Can Bevacizumab Be Recommended in High-Risk Melanoma?

Treatment of high-risk melanoma with adjuvant bevacizumab following surgical resection improves disease-free survival over standard observation, but not overall survival, according to analysis of the AVAST-M trial.

“VEGF is over-expressed in melanoma and high levels have been reported to be associated with poorer outcome,” wrote study authors led by Pippa G. Corrie, MD, of the Cambridge Cancer Centre in the United Kingdom. Bevacizumab targets VEGF, and previously has shown modest activity in advanced melanoma. The new trial evaluated whether bevacizumab can improve outcomes in patients with resected cutaneous melanoma at high risk of recurrence.

The study included a total of 1,343 patients recruited between 2007 and 2012; all had resected stage IIB, IIC, or III melanoma, and were randomized to receive either adjuvant bevacizumab (671 patients) or standard observation (672 patients). Most patients were stage III (73%), and their median age was 56 years; the median follow-up period was 6.4 years. Results were published in Annals of Oncology.

A total of 515 patients (38%) died during the follow-up period, including 38% of those in the bevacizumab group and 39% of those in the observation group. The 5-year overall survival rate was 64% for both groups, and the hazard ratio (HR) for overall survival was 0.98 (95% CI, 0.82–1.16; P = .78). A multivariate analysis found that the treatment was not independently prognostic of overall survival.

The 5-year disease-free survival rate was higher with bevacizumab, at 51% compared with 45% in the observation group, for an HR of 0.85 (95% CI, 0.74–0.99; P = .03). This remained consistent after adjustment for stratification variables. The median disease-free interval was 63 months with bevacizumab, compared with 37 months with observation.

The distant metastasis–free interval was not significantly better with bevacizumab; at 5 years, the rate was 58% compared with 54% with observation, for an HR of 0.91 (95% CI, 0.78–1.07; P = .25).

Most patients in the study completed quality-of-life questionnaires (89%), and these showed no significant differences between the two groups.

Among patients with BRAF mutations, there was a trend toward improved overall survival with bevacizumab, with an HR of 0.80 (95% CI, 0.57–1.13; P = .21). This was not seen in those with BRAF wild-type melanoma.

Based on the study design, the authors concluded that “adjuvant bevacizumab cannot be recommended as a standard adjuvant therapy after resection of melanoma at high risk of recurrence.” However, the findings regarding BRAF mutations, along with other research on the mutations’ connection to response to immune checkpoint inhibition, “raise the hypothesis that combining bevacizumab with adjuvant immune checkpoint inhibitors may benefit high-risk BRAF-mutant melanoma patients.”