A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma

Our plain-English summary of A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma, by J.E. Dowell, F.R. Dunphy, R.N. Taub, et al (Lung Cancer, 2012).

The study

• Authors: J.E. Dowell, F.R. Dunphy, R.N. Taub, D.E. Gerber, L. Ngov, J. Yan, Y. Xie, H.L. Kindler
• Journal: Lung Cancer
• Published: 2012;77(3):567-71
• Cited by: 64 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant mesothelioma (MM) cells express the vascular endothelial growth factor (VEGF) receptor, and VEGF protein expression is detected in a majority of human mesothelioma biopsy specimens. Bevacizumab is a recombinant humanized monoclonal antibody that blocks the binding of VEGF to its receptor. We evaluated the addition of bevacizumab to cisplatin and pemetrexed as first-line treatment in patients with advanced, unresectable MM.

Methods: Previously untreated MM patients with advanced, unresectable disease received cisplatin (75 mg/m(2)), pemetrexed (500 mg/m(2)), and bevacizumab (15 mg/kg) intravenously every 21 days for a maximum of 6 cycles. Patients with responsive or stable disease received bevacizumab (15 mg/kg) intravenously every 21 days until progression or intolerance. The primary endpoint was progression-free survival rate at 6 months.

Results: 53 patients were enrolled at 4 centers; 52 were evaluable for this analysis. The progression-free survival rate at 6 months was 56% and the median progression-free survival was 6.9 months (95% confidence interval [CI], 5.3-7.8 months). The partial response rate was 40% and 35% of patients had stable disease. Median overall survival was 14.8 months (95% CI; 10.0-17.0 months). Grade 3/4 toxicities included neutropenia in 11%, hypertension in 6%, and venous thromboembolism in 13% of patients.

Conclusion: This trial evaluating the addition of bevacizumab to cisplatin and pemetrexed in patients with previously untreated, advanced MM failed to meet the primary endpoint of a 33% improvement in the progression-free survival rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone.

Published by Elsevier Ireland Ltd.

In plain English

This single-arm phase II trial added bevacizumab to cisplatin and pemetrexed chemotherapy in previously untreated patients with advanced, inoperable malignant mesothelioma. Fifty-three patients enrolled at four US centers from March 2006 to June 2009; 52 were analyzed for effectiveness. Most (85%) had pleural mesothelioma; others had peritoneal or tunica vaginalis disease. The article did not report asbestos exposure. The 6-month progression-free survival rate was 56%. Median progression-free survival was 6.9 months (95% confidence interval 5.3 to 7.8) and median overall survival was 14.8 months (95% confidence interval 10.0 to 17.0). Forty percent had a partial tumor response. Of all 53 patients, 11% had grade 3 or 4 neutropenia (low white blood cells), 6% had grade 3 high blood pressure and 13% had blood clots in the veins. Two patients had fatal events possibly related to bevacizumab. The authors concluded the trial failed to meet its main goal: a 33% improvement in the 6-month progression-free survival rate over historical patients given cisplatin and pemetrexed alone. They noted the trial lacked a chemotherapy-only comparison group and that bevacizumab's contribution to the side effects is unclear.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicenter, single-arm phase II clinical treatment trial with no internal control group. It was compared against historical results for cisplatin and pemetrexed alone. The study was designed to detect a 33% improvement over the 48% six-month progression-free probability expected with standard treatment.
• Who was studied: Fifty-three patients with previously untreated, advanced, unresectable malignant mesothelioma were enrolled at four US centers (UT Southwestern, University of Chicago, Duke, Columbia) from March 2006 to June 2009. Fifty-two were evaluable for efficacy; all 53 were included in the toxicity analysis. Median age was 66, and 85% were men. Primary sites were pleura in 44 (85%), peritoneum in 7 (13%) and tunica vaginalis in 1 (2%).
• Exposure: Not an asbestos exposure study. The treatment was pemetrexed 500 mg/m2, cisplatin 75 mg/m2 and bevacizumab 15 mg/kg intravenously every 21 days for up to 6 cycles. This was followed by bevacizumab alone every 21 days for patients without progression.
• Main results:
  • Primary objective: the trial did not meet its goal of a 33% improvement in the 6-month progression-free survival rate compared with historical controls treated with cisplatin and pemetrexed alone.
  • All evaluable patients: 6-month progression-free survival rate was 56%, and median progression-free survival was 6.9 months (95% CI 5.3 to 7.8).
  • All evaluable patients: the objective partial response rate was 40%, and 35% had stable disease as their best response.
  • All evaluable patients: median overall survival was 14.8 months (95% CI 10.0 to 17.0).
  • Toxicity (53 patients): 11% developed grade 3/4 neutropenia.
  • Toxicity (53 patients): grade 3 hypertension occurred in 6% and venous thromboembolic disease in 13%.
  • Two patients (3.8%) had fatal adverse events possibly related to bevacizumab: a cerebrovascular accident and a small bowel obstruction.
  • Unplanned post hoc analysis of the 44 patients with pleural mesothelioma: median overall survival was 14.1 months (95% CI 8.1 to 16.2).
  • 32 patients with epithelial histology: median progression-free survival was 7.9 months (95% CI 5.6 to 9.7) and median overall survival was 16.2 months (95% CI 10.3 to 19.1).
  • 20 patients with non-epithelial histology: median progression-free survival was 5.4 months (95% CI 2.8 to 7.4) and median overall survival was 9.4 months (95% CI 6.1 to 28.4).
• The authors' conclusion: The authors concluded that the trial failed to demonstrate a significant improvement in progression-free survival with the addition of bevacizumab to cisplatin and pemetrexed in advanced, untreated malignant mesothelioma.
• Limitations the authors state:
  • There was no chemotherapy-alone comparison arm, so firm conclusions about any overall survival improvement from bevacizumab cannot be drawn.
  • Progression was assessed with different criteria (RECIST version 1.0) from those used in the historical comparator trial.
  • The true contribution of bevacizumab to the observed toxicity, including the blood clots and fatal events, is unclear.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cisplatin, Pemetrexed (Alimta), Bevacizumab, Malignant Mesothelioma, Mesothelioma, Biopsy, Monoclonal Antibody, Unresectable.

Related studies

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• The efficacy of pemetrexed and bevacizumab intrapleural injection for malignant pleural mesothelioma-mediated malignant pleural effusion — D. Chen, X. Li, et al. (2014)
• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)
• Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma — A.S. Tsao, N. Harun, et al. (2014)
• Cost-effectiveness analysis of additional bevacizumab to pemetrexed plus cisplatin for malignant pleural mesothelioma based on the MAPS trial — M. Zhan, H. Zheng, et al. (2017)
• Bevacizumab plus cisplatin/pemetrexed then bevacizumab alone for unresectable malignant pleural mesothelioma: A Japanese safety study — T. Nakano, K. Kuribayashi, et al. (2021)

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