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Serum VEGF levels predicted response to ipilimumab in advanced melanoma
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Patients with advanced melanoma who had high serum vascular endothelial growth factor levels at baseline demonstrated inferior response and shorter OS after ipilimumab treatment than patients who had lower levels, according to study results.
“VEGF is known to suppress the maturation of immune cells and their antitumor responses, and evidence points toward an association between high serum VEGF levels and poor prognosis in melanoma patients,” F. Stephen Hodi, MD, director of the Melanoma Center at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, said in a press release. “VEGF has also been shown to be a potential biomarker for other immunotherapies, thus it seemed logical to test the ability of VEGF to predict responses to ipilimumab.”
F. Stephen Hodi
Hodi and colleagues evaluated blood samples from 176 patients with metastatic melanoma. The median age of patients was 62 years (range, 16-91). Most were male (70%) and had stage IV disease (98.7%).
Overall, serum VEGF levels ranged from 0.1 pg/ml to 894.4 pg/ml in patients before treatment with ipilimumab (Yervoy, Bristol-Myers Squibb).
Patients received 3-mg/kg (n=98) or 10-mg/kg (n=68) doses of ipilimumab.
After 24 weeks of treatment, patients with baseline serum VEGF levels below the cutoff — defined as 43 pg/ml — were more likely to achieve a complete or partial response to treatment than patients with baseline serum VEGF levels above the cutoff (41.1% vs. 23.2%; P=.019).
Baseline serum VEGF levels higher than the cutoff also were associated with inferior median OS (6.6 months vs. 12.9 months; P=.006). This association remained significant among patients assigned 3-mg/kg (7.4 months vs. 14.3 months; P=.037) and 10-mg/kg (6.2 months vs. 10.9 months; P=.048) doses.
Researchers determined changes in serum VEGF levels during treatment were not associated with response or OS.
“We found that VEGF may actually hinder some of the effects of the immune-checkpoint inhibitor,” Hodi said. “We are beginning to better define predictive biomarkers for immune-checkpoint blockers, specifically ipilimumab. Our study further suggests that there is a potential interaction existing between the biology of angiogenesis and immune-checkpoint blockade. It may be worthwhile to investigate combining immune-checkpoint inhibitors and angiogenesis inhibitors in advanced melanoma with high serum VEGF levels.”
Disclosure: The researchers report commercial research support from and consultant/advisory board roles with Bristol-Myers Squibb.
Perspective
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Geoffrey T. Gibney, MD
The clinical development of the anticytotoxic T-lymphocyte–associated antigen 4 antibody ipilimumab for the management of metastatic melanoma patients has been a great achievement. Although OS was clearly improved in the phase 3 studies, the objective response rates were modest. This has led investigators to search for predictive biomarkers that would allow clinicians to identify patients most likely to respond to therapy.
In the manuscript by Hodi and colleagues, the possibility of VEGF level serving as a biomarker is explored. As in studies of other cancer types, lower levels of VEGF were associated with better OS. Even more interestingly, lower baseline VEGF levels were associated with a higher rate of clinical benefit (complete response, partial response and stable disease) with ipilimumab compared with patients who had elevated VEGF levels. This suggests that VEGF might be a viable predictive biomarker. When looking at the data closer, there were similar objective response rates between the two groups (11% vs. 9%). Therefore, using VEGF level as a selection criterion for the use of ipilimumab would exclude potential patients that could benefit from this therapy. Further evaluation of VEGF as a biomarker in the setting of immune therapies is warranted, especially in studies involving ipilimumab and anti-angiogenic agents.
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