Bevacizumab/Erlotinib Combo Approved in Europe for NSCLC

Sandra Horning, MD

The European Commission approved bevacizumab (Avastin) in combination with erlotinib (Tarceva) as a frontline treatment for patients with unresectable advanced, metastatic, or recurrent EGFR-mutant non—small cell lung cancer (NSCLC).

The approval was based on findings from the phase II JO25567 study, which showed a 46% reduction in the risk of progression or death with the combination versus single-agent erlotinib. The median progression-free survival (PFS) with the addition of bevacizumab was 16 versus 9.7 months with erlotinib alone (HR, 0.54; 95% CI, 0.36-0.79; P = .0015).

“The combination of Avastin and Tarceva represents a new standard of care for patients with this type of lung cancer,” Sandra Horning, MD, chief medical officer and Global Head of Product Development at Roche, the company developing the combination, said in a statement. “This approval provides physicians in Europe with a powerful combination therapy that can significantly extend progression-free survival beyond 1 year, representing important progress for a group of patients who typically face a poor prognosis.”

In the open-label JO25567 study, which was conducted in Japan, 152 patients with untreated EGFR-mutant NSCLC received erlotinib alone (n = 77) or in combination with bevacizumab (n = 75). Erlotinib was administered at 150 mg per day and bevacizumab was given at 15 mg/kg every 3 weeks.

Patient characteristics were well balanced between the 2 arms, with a median age of 67 years in both groups. Eighteen percent of patients were over the age of 75. More than half of patients were never smokers (56% to 58%) and all patients had an ECOG PS of 0 or 1. EGFR mutations subtypes were well balanced between exon 19 deletions and exon 21 mutations.

Benefits in PFS with the addition of bevacizumab were seen across patient subgroups, including those aged ≥75 years (HR, 0.23; 0.17-0.74). Overall survival data were immature at the time of the analysis.

In those with exon 19 deletions, the median PFS was 18.0 months with the combination versus 10.3 months with erlotinib alone (HR, 0.41; 95% CI, 0.24-0.72; P = .0011). In the exon 21 mutation group, the median PFS was 13.9 versus 7.1 months, for the combination and single-agent, respectively (HR, 0.67; 95% CI, 0.38-1.18; P = .1653).

The objective response rate in the combination arm was 69% versus 64% with erlotinib alone (P = .4951). There were 3 complete responses in the bevacizumab arm versus 1 with erlotinib alone. The median duration of response was 13.3 months with the combination versus 9.3 months with erlotinib alone (P = .1118). The disease control rate was 99% with the combination versus 88% for erlotinib alone (P = .0177).

Grade 3/4 adverse events (AEs) were experienced by 91% of patients treated with the combination compared with 53% with the single-agent. The most frequently observed grade 3/4 AEs for the combination versus single-agent, respectively, were rash (25% vs 19%), hypertension (60% vs 10%), and proteinuria (8% vs 0%). Serious AEs were experienced by 24% of those in the combination arm versus 25% with erlotinib alone.

AEs led to erlotinib discontinuation for 16% of patients in the combination arm versus 18% for the single-agent group. In the combination arm, both agents were discontinued for 10 patients as a result of AEs. The primary causes for treatment discontinuations were liver disorders, interstitial lung disease, and rash.

A phase II study is currently assessing erlotinib with or without bevacizumab as a frontline treatment for patients with EGFR-mutant stage IV NSCLC (NCT01532089). Additionally, the phase III BEVERLY study is comparing bevacizumab plus erlotinib versus erlotinib alone for patients with EGFR-mutant NSCLC (NCT02633189). The study, which has a primary endpoint of PFS, plans to enroll 200 patients.

Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236—1244.