PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer

Abstract

Purpose: PointBreak (A Study of Pemetrexed, Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer) compared the efficacy and safety of pemetrexed (Pem) plus carboplatin (C) plus bevacizumab (Bev) followed by pemetrexed plus bevacizumab (PemCBev) with paclitaxel (Pac) plus carboplatin (C) plus bevacizumab (Bev) followed by bevacizumab (PacCBev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC).

Patients and methods: Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were randomly assigned to receive pemetrexed 500 mg/m(2) or paclitaxel 200 mg/m(2) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles. Eligible patients received maintenance until disease progression: pemetrexed plus bevacizumab (for the PemCBev group) or bevacizumab (for the PacCBev group). The primary end point of this superiority study was overall survival (OS).

Results: Patients were randomly assigned to PemCBev (n = 472) or PacCBev (n = 467). For PemCBev versus PacCBev, OS hazard ratio (HR) was 1.00 (median OS, 12.6 v 13.4 months; P = .949); progression-free survival (PFS) HR was 0.83 (median PFS, 6.0 v 5.6 months; P = .012); overall response rate was 34.1% versus 33.0%; and disease control rate was 65.9% versus 69.8%. Significantly more study drug-related grade 3 or 4 anemia (14.5% v 2.7%), thrombocytopenia (23.3% v 5.6%), and fatigue (10.9% v 5.0%) occurred with PemCBev; significantly more grade 3 or 4 neutropenia (40.6% v 25.8%), febrile neutropenia (4.1% v 1.4%), sensory neuropathy (4.1% v 0%), and alopecia (grade 1 or 2; 36.8% v 6.6%) occurred with PacCBev.

Conclusion: OS did not improve with the PemCBev regimen compared with the PacCBev regimen, although PFS was significantly improved with PemCBev. Toxicity profiles differed; both regimens demonstrated tolerability.

Trial registration: ClinicalTrials.gov NCT00762034.

Fig 1.

CONSORT diagram. PacCBev, paclitaxel (Pac), carboplatin (C), and bevacizumab (Bev) followed by bevacizumab; PemCBev, pemetrexed (Pem), carboplatin, and bevacizumab followed by pemetrexed and bevacizumab; AE, adverse event.

Fig 2.

Kaplan-Meier overall survival (OS) from random assignment for (A) the intent-to-treat (ITT) population (censoring rates for PemCBev and PacCBev arms, 27.8% and 27.2%) and (B) the maintenance population (censoring rates for PemCBev and PacCBev, 36.0% and 30.2%). The duration of OS was measured from the date of random assignment to the date of death from any cause. If a patient had not died at the time of the data inclusion cutoff date for the analysis, OS was censored at the last date the patient was known by the treating physician to still be alive. HR, hazard ratio; mo, months; PacCBev, paclitaxel (Pac), carboplatin (C), and bevacizumab (Bev) followed by bevacizumab; PemCBev, pemetrexed (Pem), carboplatin, and bevacizumab followed by pemetrexed and bevacizumab.

Fig 3.

Kaplan-Meier progression-free survival (PFS) from random assignment for (A) the intent-to-treat population (censoring rates for PemCBev and PacCBev arms, 26.9% and 23.3%) and (B) the maintenance population (censoring rates for PemCBev and PacCBev arms, 24.7% and 14.1%). The duration of PFS was measured from the date of random assignment to the date of objective progression of disease or the date of death from any cause, whichever was earlier. For patients who received subsequent systemic anticancer therapy (after discontinuation from the study chemotherapy) before objective progression or death, PFS was censored at the date of the last objective progression-free disease assessment before starting the subsequent systemic anticancer therapy. For patients not known to have died as of the data inclusion cutoff date and who did not have objective progressive disease, PFS was censored at the date of the last objective progression-free disease assessment before the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier. HR, hazard ratio; mo, months; PacCBev, paclitaxel (Pac), carboplatin (C), and bevacizumab (Bev) followed by bevacizumab; PemCBev, pemetrexed (Pem), carboplatin (C), and bevacizumab (Bev) followed by pemetrexed and bevacizumab.

Fig 4.

Forest plots for the intent-to-treat population for (A) overall survival and (B) progression-free survival. ECOG PS, Eastern Cooperative Oncology Group performance status; PacCBev, paclitaxel (Pac), carboplatin (C), and bevacizumab (Bev) followed by bevacizumab; PemCBev, pemetrexed (Pem), carboplatin (C), and bevacizumab (Bev) followed by pemetrexed and bevacizumab.

Fig 4.

Forest plots for the intent-to-treat population for (A) overall survival and (B) progression-free survival. ECOG PS, Eastern Cooperative Oncology Group performance status; PacCBev, paclitaxel (Pac), carboplatin (C), and bevacizumab (Bev) followed by bevacizumab; PemCBev, pemetrexed (Pem), carboplatin (C), and bevacizumab (Bev) followed by pemetrexed and bevacizumab.

Fig A1.

Kaplan-Meier progression-free survival (PFS) from random assignment for the progression-free survival without grade 4 toxicity (G4PFS) population (censoring rates for PemCBev and PacCBev arms, 19.3% and 15.2%, respectively). HR, hazard ratio; mo, months; PacCBev, paclitaxel (Pac), carboplatin (C), and bevacizumab (Bev) followed by bevacizumab; PemCBev, pemetrexed (Pem), carboplatin (C), and bevacizumab (Bev) followed by pemetrexed and bevacizumab.