Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma

Our plain-English summary of Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma, by G.L. Ceresoli, P.A. Zucali, M. Mencoboni, et al (British Journal of Cancer, 2013).

The study

• Authors: G.L. Ceresoli, P.A. Zucali, M. Mencoboni, M. Botta, F. Grossi, D. Cortinovis, N. Zilembo, C. Ripa, M. Tiseo, A.G. Favaretto, H. Soto-Parra, F. De Vincenzo, A. Bruzzone, E. Lorenzi, L. Gianoncelli, B. Ercoli, L. Giordano, A. Santoro
• Journal: British Journal of Cancer
• Published: 2013;109(3):552-8
• Cited by: 72 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM).

Methods: Eligible patients received pemetrexed 500 mg m(-2), carboplatin area under the plasma concentration-time curve (AUC) 5 mg ml(-1) per minute and bevacizumab 15 mg kg(-1), administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.

Results: Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7-46.0%). Forty-four (57.9%, 95% CI 46.0-69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3-4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.

Conclusion: The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.

In plain English

This was a multicentre, open-label, single-arm phase II trial. It added bevacizumab to pemetrexed and carboplatin for previously untreated, unresectable malignant pleural mesothelioma. Of 77 patients enrolled at 10 Italian institutions (2007 to 2009), 76 were analysed. Patients received three drugs every 21 days for up to six cycles; those without progression or severe toxicity could continue bevacizumab alone, which 48 of 76 started. The goal was raising median progression-free survival (time until worsening or death from any cause) from 6 to 9 months. Median progression-free survival was 6.9 months, missing the goal; median overall survival was 15.3 months. Tumours partially shrank in 26 of 76 patients (34.2%, 95% CI 23.7 to 46.0%); 44 (57.9%, 95% CI 46.0 to 69.1%) had stable disease. Most side effects were mild, but three patients had bowel perforation. Three 'toxic deaths' occurred: one after bowel perforation, one from pneumonitis with H1N1 infection, and one sudden death at home without autopsy. The authors concluded the trial failed its main goal and that, without a comparison group, firm conclusions about bevacizumab require a randomised trial.

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: Multicentre, open-label, single-arm phase II clinical trial (registered NCT00407459)
• Who was studied: 77 patients entered the study from 10 Italian institutions between September 2007 and October 2009. All had previously untreated, histologically proven, unresectable malignant pleural mesothelioma. One patient was diagnosed with acute myeloid leukaemia before treatment, received no study treatment and was excluded, leaving 76 for analysis. Median age was 67 (range 27 to 78). 49 were male and 27 female, and 61 had epithelioid histology.
• Exposure: The exposure studied was a drug treatment, not asbestos; the article does not report the patients' asbestos exposure. Patients received pemetrexed 500 mg per square metre, carboplatin at AUC 5 and bevacizumab 15 mg per kg, all intravenously on day 1 every 21 days for up to six cycles. Patients without progression or severe toxicity then received maintenance bevacizumab for up to 1 year. 48 of 76 patients (63.1%) started maintenance.
• Main results:
  • Of 76 patients assessed, 26 had a partial response, an objective response rate of 34.2% (95% CI 23.7 to 46.0%).
  • 44 patients (57.9%, 95% CI 46.0 to 69.1%) had stable disease and 6 (7.9%) had disease progression. Disease control was achieved in 70 patients (92.1%, 95% CI 83.6 to 97.1%).
  • 48 of 76 patients (63.1%) started maintenance bevacizumab, which continued for a median of seven cycles (range 1 to 18).
  • Median progression-free survival for all 76 patients was 6.9 months. Progression-free survival was defined as time from the first treatment day until progression or death from any cause. The 1-year and 2-year estimates were 25.4% and 8.0%.
  • Median overall survival was 15.3 months. The 1-year and 2-year survival estimates were 62.6% and 25.9%.
  • The trial did not achieve its primary goal: a 50% improvement in median progression-free survival, from 6 to 9 months, compared with standard pemetrexed/platinum combinations.
  • In univariate analysis, longer survival was associated with epithelioid histology and a good EORTC prognostic score. In the multivariate model, none of the variables analysed was significantly related to progression-free or overall survival.
  • Three patients had bowel perforation. They were aged 75, 76 and 78, and all had a history of diverticular disease that caused no symptoms at enrollment. A grade 3 pulmonary embolism and a severe gastrointestinal bleed were also reported as severe events probably related to bevacizumab.
  • The authors reported three deaths they called 'toxic deaths' (3.9%). One was in a patient with bowel perforation. One was from pneumonitis with a documented H1N1 viral infection. One was a sudden death at home 2 weeks after the last treatment, with no autopsy performed.
• The authors' conclusion: The authors concluded that the study failed to achieve a significant improvement in median progression-free survival, although they observed longer overall survival and a higher rate of long survivors than in historical results. They said only the results of an ongoing randomised trial would allow definite conclusions about bevacizumab in malignant pleural mesothelioma.
• Limitations the authors state:
  • The study was a single-arm phase II trial with no randomised comparison group.
  • Comparisons with earlier studies are indirect and must be viewed cautiously, because patient selection, trial designs and later treatments differed.
  • The VEGF analysis had a small sample size.

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Carboplatin, Bevacizumab, First-line Therapy, Pleural Mesothelioma, Unresectable, Progression-Free Survival, Overall Survival.

Related studies

• Carboplatin plus pemetrexed as first-line treatment of patients with malignant pleural mesothelioma: a phase II study — N. Katirtzoglou, I. Gkiozos, et al. (2010)
• Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials — G.L. Ceresoli, B. Castagneto, et al. (2008)
• A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma — J.E. Dowell, F.R. Dunphy, et al. (2012)
• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)
• Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma — R. Federico, F. Adolfo, et al. (2013)
• First-line chemotherapy with pemetrexed plus cisplatin for malignant peritoneal mesothelioma — E. Fujimoto, T. Kijima, et al. (2017)

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