CHMP Recommends Approval for Bevacizumab/Erlotinib Regimen for NSCLC

Sandra Horning, MD

Sandra Horning, MD

The Committee for Medicinal Products for Human Use (CHMP) has recommended the first-line approval of bevacizumab (Avastin) in combination with erlotinib (Tarceva) for patients with advanced or metastaticEGFR-mutant non—small cell lung cancer (NSCLC).

The positive opinion 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 16.0 versus 9.7 months with erlotinib alone (HR, 0.54; 95% CI, 0.36-0.79;P= .0015).

“Patients withEGFR-mutated lung cancer who were treated with the combination of Avastin plus Tarceva lived significantly longer without their disease progressing compared to patients treated with Tarceva alone,” Sandra Horning, MD, chief medical officer and Global Head of Product Development at Roche, the company developing the combination, said in a statement. “Today’s CHMP opinion brings us one step closer to providing this combination therapy option to patients.”

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 two 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). OS 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 (ORR) 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.

“There were no new safety signals identified, and the addition of bevacizumab did not significantly impact quality of life,” said lead investigator Terufumi Kato, MD, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan, when he presented findings from the study at the 2014 ASCO Annual Meeting. “JO25567 is the first prospective randomized trail to investigate erlotinib plus bevacizumab as first-line treatment in patients with EGFR mutation-positive NSCLC.”

The positive CHMP opinion will be sent to the European Commission (EC) for a final regulatory decision. Following the EC decision, further reimbursement discussions will take place within each member state in the European Union.

A phase II study is currently assessing erlotinib with or without bevacizumab as a frontline treatment for patients withEGFR-mutant stage IV NSCLC (NCT01532089). Additionally, the phase III BEVERLY study is comparing bevacizumab plus erlotinib versus erlotinib alone for patients withEGFR-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.