 4 cycles of Platinum-based Chemotherapy (EGFR wild type) NPD R A N D O M I Z E Erlotinib Placebo NPD Erlotinib Primary endpoint: OS N = 610 Starting 11/11

26 The Role of Maintenance Therapy SWOG 0023 Definitive TX Consolidation Maintenance CDDP 50 mg/2 d 1,8,29,36 VP mg/m2 d1-5, XRT Gy/d 61 Gy DOCETAXEL 75 mg/m2 x 3 cycles R A N D O M I Z E PLACEBO GEFITINIB 500 mg/day 250 mg/day (5-1-03) 1 o Endpoint: Overall Survival; 2 0 Endpoint: PFS, toxicity and correlative science Maintenance therapy could continue for a maximum of 5 years Stratification factors: IIIA vs IIIB; Measurable vs Non-measurable disease; squamous vs nonsquamous

27 SWOG 0023: Overall Survival From Randomization 100% Gefitinb N 118 Events 71 Median in Months 23 1 YR OS 2 YR OS 73% 46% 80% Placebo P = % 59% 60% 40% 20% 0% Median FU time: 27 months Months After RANDOMIZATION Kelly, K et al. J Clin Oncol. 26: , 2008

28 BR.19 - Schema Pts with completely resected stage IB,II, and IIIA NSCLC Stratified by - stage - histology - post-op RT - sex - adjuvant chemotherapy* Randomized 1:1 Gefitinib 250 mg po daily x 2 yrs Placebo 0 mg po daily x 2 yrs *Protocol amended January 2003 to allow adjuvant chemotherapy which became a stratification factor Goss, G. et al. J Clin Oncol 28: #7005, 2010

29 Percentage *Stratified Log Rank BR.19 - Overall Survival HR : 1.23 (95% CI ) p=0.136* Median survival: Gefitinib yrs Placebo - N.E. Number at risk Gefitinib Placebo Placebo Gefitinib 3 Time (Years)

30 Percentage *Stratified Log Rank BR.19 - Disease Free Survival HR: 1.22 (95% CI ) p=0.152* Median survival: Gefitinib yrs Placebo - N.E. 0 Placebo Gefitinib Number at Risk Gefitinib Placebo Time (Years)

31 Percentage Percentage Overall Survival by EGFR Mutation Status and Treatment Wild type Placebo Gefitinib Sensitizing mutation Placebo Gefitinib # at Risk Placebo Gefitinib Time (Years) # at Risk Placebo Gefitinib Time (Years) HR (95% C.I.) Gefitinib/Placebo: 1.21 (0.84, 1.73) Log Rank: p=0.301 Median (95% C.I.) -Placebo: Not reached (5.1, inf.) -Gefitinib: 5.0 (4.3, inf.) HR (95% C.I.) Gefitinib/Placebo: 1.58 (0.83, 3.00) Log Rank: p=0.160 Median (95% C.I.) - Placebo: 5.1 (4.4, inf.) - Gefitinib: 3.7 (2.6, inf.)

32 International Phase III Adjuvant Trial RADIANT N = 945 Erlotinib Stage IB-IIIA Surgery CTX4/ No CT R* * Selection FISH + and/or IHC+ Placebo Primary endpoint: Disease Free Survival

33 Sunitinib as Maintenance Therapy Multicenter Phase II Trial Patients with untreated stage IIIB/IV NSCLC and ECOG PS 0 1 Four cycles Paclitaxel / Carboplatin Sunitinib 50 mg/day 4/2 weeks Continue until disease progression Planned follow-up: 1 year 1 0 Endpoint Overall Survival at 1 YR 55% ITT N= 84 Non-progressors N =54 1 YR OS 40.5% 38.7% Median OS 10.4 mos 8.7 mos PFS 5.8 mos 3.9 mos Grade 3/4 AEs Fatigue 24% Diarrhea 9% Gervais R et al. Lung Cancer Epublished June 2011

34 CALGB 30607: Sunitinib as Maintenance Therapy in Non-progressing Advanced NSCLC Patients Following Chemotherapy Phase III, randomized, placebo-controlled trial Planned randomization: 250 patients Patients with untreated stage IIIB/IV NSCLC and ECOG PS 0 1 Four cycles of platinum-based chemotherapy* Randomization of responding patients or patients with stable disease stratified by prior treatment with/without Bevacizumab Sunitinib 37.5 mg/day Placebo Continue until disease progression Planned follow-up: 1 year 1 0 Endpoint - PFS *Platinum-based regimen may include Carboplatin/Cisplatin plus Paclitaxel, Docetaxel, Vinorelbine or Gemcitabine with or without Bevacizumab (Bevacizumab discontinued after four cycles) At progression, patients receiving placebo may cross over to the Sunitinib arm

35 Pazopanib Maintenance Nonprogressors after 4 cycles of First line Chemotherapy For advanced NSCLC R A N D O M I Z E Pazopanib Placebo Primary endpoint: OS N = 587 Activated 7/11 Patients with EGFR mutated tumors are excluded

36 Summary Erlotinib is FDA approved for maintenance treatment in nonprogressing patients treated with a first line platinum-based regimen. Most of the clinical benefit is seen in patients with EGFR mutations and unselected patients with SD. No role for maintenance targeted therapy in early stage disease (Stage I- III). Detrimental effects seen with EGFR-TKIs.