Experimental Regimen Treatment Provides Equivalent Survival Rate to Standard Chemotherapy in Late-Stage Lung Cancer Patients
Treatment with pemetrexed, carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab (Pem+Cb+B) is no better than standard therapy with paclitaxel, carboplatin and bevacizumab followed by bevacizumab (Pac+Cb+B) in patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC), according to research presented at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology. This symposium is sponsored by the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), the International Association for the Study of Lung Cancer (IASLC) and The University of Chicago.
According to the American Cancer Society, lung cancer is the number one cause of cancer deaths in men and women each year. The current standard treatment for advanced NS-NSCLC patients, the most common form of advanced NSCLC, is either Pac+Cb+B or pemetrexed plus cisplatin. This trial sought to define a new standard of care by comparing Pac+Cb+B to the experimental chemotherapy regimen Pem+Cb+B to determine if either improved overall survival for late-stage lung cancer patients. Pemetrexed plus cisplatin was not tested in this trial.
The 939 patients were randomized to receive one of the two treatment arms every three weeks for up to four cycles. The patients received the same arm for each cycle. Overall survival was not statistically different between the two arms, 12.6 months in Pem+Cb+ Bev versus 13.4 months for the Pac+Cb+B arm, The experimental arm of Pem+Cb+Bev led to a increase in time before progression of disease (PFS) compared with the standard arm of Pac+ Cb+Bev – 6 months versus 5.6 months, respectively.
“The fact that there was no improvement in survival with the experimental regimen was disappointing, but these findings are important as we continue to navigate ways to improve survival for this devastating disease,” said Jyoti Patel, MD, lead author of the study and an associate professor in Medicine-Hematology/Oncology at Northwestern University in Chicago. “It is important to note that both regimens demonstrated tolerability, although their toxicities differed. These differences can be important for our patients.”
The abstract, “A Randomized, Open-label, Phase 3, Superiority Study of Pemetrexed (Pem) + Carboplatin (Cb) + Bevacizumab (B) Followed by Maintenance Pem + B versus Paclitaxel (Pac) + Cb + B Followed by Maintenance B in Patients (pts) with Stage IIB or IV Non-squamous Non-small Cell Lung Cancer (NS-NSCLC),” was presented during the Plenary Session at 12:30 p.m., Central time on September 7, 2012.
A Randomized, Open-label, Phase 3, Superiority Study Of Pemetrexed (Pem)+Carboplatin (Cb)+Bevacizumab (B) Followed By Maintenance Pem+B Versus Paclitaxel (Pac)+Cb+B Followed By Maintenance B In Patients (pts) With Stage IIIB Or IV Non-squamous Non-small Cell Lung Cancer (NS-NSCLC)
J. Patel1, M. A. Socinski2, E. B. Garon3, C. H. Reynolds4, D. R. Spigel5, R. C. Hermann6, J. Liu7, S. C. Guba7, P. Bonomi8, R. Govindan9, 1Northwestern University, Chicago, 2University of Pittsburgh Medical Center Cancer Pavilion, Pittsburgh, 3University of California Los Angeles/Translational Oncology Research International, Los Angeles, 4Ocala Oncology and US Oncology Research Inc., Ocala, Hawaii, 5SCRI/Tennessee Oncology, PLLC, Nashville, Tenn, 6Northwest Georgia Oncology Centers, Marietta, Ga., 7Eli Lilly and Company, Indianapolis, 8Rush University Medical Center, Chicago, 9Washington University School of Medicine, St. Louis
Purpose/Objective(s): Both Pac+Cb+B and Pem+cisplatin are approved for first-line treatment of advanced NS-NSCLC. In a Ph. 2 study, Pem+Cb+B showed promising overall survival (OS) and progression-free survival (PFS). The objective of this Ph. 3 study was to compare Pem+Cb+B followed by Pem+B (Pem Arm) with Pac+Cb+B followed by B (Pac Arm) in pts with advanced NS-NSCLC.
Materials/Methods: Pts with previously untreated stage IIIB/IV NS-NSCLC and ECOG performance status (PS) of 0-1 were randomized to receive Pem+Cb+B (Pem 500 mg/m2; Cb AUC 6; B 15 mg/kg) and folic acid, vitamin B12 and dexamethasone supplementation or Pac+Cb+B (Pac 200 mg/m2 ; Cb AUC 6; B 15 mg/kg), and dexamethasone, diphenhydramine, and cimetidine or ranitidine premedications, every 3 weeks for up to 4 cycles. Pts continuing without progressive disease received maintenance Pem+B (Pem Arm) or B (Pac Arm). The primary endpoint of this superiority study was OS; secondary endpoints included PFS, objective response rate (ORR), disease control rate (DCR) and toxicity. The study assumed a hazard ratio (HR) of 0.80 and required 676 events in 900 pts to yield at least an 80% power to demonstrate superiority of Pem Arm over Pac Arm using a log-rank test with 1-sided type I error of 0.025. Efficacy analyses included all randomized pts; safety analyses included pts who received at least 1 dose of a study drug.
Results: 939 pts were randomized to Pem+Cb+B (n=472) or Pac+Cb+B (n=467). Prognostic factors and characteristics were well balanced between arms: median age 64.7 years, 53.2% male, 55.9% PS 1, 90.0% stage IV NSCLC, 85.7% Caucasian, 79.2% adenocarcinoma and 11.6% never smokers. For Pem Arm vs. Pac Arm, median OS was 12.6 vs. 13.4 mo (HR 1.00, p=0.949); median PFS, 6.0 vs. 5.6 mo (HR 0.83, p=0.012); ORR, 34.1% vs. 33.0%; and DCR, 65.9% vs. 69.8%. Significantly more study drug-related grade 3/4 anemia (14.5% vs. 2.7%), thrombocytopenia (23.3% vs. 5.6%) and fatigue (10.9% vs. 5.0%) were seen on Pem Arm; significantly more grade 3/4 neutropenia (40.6% vs. 25.8%), febrile neutropenia (4.1% vs. 1.4%), sensory neuropathy (4.1% vs. 0) and complete alopecia (grade 2) (21.4 % vs. 1.1%) were seen on Pac Arm. Study drug-related discontinuations due to SAE (2.7% vs. 3.6%), AE (10.4% vs. 9.0%) and study drug-related deaths due to AE (1.8% vs. 2.3%) were similar (Pem vs. Pac, respectively). Exploratory KM analyses for pts treated with maintenance therapy were 17.7 vs. 15.7 mo for OS and 8.6 vs. 6.9 mo for PFS (Pem n=292 vs. Pac n=298 respectively).
Conclusions: The primary endpoint of superior OS was not met in this trial, although Pem+Cb+B improved PFS. Toxicity profiles differed and both regimens demonstrated tolerability.
Author Disclosure Block: J. Patel: E. Research Grant; Eli Lilly and Company. M.A. Socinski: E. Research Grant; Pfizer, Synta, Genentech, Eli Lilly and Company, Merrimack, GSK. F. Honoraria; Genentech, Eli Lilly and Company. E.B. Garon: None. C.H. Reynolds: F. Honoraria; Eli Lilly and Company, Genentech. G. Consultant; Eli Lilly and Company, Genentech. D.R. Spigel: None. R.C. Hermann: B. Independent Contractor; Eli Lilly and Company. J. Liu: A. Employee; Eli Lilly and Company. K. Stock; Eli Lilly and Company. S.C. Guba: A. Employee; Eli Lilly and Company. K. Stock; Eli Lilly and Company. P. Bonomi: E. Research Grant; Eli Lilly and Company, ImClone, Genentech. R. Govindan: F. Honoraria; Covidien, Pfizer, Astra-Zeneca, GSK, Boehringer-Ingelheim, BMS, Genentech. G. Consultant; Covidien, BMS, Pfizer, GSK, Boehringer-Ingelheim, Astra-Zeneca, Genentech.