Slide 1 Maintenance Therapy in the Management of Non-Small Cell Lung Cancer Frances A Shepherd, MD FRCPC Scott Taylor Chair in Lung Cancer Research Princess Margaret Hospital, Professor of Medicine, University of Toronto Slide 2 Maintenance Therapy Options Chemotherapy Continue same doublet chemotherapy Continue same single agent chemotherapy Switch to new single agent chemotherapy Targeted agents Continue targeted agent used with chemotherapy Switch to a new targeted agent Add a new (2 nd ) targeted agent Slide 3 Maintenance Chemotherapy Continuing Same First-Line Single Agent Induction Chemotherapy Without the Platinum Analogue
Slide 4 Advanced NSCLC Gemcitabine Maintenance Therapy Stage IV NSCLC (n=352) CR / PR / SD after cisplatin/gemcitabine (n=26) R A N D O M IZ E 138 68 Primary endpoint: median time to progression Maintenance gemcitabine 125 mg/m 2 day 1, 8 Q3W plus BSC (No cisplatin) BSC only Brodowicz et al, Lung Cancer 26; 52: 155-163 Slide 5 Advanced NSCLC Gemcitabine Maintenance Therapy Progression-Free Survival PFS from the date of starting first-line chemotherapy P<.1 PFS from the date of randomiztion to maintenance P<.1 Overall survival: 13. mos vs 11. mos, p=.19 Brodowicz et al, Lung Cancer 26; 52: 155-163 Slide 6 POI-1-3-5: Phase III Study of Maintenance Gemcitabineafter Standard First-Line Therapy in Advanced NSCLC Stage IIIb/IV NSCLC PS - 2 N=6 Gem d 1,8 + carbo AUC 5 d1 X 4 cycles PD Off study CR, PR, or SD Primary endpoint: OVERALL Survival R Gemcitabine 1 mg/m 2 d 1,8 + BSC 21 day cycle N=332 Until progression BSC
Slide 7 Progression-Free Survival HR=1.9 (.81-1.45) P =.575 BSC 7.7 mos Gemcitabine 7.4 mos 6 12 18 24 3 36 42 48 54 Belani et al. Proc ASCO, 21 Slide 8 1..9.8.7 Overall Survival HR=.97 (72-1.3) P =.838.6.5.4 BSC 9.3 mos..3.2.1. Gemcitabine 8. mos. 6 12 18 24 3 36 42 48 54 Overall Survival (months) Belani et al. Proc ASCO, 21 Slide 9 IFCT-GFPC 52 Study Design PD: off Maintenance Progression: treatment 2 nd line A Observation PD Pem Cisplatin Objective N=155 gemcitabine response or R* B x 4 cycles Gemcitabine PD Pem stable disease N=464 N=834 N=154 C Erlotinib PD Pem NSCLC N=155 Stage IIIB wet IV Tumor tissue PS -1, 18-7 years EGFR IHC Primary endpoint: PFS Asymptomatic brain EGFR mutation mets allowed Induction chemo: cisplatin 8 mg/m 2 d1 + gemcitabine 1,25 mg/m 2 d1, d8 Arm B: gemcitabine 1,25 mg/m 2 d1, d8 Q 3 wks Arm C: erlotinib 15 mg PO daily
Slide 1 Probability 1..8.6.4.2 PFS by Independent Review Gemcitabine vs Observation Median PFS, months PFS at 6 months, % 8.6 22.1 HR=.55 (.43.7) Log-rank test, p<.1 Observation N=152 Observation Gemcitabine Gemcitabine N=149 1.9 3.8 PFS at 3 months, % 3.3 55. 5 1 15 2 25 3 35 4 Time (months) Perol et al. Proc ASCO, 21 Slide 11 PARAMOUNT Study Design Induction treatment period (unblinded): Four cycles of pemetrexed (5 mg/m 2, Day 1) + cisplatin (75 mg/m 2, Day 1)* (approximately 9 patients) Patients who have a documented response of CR, PR, or SD and have an ECOG PS of or 1 Blinded Pemetrexed 5 mg/m 2 Placebo + BSC* maintenance + BSC* (D1, q21d) period (D1, q21d) until disease progression until disease progression 2:1 (approximately 372 (approximately 186 patients) randomization patients) *Patients received folic acid, vitamin B 12, and dexamethasone. Slide 12 PARAMOUNT: Investigator Assessed PFS (from Maintenance) Survival Probability 1..9.8.7.6.5.4.3.2.1 Pemetrexed: median = 4.1 mos (3.2-4.6) Placebo: median =2.8 mos (2.6-3.1) Log-rank P=.6 Unadjusted HR:.62 (.49-.79). 3 6 9 12 15 Time (Months) Paz-Ares et al. Proc World Lung Conference, 211
Slide 13 Survival Probability.6.5.4.3.2.1. PARAMOUNT: Independently Reviewed PFS (472/539) 1. Pemetrexed: median =3.9 mos (3.-4.2).9 Placebo: median =2.6 mos (2.2-2.9).8 Log-rank P=.2.7 Unadjusted HR:.64 (.51-.81) 3 6 9 12 15 Time (Months) Paz-Ares et al. Proc World Lung Conference, 211 Slide 14 PARAMOUNT: Subgroup PFS HRs All Randomized Patients (N=539) Stage IV (n=489) Stage IIIB (n=5) Induction Response CR/PR (n=242) Induction Response SD (n=28) Pre-randomization PS 1 (n=366) Pre-randomization PS (n=17) Non-smoker (n=116) Smoker (n=419) Male (n=313) Female (n=226) Age <7 (n=447) Age 7 (n=92) Age <65 (n=35) Age >65 (n=189) Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471)..2.4.6.8 1. 1.2 1.4 1.6 1.8 2. Favors Pemetrexed Treatment Hazard Ratio (95% CI) Favors Placebo PFS results were internally consistent; benefit was seen across all subgroups.62.62.55.48.74.67.53.41.7.74.49.69.34.7.5.64.39.62 Slide 15 Survival Probability.6.5.4.3.2.1. PARAMOUNT: Independently Reviewed PFS (472/539) 1. Pemetrexed: median =3.9 mos (3.-4.2).9 Placebo: median =2.6 mos (2.2-2.9).8 Log-rank P=.2.7 Unadjusted HR:.64 (.51-.81) Survival Results Awaited 3 6 9 12 15 Time (Months) Paz-Ares et al. Proc World Lung Conference, 211
Slide 16 PointBreak: Pem/Carbo/Bev Followed by Maintenance Pem/Bev vs Paclitaxel/Carbo/Bev in Stage IIIB or IV Nonsquamous NSCLC Determination of eligibility R A N D O M I Z A T IO N Pem 5mg/m² q 21 D Carb AUC 6 q 21 D Bev 15 mg/kg q 21 D Vitamin Supplement as per label N=45 Pac 2 mg/m² q21 D Carb AUC 6 q 21 D Bev 15 mg/kg q 21 D Premedication as per label N=45 Induction Therapy Up to 4 21 day cycles Pts CR, PR, or SD after 4 cycles of induction therapy continue on maintenance therapy Patel JD et al. Clinical Lung Cancer 29;1(4):252-256. Pem 5mg/m² q 21 D Bev 15 mg/kg q 21 D Vitamin supplement as per label Bev 15 mg/kg q 21 D Maintenance Therapy Until PD or treatment discontinuation Post- Discontinuation Follow-up Pts with PD FU every 9 days until death Pts without PD FU every 6 weeks until PD; thereafter, followup every 9 days until death Slide 17 Maintenance Chemotherapy Switching to a New Chemotherapy Agent in Responding and Stable Patients (Usually a Single Agent) Slide 18 Immediate versus Delayed Docetaxel Chemonaϊve Stage IIIb/IV NSCLC N = 562 GC Phase N = 552 (388 received 4 cycles) ORR 29% SD, PR, CR N = 37 Immediate N = 153 Randomized Immediate Treated N = 142 Treated Off Study N = 245 Delayed N = 154 Delayed Treated N = 91 Fidias et al. J Clin Oncol 27: 591, Feb, 29
Survival Probability Proportion Surviving Slide 19 Progression-Free Survival Total Randomized Population 1..8.6 Please note: the PFS curves only showed up to Immediate Delayed LR 24 months since very few patients left without PD/survival 24 months (n=153) after randomization. (n=154) p-value Median PFS months (95% CI) 6.5 (4.4, 7.2) 2.8 (2.6, 3.4) <.1.4.2 12-month PFS, % (95% CI) 2% (13, 26) 9% (5, 14). therapy Delayed Immediated 3 6 9 12 15 18 21 24 Progression Free Survival (months) I: 153 72 27 11 5 D 154 28 1 4 2 Patients at Risk Slide 2 Overall Survival Total Randomized Population Median OS, months (95% CI) Immediate (n=153) 11.9 (1., 13.7) Delayed (n=154) 9.1 (8., 11.2) LR p-value.71 12-mo survival (95% CI) 48.5% (39.9, 57.1) 38.3% (3., 46.5) Overall Survival Time (in Months) Patients at I: 153 111 56 27 12 5 2 D: 154 98 45 22 9 3 2 Risk Is this negative for survival benefit or under-powered?? Slide 21 JMEN: Phase III Study of Maintenance Pemetrexed after Standard First-Line Therapy in Advanced NSCLC Stage IIIB or IV NSCLC who has not progressed after 4 cycles of a standard chemotherapy R Pemetrexed 5 day 1 N = 66 Patients Placebo + day 1 Primary objective: PFS, Superiority design Secondary objectives: RR, OS, TTPD, TWQ (Time to Worsening QOL), QOL based on LCSS
Progression-free Probability Slide 22 JMEN: Progression-Free Survival 1. N=581 HR=.599 (95% CI:.49.73) p <.1 Pemetrexed: 4.4 mos (95% CI: 3.6 4.44) Placebo: 1.97 mos (95% CI: 1.54 2.76) Time (months) 24% censored Ciuleanu, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, June 2, 28; Chicago, IL. Slide 23 Overall Survival, All Randomized Patients HR.79, CI.67-.95, p=.12 Ciulanu et al. Lancet, 29 Slide 24 Non-Squamous Subset PFS and OS in the non-squamous subset PFS HR.44, p<.1 OS HR.7, p=.2 16.4 vs 11.7 months for adeno Ciulanu et al. Lancet, 29
Slide 25 Meta-Analysis of Continuation vs Switch Maintenance Population HR PFS P HR OS P All.84 <.1.87.3 Switch.77 <.1.86.5 Continuation.92.7.92.33 Chemotherapy.87 <.1.88.18 EGFR Rx.76.1.86.6 Behera M. Proc ASCO, Abst 7553, 211 Slide 26 Maintenance Therapy With Molecularly Targeted Agents Continuation of the molecularly targeted agent after chemotherapy is completed Introduction of a new molecularly targeted agent Slide 27 Continuation of the Molecularly Targeted Agent After Chemotherapy is Completed Angiogenesis Inhibitors Bevacizumab Other angiogenesis inhibitors
Slide 28 ATLAS: Bevacizumab +/- Erltoinib Maintenance After First-Line Treatment Chemotherapy naïve stage IIIb/IV non-squamous NSCLC Bevacizumab plus chemotherapy* PD or significant toxicity Non-PD Bevacizumab + Erlotinib 1:1 Bevacizumab + placebo PD PD Off study Erlotinib Off study PI: Dr W Navarro (USA) Primary endpoint: PFS AVG3671g (phase IIIb) Bevacizumab 15mg/kg every 3 weeks; Erlotinib 15mg/day *Either carboplatin/paclitaxel, carboplatin/gemcitabine or carboplatin/docetaxel Slide 29 PointBreak: Pem/Carbo/Bev Followed by Maintenance Pem/Bev vs Paclitaxel/Carbo/Bev in Stage IIIB or IV Nonsquamous NSCLC Determination of eligibility R A N D O M I Z A T IO N Pem 5mg/m² q 21 D Carb AUC 6 q 21 D Bev 15 mg/kg q 21 D Vitamin Supplement as per label N=45 Pac 2 mg/m² q21 D Carb AUC 6 q 21 D Bev 15 mg/kg q 21 D Premedication as per label N=45 Induction Therapy Up to 4 21 day cycles Pts CR, PR, or SD after 4 cycles of induction therapy continue on maintenance therapy Patel JD et al. Clinical Lung Cancer 29;1(4):252-256. Pem 5mg/m² q 21 D Bev 15 mg/kg q 21 D Vitamin supplement as per label Bev 15 mg/kg q 21 D Maintenance Therapy Until PD or treatment discontinuation Post- Discontinuation Follow-up Pts with PD FU every 9 days until death Pts without PD FU every 6 weeks until PD; thereafter, followup every 9 days until death Slide 3 Maintenance Therapy With Oral Angiogenesis Inhibitors Randomized trials performed with numerous agents administered with chemotherapy All continued oral AI when chemotherapy stopped (in the absence of toxicity) Until there is a positive trial of an oral AI, this question is of academic interest only
Slide 31 CALGB 367: Sunitinib Maintenance Therapy Post Chemotherapy Phase III, randomized, placebo-controlled trial Planned randomization: 156 patients Patients with untreated stage IIIB/IV NSCLC and ECOG PS 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 1 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 Continue until disease progression Planned follow-up: 1 year Slide 32 EORTC 892: Pazopanib Maintenance Therapy Post Chemotherapy Phase III, randomized, placebo-controlled trial Planned randomization: 54 patients Patients with untreated stage IIIB/IV NSCLC and ECOG PS 2 Four cycles of platinum-based chemotherapy* Randomization of responding patients or patients with stable disease Pazopanib 8mg/day Continue until disease progression Placebo 1 Endpoint - OS Slide 33 Continuation of the Molecularly Targeted Agent After Chemotherapy is Completed EGFR Monoclonal Antibodies Cetuximab
Proportion Without Event Slide 34 Introduction of Switch Maintenance Therapy with EGFR TKIs ATLAS SWOG 23 WJTOG-23 (EORTC 821) SATURN INFORM Slide 35 ATLAS: Bevacizumab +/- Erltoinib Maintenance After First-Line Treatment Chemotherapy naïve stage IIIb/IV non-squamous NSCLC Bevacizumab plus chemotherapy* PD or significant toxicity Non-PD Bevacizumab + Erlotinib 1:1 Bevacizumab + placebo PD PD Off study Erlotinib Off study PI: Dr W Navarro (USA) Primary endpoint: PFS AVG3671g (phase IIIb) Bevacizumab 15mg/kg every 3 weeks; Erlotinib 15mg/day *Either carboplatin/paclitaxel, carboplatin/gemcitabine or carboplatin/docetaxel Slide 36 ATLAS: Progression-Free Survival (ITT population, investigator assessment) 1..8 Bev + Placebo (n=373), Median 3.75 mo Bev + Erlotinib (n=37), Median 4.76 mo.6.4.2 HR=.722 (.592-.881) Log-rank P=.12. 3 6 9 12 15 18 21 Progression-Free Survival (months) No. of patients at risk: Bev + Placebo Bev + Erlotinib 373 142 58 27 15 6 3 37 178 81 43 2 6 3 1 36
Proportion Without Event Slide 37 ATLAS: Progression-Free Survival (ITT population, investigator assessment) 1..8.6.4.2 October 15, 29, Bev Roche + Placebo has (n=373) Bev + Erlotinib (n=37) communicated to OSI that an exploratory ATLAS HR=.722 data (.592-.881) sweep Log-rank P=.12 for survival was not positive. OS was a 2 endpoint and the study was not powered for OS!!!!!. 3 6 9 12 15 18 21 Progression-Free Survival (months) No. of patients at risk: Bev + Placebo Bev + Erlotinib 373 142 58 27 15 6 3 37 178 81 43 2 6 3 1 37 Slide 38 ATLAS: PFS K-M Curves by EGFR Mutation Status EGFR Wild-Type EGFR Mutant HR =.85 (95% CI:.638-1.131) Log-rank P=.262 HR =.439 (95% CI:.223 -.864) Log-rank P=.137 Johnson et al. ESMO 29 Slide 39 SWOG 23 (Update): Schema Definitive Tx Cis 5 mg/m 2 Days 1, 8, 29, 36 Etop-16 5 mg/m 2 Days 1-5, 29-33 XRT 1.8-2 Gy/d, Total 61 Gy Consolidation Docetaxel 75 mg/m 2 x 3 cycles R A N D O M I Z A T I O N Maintenance Placebo Gefitinib 5 mg/day 25 mg/day (5-1-3) 1 o end point: overall survival; 2 o end points: 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 non-squamous
Progression-Free Survival, % Overall Survival, % Slide 4 SWOG 23 (Update): Survival Progression-Free Survival Median N Events (mo) Gefitinib 118 84 8 Placebo 125 81 12 Gefitinib Placebo Overall Survival Median n Events (mo) 118 71 23 125 54 35 1 Yr 2 Yr OS OS 73% 46% 81% 59% 1 8 6 P=.28 1 8 6 P=.1 4 4 2 12 24 36 48 6 2 Median Follow-up Time: 27 Months 12 24 36 48 6 Months After Randomization Months After Randomization Kelly K et al. J Clin Oncol 26: 245, 28 Slide 41 WJTOG -23: Maintenance with Gefitinib in Patients with NSCLC IIIB/IV NSCLC PS -1 (n=64) Stratify Institution Histology Stage Chemo R A N D O M I Z E 1st-line platinum-based chemotherapy x 6 cycles 1st-line platinum-based chemotherapy x 3 cycles Gefitinib 25 mg/d 1 Endpoint Overall Survival Designed to detect a 3 mo difference from 9 to 12 mos Slide 42 WJTOG-23: Survival Results Overall Survival MST: 12.9 m vs 13.7 m HR:.86, p=.11 Median PFS MST: 4.3 m vs 4.6 m HR:.67, p<.1 Takeda et al. J Clin Oncol 28: 753, 21
Slide 43 WJTOG-23: Post-Study Therapy EGFR TKI at any time 54% 75% Takeda et al. J Clin Oncol 28: 753, 21 Slide 44 WJTOG-23: Post-Study Therapy MST in Non-smoking patients with adenocarcinoma Arm A 23.5 months Arm B 25.1 months >75% of these patients on Arm A received an EGFR TKI at the time of progression Takeda et al. J Clin Oncol 28: 753, 21 Slide 45 SATURN: First-line Phase III Erlotinib Maintenance Trial in Patients with NSCLC 1 st -line IIIB/IV NSCLC (n=1,7) Collect tissue 1st-line platinum-based chemotherapy x 4 cycles PD patients enter the 2nd-line study TITAN Stratify for EGFR IHC Placebo CR/PR/SD (n=85) Erlotinib Treatment to PD, unacceptable toxicity or death 1 Endpoint PFS Overall: 25% better EGFR IHC+: 3% better
OS probability Slide 46 SATURN: PFS in All Patients (ITT) PFS probability 1..8 Erlotinib Placebo PFS at 12 wks (%) 53 4 PFS at 24 wks (%) 31 17.6.4.2 HR=.71 (.62.82) Log-rank p<.1 P<.1 8 16 24 32 4 48 56 64 72 8 88 96 Time (weeks) Erlotinib (n=437) Placebo (n=447) Slide 47 1..8.6.4 Saturn: OS in all patients (ITT) HR=.81 (.7.95) Log-rank p=.88 Erlotinib (n=438) Placebo (n=451).2 11. 12. 3 6 9 12 15 18 21 24 27 3 33 36 Time (months) *OS is measured from time of randomisation into the maintenance phase; ITT = intent-to-treat population Slide 48 EORTC 821 Closed early Gafaar et al. J Clin Oncol 28: (Suppl) Abst 7518, 21
Slide 49 EORTC 821 HR=.61, p=.2 HR=.81, p=.2 Gafaar et al. J Clin Oncol 28: (Suppl) Abst 7518, 21 Slide 5 IFCT- GFPC 52 study design PD: off Maintenance Progression: treatment 2 nd line A Observation PD Pem Cisplatin Objective N=155 gemcitabine response or R* B x 4 cycles Gemcitabine PD Pem stable disease N=464 N=834 N=154 C Erlotinib PD Pem NSCLC N=155 Stage IIIB wet IV Tumor tissue PS -1, 18-7 years EGFR IHC Primary endpoint: PFS Asymptomatic brain EGFR mutation mets allowed Induction chemo: cisplatin 8 mg/m 2 d1 + gemcitabine 1,25 mg/m 2 d1, d8 Arm B: gemcitabine 1,25 mg/m 2 d1, d8 Q 3 wks Arm C: erlotinib 15 mg PO daily Slide 51 Probability 1..8.6.4.2 IFCT- GFPC 52 : PFS Erlotinib vs Observation PFS at 6 months, 8.6 % 16.3 % HR=.82 (.73.93) Log-rank test, p=.2 Observation N=152 Observation Erlotinib Erlotinib N=153 Median PFS, 1.9 mo 2.9 mo PFS at 3 months, 3.3 % 35.3 % 5 1 15 2 25 3 35 4 Time (months) PFS is measured from time of randomisation into the maintenance phase
ORR (%) DCR (%) Probability of PFS (%) Slide 52 INFORM: Study Design Patients Age 18 years Completed 4 cycles of first-line platinum-based chemotherapy without PD or unacceptable toxicity Life expectancy 12 weeks WHO PS -2 Measurable Stage IIIB/IV disease Gefitinib (25 mg/day) 1:1 randomization Placebo (once daily) EGFR, epidermal growth factor receptor; PD, progressive disease PS, performance status; WHO, World Health Organization 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 Slide 53 INFORM: Progression-Free Survival 1 9 8 7 6 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) Placebo (n=148) 2.6 15. 2.9 144 (97.3) 5 4 3 HR.42 (.33,.55); p<.1 2 1 8 24 32 48 64 8 88 14 16 4 56 72 96 112 Time since randomization (weeks) Patients at risk : Placebo 82 26 16 6 3 2 2 148 46 1 4 2 19 7 65 49 38 2 15 1 148 82 56 42 31 6 Zhang et al. Proc ASCO, 211 LBA 7511 Slide 54 ORR & DCR (RECIST; ITT Population) 5 4 3 2 1 Odds ratio (95% CI) = 54.1 (7.17, 48); p=.1 23.6 Gefitinib (n=148).7 Placebo (n=148) Odds ratio >1 implies a greater chance of response on gefitinib Odds ratio and p-value from logistic regression with covariates ITT, intent-to-treat; RECIST, Response Evaluation Criteria In Solid Tumors 8 7 6 5 4 3 2 1 Odds ratio (95% CI) = 2.69 (1.62, 4.46); 71.6 p=.1 Gefitinib (n=148) 5.7 Placebo (n=148) Zhang et al. Proc ASCO, 211 LBA 7511
Overall survival (%) Slide 55 Post-discontinuation Treatments None: 49.3% Gefitinib Placebo Targeted therapy: 8.1% Chemotherapy: 39.9% Others: 24.4% None: 33.1% Targeted therapy: 31.8% Chemotherapy: 53.4% Others: 23.7% Zhang et al. Proc ASCO, 211 LBA 7511 Slide 56 INFORM: Overall Survival 1 9 8 7 6 5 4 3 Gefitinib Placebo (n=148) (n=148) Median OS, months 18.7 16.9 6-month survival rate, % 82.2 84.9 12-month OS rate, % 68.8 66. No. events, n (%) 79 (53.4) 93 (62.8) HR.84 (.62, 1.14); p=.268 2 1 Patients at risk: 16 4 56 72 96 112 8 24 32 48 64 8 88 14 12 128 Time (weeks) Zhang et al. Proc ASCO, 211 LBA 7511 Slide 57 Phase III H3E-CR-S131 Study Schema Eligibility NSCLC: Non-squamous histology Stage IIIb/IV Chemo-naïve (1st line) PS: -1 Never smoker or light exsmoker** Unknown, untested, inconclusive EGFR mutation status R Randomization (Stratification) Factors Gender Pemetrexed 5mg/m 2 + Cisplatin 75mg/m 2, IV x 6 cycles, q3w + Vit B12/Folic Acid Gefitinib 25mg/day PO Smoking History (Never smoker/light ex-smoker) Performance status N=226 Adenocarcinoma/Non-adenocarcinoma ** light ex-smoker: quit from smoking for 5 years and 1 pack year. CR/PR/SD PD Gefitinib 25mg/day PO Primary Endpoint: Superiority in PFS HR:.68 Secondary Endpoints: PD OS, RR, Safety, BioMarkers Translational Research: Analysis of Outcomes by EGFR Mutation status * Pre-planned, pre-specified subset analysis * Presence of activating mutation(s) in exon 18 to exon 21 of the EGFR-receptor will be confirmed by direct DNA sequencing of NSCLC tumor tissue
Slide 58 Meta-Analysis of Continuation vs Switch Maintenance Population HR PFS P HR OS P All.84 <.1.87.3 Switch.77 <.1.86.5 Continuation.92.7.92.33 Chemotherapy.87 <.1.88.18 EGFR Rx.76.1.86.6 Behera M. Proc ASCO, Abst 7553, 211 Slide 59 Why Was There Such a Dramatic Difference Among The Three Trials of Maintenance Gemcitabine??? Are There Clues to Patient Selection? Slide 6 Potential Predictors of Benefit From Maintenance Therapy Chemotherapy PS Response to first-line treatment Histology EGFR TKIs EGFR expression EGFR copy EGFR mutation Histology
Slide 61 Survival by Performance Status Brodowicz et al, Lung Cancer 26; 52: 155-163 Slide 62 Patient Demographics Maintenance Phase Maintenance Phase GEM N=128 % BSC N=127 % Median age, years 67.2 67.5 Age 65 years /<65 years 61/39 59/41 Stage IIIB/IV disease 22/78 9/91 Male/Female 6/4 67/33 Caucasian/AA/Other 83/13/4 88/6/6 ECOG PS /1/2/3 /44/52/4 /43/54/4 Belani et al. Proc ASCO, 21 Slide 63 Performance Status in Other Trials JMEN - PS 2 patients not eligible IFCT 52 - PS 2 patients not eligible; only 5% of randomized patients PS 2 SATURN - PS 2 patients not eligible PARAMOUNT - PS 2 patients not eligible All the above trials were Positive!!! PointBreak - PS 2 patients not eligible
Survival Probability Survival Probability Slide 64 Response to First-Line Chemotherapy CR/PR versus SD Slide 65 Survival by Response to First-Line Therapy Study CR/PR SD JMEN.81.61 (Non-Squam) IFCT 52 (PFS).44.68 Belani NR NR IFCT 52 (PFS).8.85 SATURN.94.72 Slide 66 1..9.8.7.6.5.4.3.2.1 6 12 18 24 3 36 42 Patients at Risk Survival Time (months) Pem Plac JMEN: Effect of Response to Induction Rx on OS (Non-Squamous) 148 78 125 59 CR or PR 84 35 5 21 Median (95% CI) Pem 14.4 (12.3, 18.2) Plac 11.7 (8.5, 15.3) HR (95% CI).81 (.58, 1.12) P =.19854 18 7 Pem 14.4 months Plac 11.4 months HR=.81, p=.198 9 2 3 1 1. Median (95% CI).9 Pem 16.6 (13., 2.9).8 Plac 8.6 (7.2, 11.3).7 HR (95% CI).6.61 (.45,.83).5 P =.171.4.3.2.1. 6 12 18 24 3 36 42 Patients at Risk Survival Time (months) Pem Plac 174 78 139 53 94 28 SD 67 21 Pem 16.6 months Plac 8.6 months = 8 mo!! HR=.61, p=.17 33 13 16 5 Eli Lilly data on file 6 2
Slide 67 Survival by Response to First-Line Therapy Study CR/PR SD JMEN (Non-Squam) PARAMOUNT.81.48.61.74 IFCT 52 (PFS).44.68 Belani NR NR IFCT 52 (PFS).8.85 SATURN.94.72 Slide 68 Selection by Histology Slide 69 PFS by Histology Study Adenocarcinoma Other JMEN.73 1.7 (squamous) IFCT 52.53.56 Study Adenocarcinoma Other IFCT 52.79.88 SATURN.6.76
Slide 7 PFS by Histology Study Adenocarcinoma Other JMEN.73 1.7 (squamous) IFCT 52.53.56 Study Adenocarcinoma Other IFCT 52.79.88 SATURN.6.76 Slide 71 Continued Doublet Chemotherapy vs Maintenance Gefitinib Takeda et al J Clin Oncol 28: 753, 21 Slide 72 Selection by Biomarkers EGFR
Slide 73 SATURN: PFS According to Biomarker Status All HR (95% CI).71 (.62.82) n 884 EGFR IHC+.69 (.58.82) 618 EGFR IHC.77 (.51 1.14) 121 EGFR FISH+ EGFR FISH.68 (.51.9).81 (.62 1.7) 231 255 KRAS mutation+.77 (.5 1.19) 9 KRAS wild-type.7 (.57.87) 43 EGFR CA-SSR1 low EGFR CA-SSR1 high.68 (.55.85).75 (.6.92) 385 396.4.6.8 1. 1.2 Favours HR erlotinib Favours placebo Slide 74 SATURN: PFS According to EGFR Mutation Status HR (95% CI) N All.71 (.62.82) 884 EGFR mutation+.1 (.4.25) 49 EGFR wild-type.78 (.63.96).5.8 1.1.2.25.1.2.4.6 HR Favours Favours erlotinib placebo 328 Slide 75 SATURN OS Subgroup Analyses for EGFR IHC & EGFR Mutations All HR (95% CI) n.81 (.7.95) 889 EGFR IHC+ EGFR IHC- *EGFR mutation+ EGFR wild-type.4.6.8 1. 1.2 Favours HR erlotinib Favours placebo 1.4 1.6 1.8 2. Quantitative not qualitative interaction.77 (.64.93) 621.91 (.59 1.38) 121.83 (.34 2.2) 49.77 (.61.97) 388 * 67% of patients with EGFR mutation+ disease in the placebo arm received a second-line EGFR TKI Cappuzzo et al. Proc IASLC, 29
OS probability OS probability 1,,9,8,7,6,5,4,3,2,1, Slide 76 1..8 OS in EGFR Wild-Type Groups HR=.77 (.61.97) Log-rank p=.243.6.4 Erlotinib (wild-type) n=199 Placebo (wild-type) n=189.2 1.2 11.3 3 6 9 12 15 18 21 24 27 3 33 36 Time (months) Slide 77 SATURN: OS in EGFR Wild-Type Group With SD on 1st-line Chemotherapy 1..8.6.4 Erlotinib (n=114) Placebo (n=13) HR=.65 (.48.87) Log-rank p=.41.2 8.7 12.4 3 6 9 12 15 18 21 24 27 3 33 36 Time (months) OS is measured from time of randomisation into the maintenance phase Slide 78 IFCT- GFPC 52: Effect of Maintenance in EGFR IHC -ve Patients Gemcitabine vs observation HR=.42 [.23-.78] Erlotinib vs observation HR =.86 [.63 ; 1.18] 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 21 22 23 24 25 26 27 28 29 3 31 32 33 34 35 36 37 38 Months 464 randomized, 24 evaluable samples 127 EGFR IHC+ ; 77 EGFR IHC- Perol et al. Proc ASCO, 21
PFS (%) PFS (%) Slide 79 PERFORM: PFS by EGFR Mutation Status EGFR mutation-positive Gefitinib (n=15) Median PFS, 16.6 months No. events, 9 (6.%) Placebo (n=15) Median PFS, 2.8 months No. events, 15 (1.%) EGFR mutation-negative Gefitinib (n=25) Median PFS, 2.7 months No. events, 25 (1.%) Placebo (n=24) Median PFS, 1.5 months No. events, 24 (1.%) 1 HR (95% CI) =.17 (.7,.42) 1 HR (95% CI) =.86 (.48, 1.51) 8 6 8 6 4 4 2 8 16 24 32 4 48 56 64 72 8 88 96 14 112 Time (weeks) 2 8 16 24 32 4 48 56 64 72 8 88 96 14 112 Time (weeks) Zhang et al. Proc ASCO, 211 LBA 7511 Slide 8 Summary There is no evidence to support prolonged administration of platinum-based doublet chemotherapy Preliminary evidence suggests a possible role for maintenance docetaxel, and perhaps gemcitabine in unselected patients Pemetrexed is approved as maintenance therapy in patients with non-squamous cell cancer Slide 81 Summary (2) SATURN and the WJTOG-23 suggest a possible role for maintenance EGFR TKI therapy Major effect on PFS in patients with EGFR mutations with only modest effect on OS Although current practice is to continue monoclonal antibody therapy after completion of chemotherapy, there are no data to support this