Safety of Bevacizumab in Patients With Non–Small-Cell Lung Cancer and Brain Metastases

TLDR

Patients with non‑small‑cell lung cancer and brain metastases have been historically excluded from bevacizumab trials because of a suspected risk of central nervous system hemorrhage. This phase II PASSPORT trial evaluated the safety of bevacizumab, specifically the incidence of grade ≥ 2 CNS hemorrhage, in NSCLC patients with previously treated brain metastases. The open‑label, multicenter study enrolled first‑line nonsquamous NSCLC patients receiving bevacizumab 15 mg/kg every three weeks with platinum‑based doublet or erlotinib, and second‑line patients receiving bevacizumab with single‑agent chemotherapy or erlotinib until progression or death. Among 106 safety‑evaluable patients, median follow‑up was 6.3 months with five bevacizumab cycles, and no grade ≥ 2 CNS hemorrhage occurred (95 % CI 0.0–3.3 %); two grade 5 pulmonary hemorrhages and one grade 4 non‑CNS hemorrhage were reported, with 24.5 % discontinuing due to adverse events and 34.9 % due to progression, supporting a low CNS hemorrhage risk.

Abstract

Purpose Patients with non–small-cell lung cancer (NSCLC) and brain metastases have previously been excluded from trials of bevacizumab because of suspected risk of CNS hemorrhage. This phase II trial, AVF3752g (PASSPORT), specifically addressed bevacizumab safety (incidence of grade ≥ 2 CNS hemorrhage) in patients with NSCLC and previously treated brain metastases. Patients and Methods This open-label multicenter trial for first- and second-line treatment of nonsquamous NSCLC enrolled patients with treated brain metastases. First-line patients received bevacizumab (15 mg/kg) every 3 weeks with platinum-based doublet therapy or erlotinib (at physician's decision), and second-line patients received bevacizumab with single-agent chemotherapy or erlotinib, until disease progression or death. Results Of the 115 enrolled patients, 66 of 76 first-line patients received carboplatin-based chemotherapy; 22 of 39 second-line patients received pemetrexed, and nine of 39 received erlotinib. As of the June 23, 2008 data cut, among 106 safety-evaluable patients, median on-study duration was 6.3 months (range, 0 to 22 months), with a median of five bevacizumab cycles (range, one to 17), and no reported episodes of grade ≥ 2 CNS hemorrhage (95% CI, 0.0% to 3.3%). Of the bevacizumab-targeted adverse events reported, two were grade 5. Both were pulmonary hemorrhages, one occurring during treatment and the other occurring 6 weeks after the data cut; there was also one grade 4, nonpulmonary/non-CNS hemorrhage. Twenty-six patients (24.5%) discontinued study treatment as a result of an adverse event, and 37 (34.9%) discontinued because of disease progression. Conclusion Addition of bevacizumab to various chemotherapy agents or erlotinib in patients with NSCLC and treated brain metastases seems to be safe and is associated with a low incidence of CNS hemorrhage.