Targeted Agents as Maintenance Therapy Karen Kelly, MD Professor of Medicine UC Davis Cancer Center
Disclosures Genentech Advisory Board
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
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)
SATURN Primary Endpoint Progression-Free Survival ITT EGFR Wild Type Cappuzzo F et al. Lancet Oncol 11:521-529, 2010
SATURN Overall Survival ITT EGFR Wild Type
SATURN Progression-Free Survival Overall Survival Cappuzzo F et al. Lancet Oncol 11:521-529, 2010
SATURN Primary Endpoint Progression-Free Survival EGFR mutated Patients Cappuzzo F et al. Lancet Oncol 11:521-529, 2010
SATURN Efficacy by Response Courdert B, et al. Ann Onc epublished May 24, 2011
SATURN Efficacy in Patients with Stable Disease Overall Survival
SATURN Efficacy in Patients with Stable Disease EGFR Wild Type Courdert B, et al. Ann Onc epublished May 24, 2011
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
Probability of PFS (%) Progression-Free Survival (ITT population) 100 90 80 70 60 50 40 30 20 10 Median PFS, months 6-month PFS rate, % 12-month PFS rate, % No. events, n (%) Gefitinib (n=148) 4.8 47.3 33.2 124 (83.8) HR (95% CI) = 0.42 (0.33, 0.55); p<0.0001 Placebo (n=148) 2.6 15.0 2.9 144 (97.3) Patients at risk : Placebo Gefitinib 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 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) 148 82 46 26 16 10 6 4 3 2 2 2 0 0 0 148 109 82 70 65 56 49 42 38 31 20 15 6 1 0
ORR (%) DCR (%) Objective Response Rate and Disease Control Rate (RECIST; ITT population) Odds ratio (95% CI) = 54.1 (7.17, 408); p=0.0001 Odds ratio (95% CI) = 2.69 (1.62, 4.46); p=0.0001 (n=148) (n=148) (n=148) (n=148)
Overall survival (%) Overall Survival (ITT Population) 100 Gefitinib (n=148) Placebo (n=148) 90 80 70 60 50 40 30 20 10 Median OS, months 18.7 6-month survival rate, % 82.2 12-month OS rate, % 68.8 No. events, n (%) 79 (53.4) 16.9 84.9 66.0 93 (62.8) HR (95% CI) = 0.84 (0.62, 1.14); p=0.2608 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 Time (weeks) Patients at risk: Placebo Gefitinib 148 147 136 127 115 107 97 91 78 66 47 37 13 6 0 0 0 148 141 129 119 114 108 102 90 84 75 56 39 18 4 0 0 0 HR <1 implies a lower risk of death on Gefitinib
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) 80 80 60 60 40 40 20 20 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks) No. of patients at risk Placebo15 9 5 3 3 2 1 1 1 1 1 1 0 0 0 Gefitinib 15 15 14 14 13 11 10 18 7 7 5 3 1 0 0 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks) No. of patients at risk Placebo24 9 5 3 2 0 0 0 0 0 0 0 0 0 0 Gefitinib 25 14 6 3 3 1 0 0 0 0 0 0 0 0 0
EGFR Mutations and Maintenance EGFR mutations predicts substantial and sustained PFS benefit from EGFR TKI INFORM SATURN
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, 18-70 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
PFS by Independent Review Erlotinib versus Observation Probability 1.0 Observation N=152 Erlotinib N=153 0.8 0.6 Median PFS, months 1.9 2.9 PFS at 3 months, % 30.3 35.3 PFS at 6 months, % 8.6 16.3 0.4 0.2 HR=0.82 (0.73 0.93) Log-rank test, p=0.002 Observation Erlotinib 0 0 5 10 15 20 25 30 35 40 Time (months) PFS is measured from time of randomisation into the maintenance phase
Erlotinib versus Observation Subgroup analysis of PFS Factor Obsv. N Erlo. N HR 95% CI All 152 153 0.822 0.73 0.93 Stable disease 73 72 0.85 0.71 1.01 Objective response 79 81 0.80 0.68 0.95 Adenocarcinoma 100 98 0.79 0.67 0.92 No Adenocarcinoma 52 55 0.88 0.72 1.08 Smoker 94 94 0.79 0.68 0.92 Non-smoker 58 59 0.88 0.72 1.08 Male 111 112 0.83 0.72 0.95 Female 41 41 0.80 0.62 1.0 Pemetrexed 116 97 0.79 0.69 0.92 No Pemetrexed 36 56 0.94 0.73 1.20 PS 0 68 57 0.75 0.61 0.91 PS 1 79 84 0.86 0.73 1.02 PS 2 3 4 10 0.48 0.22 1.03 0.2 0.4 0.6 0.8 1.0 1.2
Preliminary Overall Survival Probability 1.0 0.8 0.6 0.4 Observation Gemcitabine Erlotinib Gemcitabine vs observation HR=0.86 (0.66 1.12) Erlotinib vs observation HR=0.91 (0.80 1.04) 0.2 0 0 5 10 15 20 25 30 35 40 Time (months) Median follow-up: 21.6 months 324 deaths / 464 randomized patients (69.6%)
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 2009. Abstract 8002.
Proportion Without Event ATLAS Progression-Free Survival 1.0 0.8 Bev + Placebo (n=373) Bev + Erlotinib (n=370) 0.6 0.4 Median 4.8 months HR=0.722 (0.592-0.881) Log-rank P=0.0012 0.2 Median 3.8 months 0.0 0 3 6 9 12 15 18 21 Progression-Free Survival (months) No. of patients at risk: Bev + Placebo373 142 58 27 15 6 3 0 Bev + Erlotinib 370 178 81 43 20 6 3 1 Miller VA, et al. J Clin Oncol 27:407s, 2009
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 13.3 0.92 (0.70-1.21) 0.5604 Jan 28, 2009 357/768 (46) 14.4 vs 13.6 0.90 (0.73-1.12) 03574 Jun 19, 2009 439/768 (57) 15.9 vs 13.9 0.90 (0.74-1.09) 0.2686 Kabbinavar KK, et al, J Clin Oncol, 28:15s 2010 (suppl; abstr 7526)
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
The Role of Maintenance Therapy SWOG 0023 Definitive TX Consolidation Maintenance CDDP 50 mg/2 d 1,8,29,36 VP-16 50 mg/m2 d1-5, 29-33 XRT 1.8-2 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
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 125 54 P =.01 35 81% 59% 60% 40% 20% 0% Median FU time: 27 months 0 12 24 36 48 60 Months After RANDOMIZATION Kelly, K et al. J Clin Oncol. 26:2450-2460, 2008
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
Percentage *Stratified Log Rank BR.19 - Overall Survival 100 80 60 40 20 HR : 1.23 (95% CI 0.94-1.64) p=0.136* Median survival: Gefitinib - 5.1 yrs Placebo - N.E. Number at risk Gefitinib Placebo 0 0 251 252 Placebo 1 217 219 2 188 198 Gefitinib 3 Time (Years) 163 171 4 133 138 5 42 56 6 2 4
Percentage *Stratified Log Rank BR.19 - Disease Free Survival 100 80 60 40 20 HR: 1.22 (95% CI 0.93-1.61) p=0.152* Median survival: Gefitinib - 4.2 yrs Placebo - N.E. 0 Placebo Gefitinib Number at Risk Gefitinib Placebo 0 251 252 1 181 189 2 149 154 3 Time (Years) 131 135 4 100 109 5 29 37 6 2 3
Percentage Percentage Overall Survival by EGFR Mutation 100 80 Status and Treatment Wild type Placebo Gefitinib 100 80 Sensitizing mutation Placebo Gefitinib 60 60 40 40 20 20 # at Risk Placebo Gefitinib 0 0 145 136 1 126 121 2 118 105 3 Time (Years) 101 89 4 77 74 5 34 21 6 2 2 # at Risk Placebo Gefitinib 0 0 40 36 1 38 29 2 32 26 3 Time (Years) 30 21 4 26 17 5 6 7 6 1 0 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.)
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
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
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
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
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.