French Trial Shows Addition of First-Line Bevacizumab to Cisplatin/Pemetrexed Improves Survival in Malignant Pleural Mesothelioma


Key Points

  • The addition of bevacizumab to cisplatin-pemetrexed improved overall and progression-free survival.
  • The bevacizumab regimen was associated with increased frequency of adverse events typically associated with bevacizumab.  

In the French phase III MAPS trial reported in The Lancet, Zalcman et al found that the addition of bevacizumab (Avastin) to standard cisplatin/pemetrexed (Alimta) treatment increased overall and progression-free survival in patients with newly diagnosed pleural mesothelioma. Vascular endothelial growth factor (VEGF) is an important mitogen for malignant pleural mesothelioma cells, providing the rationale for assessment of bevacizumab in this setting.

Study Details

In this open-label trial, 448 patients with unresectable disease and no prior chemotherapy from 73 sites in France were randomly assigned between February 2008 and January 2014 to receive cisplatin at 75 mg/m2 and pemetrexed at 500 mg/m2 with (n = 223) or without (n = 225) bevacizumab at 15 mg/kg in 21-day cycles for up to six cycles. Patients with central nervous system (CNS) metastases and those receiving antiplatelet treatment, antivitamin K drugs at a curative dose, treatment with low–molecular-weight heparin at a curative dose, or nonsteroidal anti-inflammatory drug treatment were excluded from the trial. Crossover from the control group to bevacizumab treatment was not permitted. The primary endpoint was overall survival in the intent-to-treat population.

Overall, patients had a median age of 66 years, 75% were male, 81% had epithelioid histology, 3% had an Eastern Cooperative Oncology Group performance status of 2, and 43% were never-smokers.

Overall Survival

On interim analysis, median overall survival was 18.8 months (95% confidence interval [CI] = 15.9–22.6 months) in the bevacizumab group vs 16.1 months (95% CI = 14.0–­17.9 months) in the control group (hazard ratio [HR] = 0.77, P = .0167). Hazard ratios favored bevacizumab in all subgroup analyses, including analysis by sex; age; histology; performance status; and platelet, hemoglobin, and leukocyte levels. No significant interactions for treatment effect according to subgroups were found.

Median progression-free survival was 9.2 months vs 7.3 months (HR = 0.61, P < .0001). Poststudy treatment was received by 62.0% vs 72.4% of patients; treatments included bevacizumab in 5%, pemetrexed in 29%, and a platinum in 27% of the bevacizumab group and pemetrexed in 35% and a platinum in 36% of the control group.

Adverse Events

Grade 3 or 4 adverse events occurred in 71% vs 62% of patients, with bevacizumab patients notably having higher rates of grade 3 or 4 hypertension (23% vs 0%) and thrombotic events (6% vs 1%). Hematologic adverse events accounted for most grade 3 or 4 events (47% vs 50%). Any grade hemorrhage was more common in the bevacizumab group (41.0% vs 7.1%), consisting primarily of grade 1 or 2 epistaxis; grade 3 or 4 hemorrhage occurred in 0.9% vs 0%. Other potentially bevacizumab-related events that were more common in the bevacizumab group included increased blood creatinine (38.7% vs 28.1% any grade, 3.6% vs 1.8% grade 3 or 4) and proteinuria (16.7% vs 0.4% any grade, 3.2% vs 0% grade 3). Adverse events led to discontinuation of study treatment in 24.3% vs 6.0% (P < .0001).

The investigators concluded: “Addition of bevacizumab to pemetrexed plus cisplatin significantly improved [overall survival] in malignant pleural mesothelioma at the cost of expected manageable toxic effects; therefore it should be considered as a suitable treatment for the disease.”

The study was funded by Intergroupe Francophone de Cancérologie Thoracique.

Gerard Zalcman, MD, of Hôpital Bichat-Claude Bernard, Assistance Publique-Hopitaux de Paris, Paris-Diderot University, is the corresponding author of The Lancet article.

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