medwireNews: The AVAST-M and E5103 trial results rule out the use of bevacizumab in the adjuvant setting in high-risk patients with cutaneous melanoma and HER2-negative breast cancer, respectively.
Treatment with the VEGF inhibitor did not lead to an overall survival (OS) benefit in either trial, and neither was invasive disease-free survival (IDFS) improved in the breast cancer study.
In line with an interim analysis of the AVAST-M trial, bevacizumab continued to impart a disease-free survival benefit in patients with melanoma, but given the OS findings, the researchers say that “bevacizumab cannot be recommended as a standard adjuvant therapy after resection of melanoma at high risk of recurrence.”
Among 1343 participants of the phase III AVAST-M trial, all of whom had undergone resection for stage IIB–III disease, the 5-year OS rate was 64% for those who were randomly assigned to receive adjuvant bevacizumab 7.5 mg/kg every 3 weeks for a year. This was identical to the rate for the patients who received standard observation.
By contrast, a significantly higher proportion of bevacizumab-treated patients than those who underwent observation were disease-free at 5 years, at 51% versus 45%, and a hazard ratio of 0.85. The corresponding median disease-free interval times were 63 and 37 months, as reported in the Annals of Oncology.
Lead author Pippa Corrie (Cambridge University Hospitals NHS Foundation Trust, UK) and colleagues identified a trend for poorer OS in patients with BRAF-mutant versus wild-type melanoma, and they also found that bevacizumab treatment was associated with improved OS in the subgroup of BRAF-mutant patients, although again this did not reach statistical significance.
Noting that BRAF mutation status has recently been reported “to describe populations with differing OS after immune checkpoint inhibitors,” the researchers conclude that their findings suggest the hypothesis that combining bevacizumab with immunotherapy “may benefit high-risk BRAF mutant melanoma patients.”
In the phase III E5103 trial, 4994 patients with breast adenocarcinoma at high risk for systemic recurrence received adjuvant doxorubicin plus cyclophosphamide (AC) followed by 12 weeks of paclitaxel. Additionally, participants were randomly assigned to receive concurrent placebo or bevacizumab, while a third group received bevacizumab not only during AC plus paclitaxel treatment, but also subsequently as monotherapy for 10 maintenance cycles.
The IDFS rate at 5 years was 77% for patients who were given placebo, 76% for those given bevacizumab alongside AC plus paclitaxel, and 80% for patients who additionally received bevacizumab monotherapy, while the corresponding 5-year OS rates were 90%, 86%, and 90%.
“When viewed within the context of similar negative trials in patients with HER2-positive breast cancer, colon cancer, melanoma, and lung cancer, we have no choice but to conclude that the underlying hypothesis, namely that inhibiting VEGF would be most effective in the adjuvant setting, is simply wrong,” comment the study authors.
Kathy Miller (Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, USA) and fellow investigators also report “a small but real increase in cardiac toxicity” with bevacizumab. The cumulative incidence of congestive heart failure at the 15-month timepoint was 1.0% in the placebo group, 1.9% in the bevacizumab group, and 3.0% in the group that also received maintenance bevacizumab. And the incidence of grade 3 or worse hypertension was also higher in the bevacizumab than placebo arms.
Furthermore, they found that “[t]he addition of bevacizumab attenuated delivery of chemotherapy, and early drug discontinuation severely limited bevacizumab exposure.”
The agent was discontinued early by around a quarter of participants taking bevacizumab concurrently with AC plus paclitaxel, and by just over half of those also using it as maintenance, report Miller et al in the Journal of Clinical Oncology.
They continue: “Because many of the bevacizumab-specific toxicities have a constant, cumulative risk over time, we cannot recommend trials exploring a longer duration of therapy.”
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