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

Ralph G Zinner, Coleman K Obasaju, David R Spigel, Robert W Weaver, J Thaddeus Beck, David M Waterhouse, Manuel R Modiano, Borys Hrinczenko, Petros G Nikolinakos, Jingyi Liu, Andrew G Koustenis, Katherine B Winfree, Symantha A Melemed, Susan C Guba, Waldo I Ortuzar, Durisala Desaiah, Joseph A Treat, Ramaswamy Govindan, Helen J Ross, Ralph G Zinner, Coleman K Obasaju, David R Spigel, Robert W Weaver, J Thaddeus Beck, David M Waterhouse, Manuel R Modiano, Borys Hrinczenko, Petros G Nikolinakos, Jingyi Liu, Andrew G Koustenis, Katherine B Winfree, Symantha A Melemed, Susan C Guba, Waldo I Ortuzar, Durisala Desaiah, Joseph A Treat, Ramaswamy Govindan, Helen J Ross

Abstract

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/m, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m, 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.

Trial registration: ClinicalTrials.gov NCT00948675.

Conflict of interest statement

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.

ClinicalTrials.gov Identifier: NCT00948675.

Figures

FIGURE 1.
FIGURE 1.
Patient CONSORT flow diagram. ITT, Intent-to-treat. *1 patient randomized to Pac+Cb+Bev but received Pem+Cb, analyzed per ITT population.
FIGURE 2.
FIGURE 2.
A, Kaplan-Meier plot of primary end point G4 progression-free survival, (B), Kaplan-Meier plot showing the progression-free survival in intent-to-treat population, (C), Kaplan-Meier plot showing the overall survival in intent-to-treat population. Bev, bevacizumab; Cb, carboplatin; G4PFS, grade 4 progression-free survival; HR, hazard ratio; OS, overall survival; Pac, paclitaxel; Pem, pemetrexed; PFS, progression-free survival.
FIGURE 3.
FIGURE 3.
A, Subgroup analysis of G4 progression-free survival, and (B), overall survival, hazard ratio (95% CI). Bev, bevacizumab; Cb, carboplatin; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; Pac, paclitaxel; Pem, pemetrexed; CI, confidence interval.

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