The addition of bevacizumab to erlotinib did not demonstrated improvement in overall survival in patients with EGFR-mutant non–small cell lung cancer treated in a phase 3 study.
Adding bevacizumab to the use of erlotinib (Tarceva) in patients with EGFR-mutated non–small cell lung cancer (NSCLC) did not prolong their survival. However, both treatment arms with and without bevacizumab (Avastin) had relatively long survival durations that encouraged researchers, according to study results published in the Lancet.1
Results from the phase 3 open-label, randomized, multicenter, trial (NEJ026) showed that median overall survival (OS) in patients was 50.7 months (95% CI, 37.3%-not estimable [NE]) in the bevacizumab plus erlotinib group compared with 46.2 months (95% CI, 2-NE) in the erlotinib only group (HR, 1.007; 95% CI, 0.681-1.490; P = 0.97).
Patients were enrolled through June 2015 to August 2016, split between 112 in the combination therapy arm and 112 in the modified intention to treat population. Data cutoff occurred in November 2019 and follow ups were conducted at a media of 50.7 months.
“We have previously shown in NEJ026 that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival [PFS] compared with erlotinib alone in these patients,” the researchers wrote. OS and an exploratory outcome of seeing the time from trial enrollment to progressive disease during second-line treatment, or death, were the primary endpoints of the study.
After a median follow up of 23.9 months (14.2-39.1 months) median time from enrollment to progressive disease during second-line treatment, or death, was 28.6 months (95% CI, 22.1%-35.9%) in the bevacizumab plus erlotinib group versus 24.3 months (20.4-29.1, months) in the erlotinib only group (HR, 0.773; 95% CI, 0.562%-1.065%).
Patients were enrolled from 69 hospitals and community based medical centers across Japan. Those eligible had stage IIIB, stage IV, or postoperative recurrent, exon 19 deletion or exon 21 Leu858Arg point EGFR mutated NSCLC and had not previously received systemic chemotherapy.
They were then randomly assigned 1:1 to receive either 150 mg of erlotinib orally once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or an intolerable toxicity. Randomization on the trial was stratified according to the patients’ sex, smoking status, EGFR mutation subtype, and clinical disease stage.
A 2019 analysis of the study results showed that after a median follow up of 12.4 months (7-15.7) median PFS was 16.9 months (95% CI, 14.2%-21%) in the combination arm compared with 13.3 months (11.1-15.3) for patients in the erlotinib group (HR, 0.605; 95% CI, 0.417%-0.877%; P = 0.016).2
This analysis also found that the most common grade 3–4 adverse events (AEs) was rash with 23 (21%) of 112 patients in the erlotinib plus bevacizumab group experiencing it vs 24 (21%) of 114 patients in the erlotinib alone group. Nine (8%) patients in the erlotinib plus bevacizumab group and 5 (4%) of 114 patients in the erlotinib alone group had serious AEs. The most common serious AEs were grade 4 neutropenia (2% in the combination arm) and grade 4 hepatic dysfunction (1% in the combination arm). No treatment related deaths were observed at the time.
In the 2021 analysis, median time between enrolment and confirmation of a minimally important difference on the EORTC quality of life scale was 6 months (95% CI, 5.2%-11.3%) in the bevacizumab plus erlotinib group versus 8.3 months (95% CI, 5.7%-13.9%) in the erlotinib only group (P = 0.47).
“Why the addition of bevacizumab to erlotinib did not affect OS is unclear,” the researchers concluded. “But it is possible that the beneficial effects of combination therapy were not seen because OS was influenced by treatment regimens used after disease progression.”
1. Kawashima Y, Fukuhara T, Saito H, et al. Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Respir Med. 2022;10(1):72-82. doi: 10.1016/S2213-2600(21)00166-1
2. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019;20(5):625-635. doi: 10.1016/S1470-2045(19)30035-X