Original Articles
PRONOUNCE: Randomized, Open-Label, Phase III Study of First-Line Pemetrexed + Carboplatin Followed by Maintenance Pemetrexed versus Paclitaxel + Carboplatin + Bevacizumab Followed by Maintenance Bevacizumab in Patients ith Advanced Nonsquamous Non–Small-Cell Lung Cancer

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Introduction

PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non–small-cell lung cancer (NSCLC).

Methods

Patients ≥18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m2, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m2, carboplatin, area under the curve = 6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed.

Results

Baseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio = 0.85, 90% confidence interval, 0.7–1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms.

Conclusions

Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed.

Key Words

Advanced nonsquamous non-small-cell lung cancer
Efficacy
Safety
Combination therapy
Pemetrexed
Carboplatin
Paclitaxel
Bevacizumab

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Disclosure: Borys Hrinczenko, J. Thaddeus Beck, Manuel R. Modiano, Robert W. Weaver, David R. Spigel, and Helen J. Ross have no conflict of interest to declare. Ralph G. Zinner received funding for research from Eli Lilly and Company. Petros G. Nikolinakos participated in the advisory boards meetings and received honoraria from Eli Lilly and Company. David M. Waterhouse was on the speaker's bureau for Eli Lilly and Company and received honoraria in the past. Ramaswamy Govindan is a consultant for Boehringer Ingelheim, GlaxoSmithKline, Pfizer, Merck, Bayer, Covidien, Bristol-Myers Squibb, Genentech, and Mallinckrodt. Coleman K. Obasaju, Jingyi Liu, Andrew G. Koustenis, Katherine B. Winfree, Symantha A. Melemed, Susan C. Guba, Waldo I. Ortuzar, Durisala Desaiah, and Joseph A. Treat are employees of Eli Lilly and Company and may hold company stock.

Data from this study were presented at the 2013 annual meeting of American Society for Clinical Oncology, Chicago, IL, on June 3, 2013 (Abstract# LBA 8003) and at the World Conference on Lung Cancer, Sydney, Australia, October 28, 2013 (Abstract# P1.10–033).

ClinicalTrials.gov Identifier: NCT00948675.