Brief report: a phase II study of sunitinib in malignant pleural mesothelioma. the NCIC Clinical Trials Group

Our plain-English summary of Brief report: a phase II study of sunitinib in malignant pleural mesothelioma. the NCIC Clinical Trials Group, by S.A. Laurie, A. Gupta, Q. Chu, et al (Journal of Thoracic Oncology, 2011).

The study

• Authors: S.A. Laurie, A. Gupta, Q. Chu, C.W. Lee, W. Morzycki, R. Feld, A.H. Foo, J. Seely, J.R. Goffin, F. Laberge, N. Murray, S. Rao, G. Nicholas, J. Laskin, T. Reiman, D. Sauciuc, L. Seymour
• Journal: Journal of Thoracic Oncology
• Published: 2011;6(11):1950-4
• Cited by: 53 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy that most often presents at an advanced, incurable stage. After the failure of standard first-line cisplatin/antifolate chemotherapy, there is no accepted treatment. The vascular endothelial growth factor pathway may be a relevant therapeutic target in MPM.

Methods: This open-labeled phase II trial evaluated single-agent sunitinib, an inhibitor of multiple receptor tyrosine kinases including the vascular endothelial growth factor receptors, given at 50 mg daily orally for 4 weeks followed by a 2-week rest, in patients with advanced MPM. Two cohorts were studied: cohort 1, in which patients had previously received cisplatin-based chemotherapy, and cohort 2, consisting of previously untreated patients. A two-stage design was used for both cohorts; the primary outcome was objective response rate as determined by the RECIST criteria modified for MPM. Secondary outcomes included rates and duration of disease control, progression-free survival and overall survival, and safety and tolerability.

Results: A total of 35 eligible patients were enrolled (17 to cohort 1 and 18 to cohort 2). Neither cohort met the criteria for continuing to the second stage of accrual; only one objective response, confirmed by independent review, was observed in a previously untreated patient. Median progression-free and overall survivals were 2.8 and 8.3 months in cohort 1, and 2.7 and 6.7 months in cohort 2, respectively. Observed toxicity was within that expected for sunitinib.

Conclusions: Sunitinib, similar to other angiogenesis inhibitors, has limited activity in MPM. Future trials of angiogenesis inhibitors given as single agents in unselected patients with MPM are not warranted.

In plain English

This was a multicenter phase II clinical trial, run by the NCIC Clinical Trials Group in Canada, of sunitinib, a drug that blocks several receptors including those for vascular endothelial growth factor. It was tested in patients with advanced, incurable malignant pleural mesothelioma. It is a treatment study and does not examine asbestos exposure. Patients took 50 mg by mouth daily for 28 days, then had a 2-week break. Between April 2007 and June 2009, 39 patients enrolled. Of these, 35 were eligible: 17 who had received earlier chemotherapy (cohort 1) and 18 who had not (cohort 2). Neither cohort met the pre-set threshold for enrolling more patients. No objective tumor responses were seen in cohort 1, where 11 patients had stable disease; one partial response, lasting 3 months, was seen in cohort 2. Median progression-free and overall survival were 2.8 and 8.3 months in cohort 1, and 2.7 and 6.7 months in cohort 2. The most common side effects were fatigue, gastrointestinal complaints and hand-foot syndrome. The authors concluded that sunitinib has limited activity in this cancer.

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, open-label, two-cohort phase II clinical trial with a two-stage design; primary end point objective response rate
• Who was studied: Adults with incurable, proven, radiologically measurable malignant pleural mesothelioma at NCIC Clinical Trials Group centres in Canada, April 2007 to June 2009. 39 enrolled and 35 eligible: 17 previously treated with chemotherapy (cohort 1) and 18 chemotherapy-naive (cohort 2).
• Exposure: Not asbestos. The study treatment was sunitinib, 50 mg orally once daily for 28 days followed by a 2-week break (one 6-week cycle), with up to two dose reductions (37.5 mg or 25 mg) for toxicity.
• Main results:
  • Of 39 patients enrolled, one was never treated and three had no measurable disease on independent radiology review, leaving 17 eligible patients in cohort 1 and 18 in cohort 2.
  • Neither cohort proceeded to the second stage of enrolment. No objective responses occurred among the previously treated patients (cohort 1).
  • In cohort 1, 11 patients had stable disease for a median of 6 months (range 2.3 to 12.7 months). On independent review the median duration of disease stabilization was 5.3 months.
  • In the previously untreated patients (cohort 2), there was one partial response lasting 3 months and 10 patients had stable disease for a median of 4.5 months. Independent review confirmed the partial response and found 14 with stable disease for a median of 3.8 months.
  • Median progression-free survival and overall survival were 2.8 and 8.3 months in the previously treated cohort, and 2.7 and 6.7 months in the previously untreated cohort.
  • Fatigue, gastrointestinal complaints and hand-foot syndrome were the most common adverse events. Hematological toxicity was mild, with one grade 4 event (asymptomatic thrombocytopenia).
• The authors' conclusion: The authors concluded that sunitinib, like other angiogenesis inhibitors, has limited activity in malignant pleural mesothelioma. They judged that future trials of angiogenesis inhibitors given as single agents in unselected patients are not warranted.
• Limitations the authors state:
  • The authors noted that the stable disease seen in most patients may simply reflect the variable natural history of the disease.
  • The authors noted that response is hard to measure in patients with only pleural rind. Agreement between investigators and independent radiologists was reached only after numerous data queries.
  • The authors attributed the longer overall survival in the previously treated cohort likely to patient selection rather than drug efficacy.

Topics

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

Medical terms in this study, explained in our Lexicon: Sunitinib (Sutent), Pleural Mesothelioma, Clinical Trial, Cisplatin, Antifolate, Chemotherapy, Progression-Free Survival, Overall Survival.

Related studies

• A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma — A.K. Nowak, M.J. Millward, et al. (2012)
• Connexin 43 enhances Bax activation via JNK activation in sunitinib-induced apoptosis in mesothelioma cells — M. Uzu, H. Sato, et al. (2017)
• Effect of enhanced expression of connexin 43 on sunitinib-induced cytotoxicity in mesothelioma cells — M. Uzu, H. Sato, et al. (2015)
• 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)
• SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model — T.T. Van, M. Hanibuchi, et al. (2012)
• Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies--results of a phase I dose-escalation study — N. Blais, D.R. Camidge, et al. (2013)

Browse more research in Journal of Thoracic Oncology, or return to medical research.