No Survival Benefit Found When Adding Bevacizumab to Gemcitabine/Cisplatin in Malignant Mesothelioma

Hedy L. Kindler, MD

The addition of the VEGF-inhibitor bevacizumab to gemcitabine/cisplatin does not significantly improve progression-free survival (PFS) or overall survival (OS) in patients with previously untreated, unresectable malignant mesothelioma (MM), according to the results of a phase II study.

Hedy L. Kindler, MD, medical director of the Gastrointestinal Oncology Division at the University of Chicago, Illinois, and colleagues elsewhere treated patients with 1250 mg/m2 of gemcitabine on days 1 and 8 every 21 days, 75 mg/m2 of cisplatin every 21 days, and 15 mg/kg of bevacizumab or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression. Random assignment was stratified by ECOG performance status (0 vs 1) and histology (epithelial vs sarcomatoid, mixed, or other subtypes).

Malignant mesothelioma is a rare malignancy, with about 2500 Americans diagnosed each year, Kindler et al wrote. Gemcitabine combined with cisplatin is active in mesothelioma, however, singlearm phase II studies have produced widely variable results. Small sample sizes, heterogeneity in patient prognostic factors, and diverse methods of response assessment are probable contributors to the divergent outcomes that have been reported, the researchers noted.

The addition of bevacizumab to chemotherapy has been shown to boost outcomes in breast, colon, lung, and kidney cancers. Because preclinical data suggested a major role for the VEGF pathway in MM biology and several VEGF inhibitors have demonstrated modest single-agent activity in phase II studies of patients with MM, the study investigators decided that it was “plausible” that the addition of bevacizumab to systemic chemotherapy in patients with MM would yield similar favorable results. Since pemetrexed was not commercially available at the start of the trial, the popular gemcitabine/cisplatin combination was selected for testing in combination with bevacizumab.

Study participants had an ECOG performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. Overall, 108 patients were evaluable. The primary endpoint was PFS.

The median PFS was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). The median OS w as 15.6 and 14.7 months in the two treatment arms, respectively (P = .91). The partial response rate was similar in the bevacizumab and placebo arms (24.5% vs 21.8%; P = .74).

Baseline VEGF values obtained in 56 patients indicated that a higher pretreatment plasma VEGF concentration was associated with shorter PFS (P = .02) and OS (P = .0066), regardless of treatment assignment. The authors described this finding as “intriguing” but emphasized that it should be interpreted “cautiously” because of the relatively small sample sizes.

There were no statistically significant differences in the rates of grade 3 or greater toxicity between treatment groups.

Kindler et al noted that, to the best of their knowledge, this was the first randomized phase II study conducted in patients with MM.

Kindler HL, Karrison TG, Gandara DR, et al. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol. 2012;30(20):2509-2515.