Bevacizumab Added to Erlotinib Increases PFS in NSCLC

The addition of bevacizumab to erlotinib as first-line therapy yielded a significantly extended progression-free survival (PFS) in patients with advanced EGFR-mutation–positive non–small-cell lung cancer (NSCLC), according to a new phase II study. Results from the randomized, open-label trial were presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

“Bevacizumab helps normalize tumor blood vessels,” meaning it could improve drug delivery and perhaps increase efficacy of erlotinib, said Terufumi Kato, MD, of the Kanagawa Cardiovascular and Respiratory Center in Yokohama, Japan. Also, simultaneous inhibition of the VEGF (with bevacizumab) and EGFR (with erlotinib) pathways could lead to a synergistic response in the tumor.

The new trial had 77 patients in a erlotinib monotherapy group and 75 in a bevacizumab plus erlotinib group. The median age was about 67 years in both groups, and more than half were never smokers.

The median PFS in the combination therapy group was 16 months, vs. 9.7 months in the erlotinib alone group, for a hazard ratio of 0.54 (95% CI, 0.36-0.79; P = .0015). “These results were highly statistically and clinically significant,” Kato said.

Interestingly, there was a distinct difference between those with different EGFR mutations. Those with exon 19 deletion had a median PFS of 18 months with the combination therapy compared with 10.3 months with erlotinib alone (HR = 0.41; 95% CI, 0.24-0.72). Those with exon 21 L858R, however, had a median PFS of 13.9 months with bevacizumab and 7.1 months without it (HR = 0.67; 95% CI, 0.38-1.18). Further subgroup analysis showed a consistent benefit with bevacizumab across all groups. The overall survival data is still immature, but Kato said the magnitude of PFS benefit suggests it may translate into an overall survival benefit as well.

The objective response rate was no different between the groups, at 69% for the combination group and 64% for the monotherapy group (P = .4951). The disease control rate was superior in the bevacizumab group, however, at 99% vs 88% (P = .0177). The median duration of response was 13.3 months in the combination group vs 9.3 months with erlotinib alone. There were three complete responses with the combination and one with monotherapy.

Fewer people lost the response after achieving it with bevacizumab, and thus Kato said “bevacizumab may act to enhance the durability of response and cause sustained tumor shrinkage.”

There were more grade 3 or greater adverse events (AEs) with the combination, occurring in 91% vs 53% of monotherapy patients; this was largely due to much higher rates of hypertension and proteinuria. Rates of “serious” AEs were similar, however; one monotherapy patient died due to an AE. The FACT-L quality-of-life questionnaire showed no differences between the groups.

Howard West, MD, of the Swedish Cancer Institute in Seattle, was the discussant for the session and noted that the increased toxicity should be of concern to clinicians. “Financial toxicity is also likely to be a factor,” he said, pointing out that bevacizumab would add about $120,000 to the median of 16 treatments received in this trial. Some may still argue that a confirmatory trial is needed, he added, but said that bevacizumab plus erlotinib “will be my preferred regimen moving forward.”