Choosing Optimal Therapy for Advanced Non-Squamous (NS) Non-Small Cell Lung Cancer

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1 Choosing Optimal Therapy for Advanced Non-Squamous (NS) Non-Small Cell Lung Cancer Jyoti D. Patel, MD Associate Professor Feinberg School of Medicine Robert H Lurie Comprehensive Cancer Center Northwestern University Chicago, IL

2 Treatment Selection in Advanced NSCLC The OLD Way: Empiric Comparison of RR, PFS, and OS only in randomized, controlled trials Best numbers = standard of care The NEW Way: Rational Emphasis on targeted therapy Molecular targets Histology guides therapeutic options OS = overall survival. PFS = progression-free survival. RR = risk ratio.

3 ECOG Trial 1594: Study Design Stratify by: PS 0-2 Weight loss Stage IIIB, IV Brain mets (±) R A N D O M I Z E Control Arm Paclitaxel 135 mg/m 2 over 24 hours, day 1 Cisplatin 75 mg/m 2, day 2 q 3 weeks Gemcitabine 1000 mg/m 2, days 1, 8, and 15 Cisplatin 100 mg/m 2, day 1 q 4 weeks Docetaxel 75 mg/m 2, day 1 Cisplatin 75 mg/m 2, day 1 q 3 weeks Paclitaxel 225 mg/m 2 over 3 hours, day 1 Carboplatin AUC = 6, day 1 q 3 weeks Schiller JH, et al. N Engl J Med. 2002;346(20):92-98.

4 Therapeutic Plateau in Metastatic NSCLC ECOG 1594 Patient Survival (%) Cisplatin/Paclitaxel Cisplatin/Gemcitabine Cisplatin/Docetaxel Carboplatin/Paclitaxel* Months Schiller JH,et al. N Engl J. Med. 2002;346(20):92-98.

5 NCCN Guidelines for First-line Treatment: Recurrent or Metastatic NSCLC TREATMENT Doublet chemotherapy (Cat 1) Chemotherapy + bevacizumab* EGFR mutation or ALK negative or unknown Cisplatin/pemetrexed (Cat 1)** Cetuximab/vinorelbine/cddp (Cat 2B) Chemotherapy (PS 2) Best supportive care (PS 3/4) Establish histologic subtype Adenocarcinoma Large cell NSCLC NOS EGFR mutation testing (Cat 1) ALK testing EGFR mutation positive ALK positive *Criteria for bevacizumab + chemotherapy: non-squamous, no recent hemoptysis **There is evidence of superior efficacy and reduced toxicity for cis/pem in pts who do not have squamous histology, in comparison to cis/gem Erlotinib (Category 1) Crizotinib Squamous cell carcinoma EGFR mutation and ALK testing are not routinely recommended Chemotherapy Cetuximab/vinorelbine/cisplatin Best supportive care (PS 3/4) Adapted Accessed 10/29/12

6 Phase III Study Comparing Gemcitabine/Cisplatin with Pemetrexed/Cisplain in Advanced NSCLC Randomization Factors Stage PS Sex Histo vs cyto dx Brain mets hx R Cisplatin 75 mg/m 2 day 1 + Pemetrexed 500 mg/m 2 day 1 Each cycle repeated q3weeks up to 6 cycles Cisplatin 75 mg/m 2 day 1 + Gemcitabine 1250 mg/m 2 days 1 & 8 Scagliotti G, et al. J Clin Oncol. 2008;26(21):

7 Overall Survival in Patients with Adenocarcinoma or Large Cell Ca. Overall Survival: ITT

8 Phase III Study Comparing Gem/Cis with Pem/Cis in Advanced NSCLC Toxicity (grades 3/4) (%) Pem/Cis Gem/Cis Neutropenia <0.001 Anemia Thrombocytopenia <0.001 Febrile neutropenia Alopecia (all grades) <0.001 Nausea Scagliotti G, et al. J Clin Oncol. 2008;26(21):

9 PARAMOUNT: Pemetrexed Maintenance in Nonsquamous NSCLC Eligibility: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 (N=939) Pemetrexed 500 mg/m 2 Cisplatin 75 mg/m 2 q21d 4 cycles CR, PR, SD (57%) days PD R A N D O M I Z E 2:1 Pemetrexed + BSC Placebo + BSC PD Primary endpoint: PFS Secondary endpoints: OS, RR, QOL, resource utilization, safety Stratified by ECOG PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) Paz-Ares L, et al. Lancet Oncol. 2012;13:

10 PARAMOUNT: Patient Characteristics Pemetrexed (n=359) Placebo (n=180) Gender, % Male/female 56/44 62/38 Age Median age, years <65 years, % Smoking status, % Ever smoker Never smoker ECOG PS at randomization, % 0 1 2/3 a Disease stage IV before maintenance therapy, b % Best tumor response to induction therapy, % CR/PR SD PD/unknown a Histology, % Adenocarcinoma Large cell Other nonsquamous Paz-Ares L, et al. Presented at: ASCO (abstr LBA7507).

11 Survival Probability PARAMOUNT: Final OS From Randomization Median OS, months (95% CI) Pem 13.9 ( ) Placebo 11.0 ( ) Censoring, % Survival rate (95% CI), % 1-year 58 (53-63) 45 (38-53) 2-year 32 (27-37) 21 (15-28) Unadjusted HR: 0.78 (95% CI: ) Log-rank P= Patients at risk Pem 359 Placebo Time From Randomization, Months Paz-Ares L, et al. Presented at: ASCO (abstr LBA7507).

12 Phase III Trial of Bevacizumab in Non-Squamous NSCLC: ECOG 4599 N=855 Eligibility: Non-squamous NSCLC No Hx of hemoptysis No CNS metastases Stratification Variables: RT vs no RT Stage IIIB or IV vs recurrent Wt loss <5% vs >5% Measurable vs non-measurable (CbP) Paclitaxel 200 mg/m 2 Carboplatin AUC = 6 (q 3 weeks) x 6 cycles No crossover to Bevacizumab permitted (CbP + Bev) CbP x 6 cycles + Bevacizumab (15mg/kg q 3 wks) to PD Sandler A, et al. New Engl J Med. 2006;355(24):

13 Patients With PFS (%) Patients Surviving (%) Carboplatin/Paclitaxel +/- Bevacizumab RR: 15% for CbP vs. 35% for CbP + Bev Progression-Free Survival Overall Survival CbP CbP + Bev P<0.001; HR=0.66 Median PFS: 6.2 months vs. 4.5 months 6-Month PFS: 55% vs. 33% 1-Year PFS: 15% vs. 6% CbP CbP + Bev P=0.003; HR=0.79 Median OS: 12.3 months vs months 1-Year OS: 51% vs. 44% 2-Year OS: 23% vs. 15% Months Months HR=hazard ratio; OS=overall survival; PFS=progression-free survival, RR: response rate Sandler A, et al. New Engl J Med. 2006;355(24):

14 Phase II Carboplatin + Pemetrexed + Bevacizumab Eligibility: Stage IIIB/IV nonsquamous NSCLC No prior chemotherapy ECOG PS 0/1 No CNS mets, hemoptysis, anticoagulation Carboplatin AUC 6 + pemetrexed 500 mg/m 2 + bevacizumab 15 mg/kg q3w 6 cycles N=50 SD or PR Primary endpoint: PFS Secondary endpoints: OS, RR, safety Pemetrexed + bevacizumab q21d N=30 PD or toxicity Parameter Patel, et al. J Clin Oncol. 2009; 27:3284. Result ORR (%) 55 (95% CI, 41-69) Median PFS (months) 7.8 (95% CI, ) Median OS* (months) 14.1 (95% CI, ) *Thirty-two of 50 events. Median follow-up: 13 months; median (range) number of cycles: 7 (1-51).

15 Bevacizumab Trials: Efficacy Study Schema N RR (%) PFS mos MST mos E4599 C + Pac + B AVAIL P + G + B NR AVAIL P + G + B NR NWU Ph 2 C + PEM + B Study Neut (%) G3-5 Toxicity FN (%) TCP (%) HTN (%) Thrombosis (%) Pulmonary Bleed (%) E * AVAIL AVAIL NWU Ph

16 PointBreak: Phase III JHMD Patel, IASLC, Chicago 2012, PLBA1 Randomized, open-label, phase III superiority study conducted in US Pemetrexed 500 mg/m 2 ; Carboplatin AUC 6; Bevacizumab 15 mg/kg Paclitaxel 200 mg/m 2 ; Carboplatin AUC 6; Bevacizumab 15 mg/kg Inclusion: - No prior systemic therapy for lung cancer - PS 0/1 - Stage IIIB-IV NS-NSCLC - Stable tx t brain mets Exclusion: - Peripheral neuropathy > Gr 1 - Uncontrolled pleural effusions R 1:1 Induction Phase q21d, 4 cycles Pemetrexed (folic acid & vitamin B 12 ) + Carboplatin + Bevacizumab 450 patients each Paclitaxel + Carboplatin + Bevacizumab Maintenance Phase q21d until PD Pemetrexed (folic acid & vitamin B 12 ) + Bevacizumab Bevacizumab Stratified for: PS (0 vs 1); sex (M vs F); disease stage (IIIB vs IV); measurable vs nonmeasurable disease

17 PointBreak: Objectives and Statistical Considerations Primary Objective: Overall Survival (OS) Assumed a hazard ratio (HR) of 0.80; required 676 events in 900 patients to yield at least an 80% power to demonstrate superiority of Pem+Cb+Bev followed by Pem+Bev over Pac+Cb+Bev followed by Bev; using a log-rank test with 1-sided type I error of Secondary Objectives: Progression Free Survival (PFS) Time to Progressive Disease (TTPD) Overall Response Rate (ORR) (RECIST 1.0) Safety and Patient Reported Outcomes (FACT-L/Ntx) Pre-specified Exploratory Analyses: OS and PFS for maintenance population PFS without Grade 4 toxicity (G4 PFS)

18 PointBreak: Final Patient Disposition 1259 Patients Enrolled 320 patients failed screening 939 Patients Randomized 30 patients not treated 24 patients not treated Pem+Cb+Bev Arm n=472 Pac+Cb+Bev Arm n=467 Discontinuations (454) Progressive Disease 251 Any Adverse Event 67 Patient Decision 49 Physician Decision 40 Other 15 Death due to -Study Disease 11 -Study Drug-related 6 -Other AE/Toxicity 15 Pem+Bev n=292 Bev n=298 Discontinuations (460) Progressive Disease 276 Any Adverse Event 61 Patient Decision 33 Physician Decision 40 Other 19 Death due to -Study Disease 12 -Study Drug-related 8 -Other AE/Toxicity 11

19 PointBreak: Patient Characteristics* (ITT) Pem+Cb+Bev (n=472) % Median age, yrs (range) 64.7 ( ) Pac+Cb+Bev (n=467) % 70 yrs Male Caucasian African American Ever Smoker ECOG PS Disease stage IV Histology Adenocarcinoma Large cell Other Previously treated brain metastases *Some patients missing values for these characteristics; %s calculated accordingly. AJCC TNM Staging System for Lung Cancer, 6th edition. ITT=intent to treat.

20 PointBreak: PFS from Randomization (ITT) Pem+Cb+Bev Pac+Cb+Bev Survival Probability PFS median (mo) HR (95% CI); P value 0.83 (0.71, 0.96); P=0.012 TTPD (mo) HR (95% CI); P value 0.79 (0.67, 0.94); P=0.006 ORR (%) G4 PFS* median (mo) HR (95% CI); P value 0.74 (0.64, 0.86); P< Time from Induction (Months) Censoring rate for Pem+Cb+Bev was 26.9%; for Pac+Cb+Bev was 23.3% *Exploratory analysis

21 PointBreak: Subgroup PFS (ITT) All Patients (N=939) Stage IIIB with pleural effusions (n=94) Stage IV (n=844) Age <=70 years (n=692) Age >70 years (n=247) Female (n=439) Male (n=500) Caucasian (n=805) Non-caucasian (n=130) Cytological (n=289) Histopathological (n=649) Measurable (n=896) Non-measurable (n=27) No Previously Treated Brain Mets (n=835) Previously Treated Brain Mets (n=104) Ever Smoked (n=825) Never Smoked (n=108) Adenocarcinoma (n=743) Large Cell (n=23) Other or Indeterminant (n=172) ECOG PS =0 (n=414) ECOG PS =1 (n=524) Progression Free Survival Hazard Ratio Treatment Hazard Ratio (95% CI) Favors Pem+Cb+Bev Favors Pac+Cb+Bev

22 PointBreak: OS from Randomization (ITT) Pem+Cb+Bev Pac+Cb+Bev Survival Probability OS median (mo) HR (95% CI); P value 1.00 (0.86, 1.16); P=0.949 Survival rate (%) 1-year year Time from Induction (Months) Censoring rate for Pem+Cb+Bev was 27.8%; for Pac+Cb+Bev was 27.2%

23 PointBreak: Subgroup OS Hazard Ratios Overall Survival Hazard Ratio All Patients (N=939) Stage IIIB with pleural effusions (n=94) Stage IV (n=844) Age <=70 years (n=692) Age >70 years (n=247) Female (n=439) Male (n=500) Caucasian (n=805) Non-caucasian (n=130) Cytological (n=289) Histopathological (n=649) Measurable (n=896) Non-measurable (n=27) No Previously Treated Brain Mets (n=835) Previously Treated Brain Mets (n=104) Ever Smoked (n=825) Never Smoked (n=108) Adenocarcinoma (n=743) Large Cell (n=23) Other or Indeterminant (n=172) ECOG PS =0 (n=414) ECOG PS =1 (n=524) Treatment Hazard Ratio (95% CI) Favors Pem+Cb+Bev Favors Pac+Cb+Bev

24 PointBreak: Pre-specified Exploratory Analysis of KM PFS from Randomization: Maintenance Group Survival Probability Time from Induction (Months) Pem+Cb+Bev (n=292) Pac+Cb+Bev (n=298) PFS median (mo) Pre-specified exploratory non-comparative subgroup analyses Censoring rate for Pem+Cb+Bev was 24.7%; for Pac+Cb+Bev was 14.1%

25 PointBreak: Pre-specified Exploratory Analysis of KM OS from Randomization: Maintenance Group Pem+Cb+Bev (n=292) Pac+Cb+Bev (n=298) OS median (mo) Survival Probability Time from Induction (Months) Pre-specified exploratory non-comparative subgroup analyses Censoring rate for Pem+Cb+Bev was 36.0%; for Pac+Cb+Bev was 30.2%

26 PointBreak: CTCAEs (Version 3) Possibly Related to a Study Drug (Safety Population) Pem+Cb+ Bev (n=442) % Pac+Cb+ Bev (n=443) % Pem+Cb+ Bev (n=442) % Pac+Cb+ Bev (n=443) % Grade 1/2 Grade 1/2 Grade 3/4 (5) Grade 3/4 (5) Anemia Thrombocytopenia Neutropenia Febrile neutropenia Fatigue Hemorrhage GI/pulmonary (0.5) 0.5 (0.7) Thromboembolic event Neuropathy/sensory Alopecia * Other Grade 5 Events (Pem Arm/Pac Arm %) Includes: CNS ischemia (0.2/0.7); Cardiac events (0.2/0.7); ARDS (0.5/0); Infection (0.2/0); Other Hemorrhage (0.2/0.2) =Significant difference between arms, for grade 3/4 toxicities *Maximum grade is grade 2.

27 AVAPERL: Phase III Trial of Maintenance Bevacizumab With or Without Pemetrexed Following First-line Bevacizumab/Pemetrexed/Cisplatin in Advanced Nonsquamous NSCLC Eligibility criteria: Advanced or recurrent NSCLC Nonsquamous histology 4 prior cycles of bevacizumab/cisplatin/ pemetrexed with CR, PR or SD Primary endpoint: progression-free survival R A N D O M I Z E (n = 362) Pemetrexed 500 mg/m 2 Bevacizumab 7.5 mg/kg q 3 weeks Bevacizumab 7.5 kg/mg q 3 weeks Pem/Bev Bev HR PFS 10.2 m 6.6 m 0.50 (p<0.001) OS NR (34 events) 15.7 m 0.75 (p=0.23) Barlesi F et al, ECCO/ESMO 2011, Abstract 34 LBA

28 So Where Are We Today? Survival Probability E4599 CP E4599 CPB JHMD CPemB JHMD CPB 4 vs 6? Cis vs Carbo? nab-paclitaxel? Time from Induction (Months)

29 Shared Decision Making Patient Preference Anticipated Toxicity Cost Efficacy

30 Shared Decision Making Patient Preference Anticipated Toxicity Cost Efficacy

31 Empiric therapy: response rate 35%, progressive disease 35% Driver targeted treatment SMARTER, FASTER TRIALS