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
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.
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.
Therapeutic Plateau in Metastatic NSCLC ECOG 1594 Patient Survival (%) 1.0 0.8 0.6 0.4 Cisplatin/Paclitaxel Cisplatin/Gemcitabine Cisplatin/Docetaxel Carboplatin/Paclitaxel* 0.2 0.0 0 5 10 15 20 25 30 Months Schiller JH,et al. N Engl J. Med. 2002;346(20):92-98.
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 http://www.nccn.org. Accessed 10/29/12
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):3543 3551.
Overall Survival in Patients with Adenocarcinoma or Large Cell Ca. Overall Survival: ITT
Phase III Study Comparing Gem/Cis with Pem/Cis in Advanced NSCLC Toxicity (grades 3/4) (%) Pem/Cis Gem/Cis Neutropenia 15.1 26.7 <0.001 Anemia 5.6 9.9 Thrombocytopenia 4.1 12.7 <0.001 Febrile neutropenia 1.3 3.7 Alopecia (all grades) 11.9 21.4 <0.001 Nausea 7.2 3.9 Scagliotti G, et al. J Clin Oncol. 2008;26(21):3543 3551.
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%) 21-42 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;13:247-255.
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 % 91 90 Best tumor response to induction therapy, % CR/PR SD PD/unknown a Histology, % Adenocarcinoma Large cell Other nonsquamous 61 66 76 23 32 68 0.3 44 53 3 86 7 7 62 62 80 19 33 66 1 42 53 6 89 7 4 Paz-Ares L, et al. Presented at: ASCO. 2012 (abstr LBA7507).
Survival Probability PARAMOUNT: Final OS From Randomization 1.0 0.8 0.6 0.4 0.2 Median OS, months (95% CI) Pem 13.9 (12.8-16.0) Placebo 11.0 (10.0-12.5) Censoring, % 28.7 21.7 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: 0.64-0.96) Log-rank P=0.0195 0.0 Patients at risk Pem 359 Placebo 180 0 3 6 9 12 15 18 21 24 27 30 33 36 333 169 272 131 235 103 Time From Randomization, Months 200 78 166 65 138 49 105 35 79 23 43 12 15 8 2 3 0 0 Paz-Ares L, et al. Presented at: ASCO. 2012 (abstr LBA7507).
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):2542-2550.
Patients With PFS (%) Patients Surviving (%) Carboplatin/Paclitaxel +/- Bevacizumab RR: 15% for CbP vs. 35% for CbP + Bev Progression-Free Survival Overall Survival 100 80 60 40 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% 100 80 60 40 CbP CbP + Bev P=0.003; HR=0.79 Median OS: 12.3 months vs. 10.3 months 1-Year OS: 51% vs. 44% 2-Year OS: 23% vs. 15% 20 20 0 0 0 6 12 18 24 30 36 Months 0 6 12 18 24 30 36 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):2542-2550.
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, 5.2-11.5) Median OS* (months) 14.1 (95% CI, 10.8-19.6) *Thirty-two of 50 events. Median follow-up: 13 months; median (range) number of cycles: 7 (1-51).
Bevacizumab Trials: Efficacy Study Schema N RR (%) PFS mos MST mos E4599 C + Pac + B 15 420 35 6.2 12.3 AVAIL P + G + B 15 351 30 6.5 NR AVAIL P + G + B 7.5 345 34 6.7 NR NWU Ph 2 C + PEM + B 15 51 55 7.8 14.1 Study Neut (%) G3-5 Toxicity FN (%) TCP (%) HTN (%) Thrombosis (%) Pulmonary Bleed (%) E4599 26* 5.2 2 7 5.7 2 AVAIL 15 36 2 23 9 10 0.9 AVAIL 7.5 40 2 27 6 9 1.5 NWU Ph 2 4 0 6 0 8 0
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
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 0.025 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)
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
PointBreak: Patient Characteristics* (ITT) Pem+Cb+Bev (n=472) % Median age, yrs (range) 64.7 (29.5 86.2) Pac+Cb+Bev (n=467) % 70 yrs 75.0 72.4 Male 53.2 53.3 Caucasian African American 86.7 8.9 84.8 11.1 Ever Smoker 89.4 87.5 ECOG PS 0 43.9 44.4 Disease stage IV 89.8 90.1 Histology Adenocarcinoma 80.1 78.3 Large cell 1.7 3.2 Other 18.2 18.5 Previously treated brain metastases 11.0 11.1 *Some patients missing values for these characteristics; %s calculated accordingly. AJCC TNM Staging System for Lung Cancer, 6th edition. ITT=intent to treat.
PointBreak: PFS from Randomization (ITT) Pem+Cb+Bev Pac+Cb+Bev Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 PFS median (mo) 6.0 5.6 HR (95% CI); P value 0.83 (0.71, 0.96); P=0.012 TTPD (mo) 7.0 6.0 HR (95% CI); P value 0.79 (0.67, 0.94); P=0.006 ORR (%) 34.1 33.0 G4 PFS* median (mo) 4.3 3.0 HR (95% CI); P value 0.74 (0.64, 0.86); P<0.001 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time from Induction (Months) Censoring rate for Pem+Cb+Bev was 26.9%; for Pac+Cb+Bev was 23.3% *Exploratory analysis
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 0.83 0.65 0.85 0.77 0.98 0.78 0.88 0.83 0.78 0.75 0.87 0.85 0.39 0.84 0.74 0.89 0.48 0.78 0.37 1.19 0.73 0.91 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Treatment Hazard Ratio (95% CI) Favors Pem+Cb+Bev Favors Pac+Cb+Bev
PointBreak: OS from Randomization (ITT) Pem+Cb+Bev Pac+Cb+Bev Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 OS median (mo) 12.6 13.4 HR (95% CI); P value 1.00 (0.86, 1.16); P=0.949 Survival rate (%) 1-year 52.7 54.1 2-year 24.4 21.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time from Induction (Months) Censoring rate for Pem+Cb+Bev was 27.8%; for Pac+Cb+Bev was 27.2%
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) 1.00 1.31 0.97 1.04 0.90 0.91 1.09 0.96 1.17 0.84 1.08 1.01 0.42 0.98 1.11 1.02 0.72 0.95 0.53 1.36 0.87 1.10 0.0 0.5 1.0 1.5 2.0 2.5 Treatment Hazard Ratio (95% CI) Favors Pem+Cb+Bev Favors Pac+Cb+Bev
PointBreak: Pre-specified Exploratory Analysis of KM PFS from Randomization: Maintenance Group Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time from Induction (Months) Pem+Cb+Bev (n=292) Pac+Cb+Bev (n=298) PFS median (mo) 8.6 6.9 Pre-specified exploratory non-comparative subgroup analyses Censoring rate for Pem+Cb+Bev was 24.7%; for Pac+Cb+Bev was 14.1%
PointBreak: Pre-specified Exploratory Analysis of KM OS from Randomization: Maintenance Group 1.0 0.9 0.8 Pem+Cb+Bev (n=292) Pac+Cb+Bev (n=298) OS median (mo) 17.7 15.7 Survival Probability 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 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%
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 31.0 24.4 14.5 2.7 Thrombocytopenia 17.9 17.2 23.3 5.6 Neutropenia 14.7 8.4 25.8 40.6 Febrile neutropenia 0.2 0.2 1.4 4.1 Fatigue 42.1 39.5 10.9 5.0 Hemorrhage GI/pulmonary 3.6 3.8 1.8 (0.5) 0.5 (0.7) Thromboembolic event 0.5 0.2 3.2 2.0 Neuropathy/sensory 11.8 35.7 0.0 4.1 Alopecia * 6.6 36.8 - - 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.
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
So Where Are We Today? 1.0 0.9 0.8 Survival Probability 0.7 0.6 0.5 0.4 0.3 E4599 CP E4599 CPB JHMD CPemB JHMD CPB 4 vs 6? Cis vs Carbo? nab-paclitaxel? 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time from Induction (Months)
Shared Decision Making Patient Preference Anticipated Toxicity Cost Efficacy
Shared Decision Making Patient Preference Anticipated Toxicity Cost Efficacy
Empiric therapy: response rate 35%, progressive disease 35% Driver targeted treatment SMARTER, FASTER TRIALS