A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma

Our plain-English summary of A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma, by A.K. Nowak, M.J. Millward, J. Creaney, et al (Journal of Thoracic Oncology, 2012).

The study

• Authors: A.K. Nowak, M.J. Millward, J. Creaney, R.J. Francis, I.M. Dick, A. Hasani, A. van der Schaaf, A. Segal, A.W. Musk, M.J. Byrne
• Journal: Journal of Thoracic Oncology
• Published: 2012;7(9):1449-56
• Cited by: 76 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: There is no accepted second-line therapy for patients with advanced malignant pleural mesothelioma (MPM), whose disease has progressed after first-line chemotherapy. The multitargeted tyrosine kinase inhibitor sunitinib malate targets several pathways overexpressed in mesothelioma. This phase II study assessed objective response to sunitinib and correlative biomarkers in patients with progressive pretreated MPM.

Methods: Eligible patients had confirmed MPM, radiological progression after chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 1, and measurable disease. Patients received oral sunitinib 50 mg daily for 28 of every 42 days. The primary endpoint was objective radiological response. Patients without prior pleurodesis had fluorodeoxyglucose positron emission tomographic response assessed by total glycolytic volume criteria. Correlative biomarkers included serum mesothelin, vascular endothelial growth factor (VEGF)-A, VEGF-C, interleukin-8, sVEGFR-2, sVEGFR-3, and s-kit.

Results: Fifty-three patients received sunitinib between July 2006 and December 2009; 51 were assessable for response. Patients received a median of two cycles (range, 1-12); 40% required dose reduction. Fatigue was the most prominent toxicity. Six patients (12%) had a confirmed radiological partial response, 34 (65%) had stable disease, and 11 (22%) had progressive disease as best response. Six of 20 patients had a decrease in fluorodeoxyglucose positron emission tomographic total glycolytic volume of 15% or more. Median overall survival was 6.1 months, and median time to progression was 3.5 months. Correlative biomarkers did not predict treatment response.

Conclusions: Sunitinib has activity in a subset of patients with pretreated MPM. Consideration should be given to different treatment schedules and examination of other biomarkers for further study of sunitinib in MPM.

In plain English

This single-center, nonrandomized phase II trial tested sunitinib in malignant pleural mesothelioma that had worsened after first-line platinum chemotherapy with pemetrexed or gemcitabine. It studied a treatment, not asbestos exposure. Fifty-three patients started treatment between July 2006 and December 2009, taking 50 mg by mouth daily for four of every six weeks. Of 51 patients whose response could be judged on CT scans, 6 (12%, 95% confidence interval 6% to 23%) had confirmed partial tumor shrinkage. Another 34 had stable disease; the article prints this as 65%, though 34 of 51 is about 67%. The remaining 11 (22%) had disease that kept growing. Median time to progression was 3.5 months (95% confidence interval 2.4 to 4.5), and median survival from the start of treatment was 6.1 months (3.8 to 8.5). Fatigue was the most common side effect; 21 of 53 patients needed dose reductions. In exploratory blood tests, higher baseline mesothelin was associated with shorter survival. The authors reported that blood markers of blood-vessel growth were only weakly associated with outcomes. The authors concluded that sunitinib showed modest antitumor activity.

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: Prospective, single-center, nonrandomized, single-arm phase II treatment trial (Simon two-stage design)
• Who was studied: 53 patients with malignant pleural mesothelioma that had progressed after platinum plus antimetabolite chemotherapy, treated at a single center between July 2006 and December 2009 (the authors are based in Western Australia). 55 consented, 53 started treatment and 51 were assessable for response. 44 were male and 9 female, with a median age of 66.
• Exposure: No asbestos exposure was studied. The intervention was oral sunitinib 50 mg daily for the first 4 weeks of each 6-week cycle, reduced to 37.5 mg or 25 mg for toxicity.
• Main results:
  • Among 51 CT-assessable patients, the radiological objective response rate was 12% (95% CI 6% to 23%), with 6 confirmed partial responses and no complete responses.
  • 34 of 51 patients had stable disease as best response, printed as 65% (34 of 51 is about 67%).
  • 11 of 51 patients (22%) had progressive disease.
  • Among 20 patients assessable by FDG-PET, 6 (30%) had a partial metabolic response, defined as a 15% or greater reduction in total glycolytic volume.
  • Median time to progression for all patients was 3.5 months (95% CI 2.4 to 4.5 months).
  • Median survival from the start of treatment was 6.1 months (95% CI 3.8 to 8.5).
  • Grade 1 to 3 fatigue was reported in 89% of patients.
  • 21 of 53 patients evaluable for toxicity had at least one dose reduction.
  • Five patients stopped treatment because of toxicity or intolerance.
  • There was one grade 5 (fatal) pneumonitis, and its attribution to the drug was uncertain.
  • Among 47 biomarker-assessable patients, baseline serum mesothelin predicted survival on univariate analysis (hazard ratio 1.06, 1.03 to 1.10, p less than 0.001).
  • Percentage change in mesothelin from baseline was associated with time to progression (HR 3.84, 1.84 to 8.13) but not with overall survival (HR 1.62, 0.85 to 3.67, p = 0.129).
  • After adjustment for age and other markers, baseline VEGF-A and VEGF-R2 were predictive of radiological response category.
  • Changes in biomarkers between baseline and the end of cycle one or three did not correlate with time to progression.
  • The authors found only a weak association between baseline serum biomarkers of angiogenesis (blood-vessel growth) and clinical outcomes.
• The authors' conclusion: The authors concluded that the study met its primary endpoint, showing modest antitumor activity of single-agent sunitinib as second-line therapy in malignant pleural mesothelioma. They stated that future trials should include a placebo-randomized control arm.
• Limitations the authors state:
  • Metabolic (FDG-PET) responses were not confirmed with a third scan.
  • Biomarker analysis was exploratory and was not included in the power calculations.
  • Response to previous treatment was not recorded and could not be assessed.
  • Patient numbers in each response category were relatively small.
  • A protocol change let in patients with prior pleurodesis, and these patients could not be assessed by FDG-PET.

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), Second-Line Therapy, Pleural Mesothelioma, Chemotherapy, Tyrosine Kinase Inhibitor, Mesothelioma, Biomarker, Performance Status.

Related studies

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• 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)
• A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma — W.S. Lam, J. Creaney, et al. (2020)
• A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma — A.K. Nowak, C. Brown, et al. (2013)
• Phase II trial of ZD0473 as second-line therapy in mesothelioma — G. Giaccone, M.E. O'Brien, et al. (2002)

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