PerspectiveIn the Journals

Bevacizumab appears tolerable in cutaneous melanoma

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May 8, 2014

Bevacizumab demonstrated promising tolerability in patients with cutaneous melanoma, according to data from a preplanned interim analysis of the phase 3 AVAST-M trial.

However, researchers indicated longer follow-up is necessary to determine whether the agent is associated with improved OS at 5 years, a measure that served as the study’s primary endpoint.

Previous research showed bevacizumab (Avastin, Genentech) has restricted activity in patients with advanced melanoma. In the current study, Pippa G. Corrie, MD, of the Oncology Center at Cambridge University Hospitals in the United Kingdom, and colleagues assessed the role of bevacizumab as adjuvant therapy in patients with resected melanoma who were at high risk for recurrence.

The multicenter, open-label, randomized, controlled AVAST-M trial included 1,343 patients aged 16 years and older who were treated at 48 centers across the United Kingdom between 2007 and 2012. Patients with American Joint Committee on Cancer stage 2B, 2C and 3 cutaneous melanoma were randomly assigned in a 1:1 fashion to 7.5 mg/kg bevacizumab every 3 weeks for 1 year (n=671) or to observation (n=672). Median follow-up was 25 months.

During the preplanned interim analysis, 21% of participants died. Researchers reported 140 deaths in the treatment arm and 146 in the observation arm. Melanoma was the cause of death in 96% of deaths in the bevacizumab arm and 95% of deaths in the observation arm.

Researchers observed no significant differences in OS between the two arms (HR=0.97; 95% CI, 0.78-1.22). This persisted even after adjustments for stratification variables (HR=1.03; 95% CI 0.81-1.29). Median duration of bevacizumab treatment was 51 weeks. Researchers reported good tolerability, with a median dose intensity of 86%.

A higher percentage of patients assigned bevacizumab experienced grade 3 or grade 4 adverse events (15% vs. 5%). Researchers reported 41 incidences of grade 3 hypertension in the treatment arm and one incidence in the observation arm.

Researchers observed improved DFS in the bevacizumab arm (HR=0.83; 95% CI, 0.70-0.98), but they observed no significant difference between arms with regard to distant metastasis-free interval (HR=0.88; 95% CI, 0.73-1.06).

“Three adverse drug reactions were regarded as both serious and unexpected: One patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors,” Corrie and colleagues wrote.

Vernon K. Sondak, MD 

Vernon K. Sondak

In an accompanying editorial, Vernon K. Sondak, MD, and Geoffrey T. Gibney, MD, both of the department of cutaneous oncology at the Moffitt Cancer Center in Tampa, wrote:

“Although major gains have been shown in systemic treatments for metastatic melanoma, prevention of recurrence in high-risk resected patients remains a priority,” Sondak, a HemOnc Today Editorial Board member, and Gibney wrote. “Interferon is the only approved adjuvant treatment for resected melanoma, with several studies showing improvement in relapse-free survival and meta-analyses showing small improvements in OS, thus setting the bar for future adjuvant trials.

“Adjuvant bevacizumab has not yet improved OS and although disease-free interval is statistically improved in the AVAST-M trial, its benefits seem to be, at best, similar to the relapse-free-survival benefit of interferon,” they wrote. “Other variables should also be considered, such as patient selection and toxic effects, balanced with the observed efficacy. Longer follow-up of patients in the AVAST-M trial will help to better define the risk versus the benefits of adjuvant bevacizumab, but in the meantime, we all need to think about where to set the bar for future progress.”

For more information:

Disclosure:The study was funded by Cancer Research UK. Sondak reports consultant fees from Bristol-Myers Squibb, GlaxoSmithKline, Merck, Navidea, Novartis and Provectus. Gibney reports consultant fees from Genentech/Roche.

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Omid Hamid

Omid Hamid

With the current approval of multiple new drugs for metastatic melanoma — four with survival advantages — the field eagerly awaits the same success in the adjuvant setting.
The AVAST-M trial’s goal was to prove the role of bevacizumab (Avastin, Genentech) as adjuvant treatment despite limited activity in the metastatic setting.
Researchers randomly assigned patients to bevacizumab or observation. Bevacizumab failed to show any advantage with regard to OS or distant metastases-free survival, but the improvement in RFS was significant (HR=0.83; 95% CI, 0.7-0.98) as a secondary outcome measure.  
The goal of finding an appropriate adjuvant therapy still remains. The recent approval of pembrolizumab (Keytruda, Merck) for advanced melanoma was buoyed by the prospect of two upcoming adjuvant PD-1 trials to follow. We can learn from the PD-1/PD-L1 experience as virtually all trials are seeking to identify predictive biomarkers that may be applicable in the adjuvant setting.
Meta-analyses have indicated ulceration as a predictor of adjuvant benefit with interferon regarding EFS (P=.04) and OS (P=.002) [Suciu S. Abstract #9067. Presented at: ASCO Annual Meeting; May 30-June 3, 2014].
Although bevacizumab has not shown adjuvant benefit for any solid tumor, the answer may be in similar biomarkers. Hodi and colleagues have shown that serum vascular endothelial growth factor (VEGF) may be a predictive biomarker for OS with ipilimumab (Yervoy, Bristol-Myers Squibb) treatment due to its role in immune evasion and angiogenesis (Yuan G. Cancer Immunol Res. 2014;2:127-132; Hodi SF. Cancer Immunol Res. 2014;2:632-642).
Besides promoting angiogenesis, VEGF suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. Bevacizumab’s benefit may lie in these long term immunologic benefits through VEGF inhibition in patients with high VEGF levels. The authors note that immunological and angiogenic biomarkers are now being explored with tumor and blood samples collected from most patients recruited to the AVAST-M trial in the hopes of identifying this subset. Meanwhile, we must continue to work to find the answers by accruing to these adjuvant trials.

Omid Hamid, MD
HemOnc Today Editorial Board Member

Disclosure: Hamid reports consultant/speaker roles with and contracted research for Bristol-Myers Squibb, Genentech, MedImmune and Merck.