A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307

Our plain-English summary of A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307, by S. Dubey, P.A. Jänne, L. Krug, et al (Journal of Thoracic Oncology, 2010).

The study

• Authors: S. Dubey, P.A. Jänne, L. Krug, H. Pang, X. Wang, R. Heinze, C. Watt, J. Crawford, R. Kratzke, E. Vokes, H.L. Kindler
• Journal: Journal of Thoracic Oncology
• Published: 2010;5(10):1655-61
• Cited by: 88 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Hypothesis: Malignant mesotheliomas (MMs) express vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and cKIT. Sorafenib is a potent inhibitor of the ras/raf/MEK pathway and also targets VEGFR and cKIT. We evaluated the activity of sorafenib in patients with unresectable mesothelioma.

Methods: MM patients who had received 0 to 1 prior chemotherapy regimens were treated with sorafenib 400 mg orally twice daily continuously. The primary end point was objective response. ERK1/2 phosphorylation in archival tissues was correlated with response and survival.

Results: A total of 51 patients were enrolled, 50 were evaluable and included in the analysis. Three patients had a partial response (6% [95% confidence interval = 1.3-16.6%]), and 27 (54% [95% confidence interval = 39.3-68.2%]) had stable disease. Median progression-free survival and median overall survival (OS) were 3.6 and 9.7 months, respectively. Median survival was superior in epithelioid histology versus other types (10.7 versus 3.7 months, p = 0.0179). The difference in median OS between pretreated and chemonaive patients was not statistically significant (13.2 versus 5 months, p = 0.3117). Low/negative baseline tumor phospho-ERK1/2 levels were associated with improved OS (13.9 versus 5.2 months, p = 0.0066).

Conclusion: Sorafenib has limited activity in advanced MM patients, similar to that seen with other VEGFR tyrosine kinase inhibitors. Additional studies of sorafenib in MM are not warranted.

In plain English

This single-arm phase II trial tested sorafenib, a drug taken by mouth (400 mg twice daily), in people whose malignant mesothelioma could not be removed by surgery. Of 51 patients enrolled between October 2004 and August 2005, 50 were treated and analyzed. Forty-five had pleural and five had peritoneal mesothelioma, and 30 had received earlier chemotherapy. The article does not describe the patients' asbestos exposure. Three patients (6%, 95% confidence interval 1.3 to 16.6%) had a partial response (tumor shrinkage) and 27 (54%, 95% confidence interval 39.3 to 68.2%) had stable disease, so the trial missed its main goal. Median progression-free survival was 3.6 months, and median overall survival was 9.7 months. Patients with epithelioid tumors lived longer than others (median 10.7 versus 3.7 months). Thirty-seven patients had tumor tissue that could be tested for a marker, phospho-ERK1/2. Among them, low or negative levels were associated with longer survival (13.9 versus 5.2 months). Five patients stopped treatment because of side effects. The authors concluded that sorafenib had limited activity and that further studies in mesothelioma were not warranted.

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: Single-arm, one-stage phase II clinical trial (Cancer and Leukemia Group B 30307)
• Who was studied: 51 patients with unresectable malignant mesothelioma, enrolled October 2004 to August 2005 at US centers. 50 were treated and analyzed; one was never treated. There were 35 men and 15 women, median age 69. Site: pleura 45 (90%), peritoneum 5 (10%). Histology: epithelioid 37, sarcomatoid 4, mixed 7, unknown 2. Prior chemotherapy: yes in 30 (60%), no in 20 (40%).
• Exposure: Treatment with sorafenib 400 mg by mouth twice daily, in 28-day cycles, until disease progression or unacceptable toxicity. The article does not report asbestos or fiber exposure.
• Main results:
  • Of 50 patients, 3 (6%, 95% CI 1.3 to 16.6%) had partial responses lasting 3, 6 and 6 months. 27 (54%, 95% CI 39.3 to 68.2%) had stable disease.
  • The trial did not show a response rate above 5%, which was its primary end point.
  • In the whole group of 50, median progression-free survival was 3.6 months (95% CI 2.3 to 5.5).
  • In the whole group of 50, median overall survival was 9.7 months (95% CI 4.4 to 14.3).
  • Median survival was 13.2 months in previously treated patients and 5.0 months in chemotherapy-naive patients. This difference was not statistically significant (p = 0.3117). The authors said it likely reflects patient selection rather than true activity of sorafenib.
  • Median overall survival was 10.7 months (95% CI 5.2 to 24.1) for epithelioid histology (n = 37) and 3.7 months (95% CI 3.0 to 13.1) for other histologies (n = 13), p = 0.0179.
  • Among 37 patients with evaluable archival tissue, medium/high phospho-ERK1/2 (n = 15) was associated with poorer overall survival than negative/low levels (n = 22): median 5.2 versus 13.9 months, HR 3.41, 95% CI 1.41 to 8.25, p = 0.0066.
  • No BRAF mutations were found in the 42 available tissue samples.
  • The most common grade 3 toxicity was fatigue (12 of 50, 24%), followed by hand-foot skin reaction (6, 12%). There were no grade 5 toxicities. Five patients (10%) stopped treatment and 16 (32%) had dose reductions because of toxicity.
• The authors' conclusion: The authors concluded that sorafenib had limited activity in advanced malignant mesothelioma, like other angiogenesis inhibitors, and that additional studies of sorafenib in mesothelioma were not warranted.
• Limitations the authors state:
  • Because of the small sample size, previous treatments and performance status could not be included in the Cox models of the biomarker.
  • Phospho-ERK1/2 could not be evaluated in the three patients who had a partial response, because their samples were insufficient.
  • The study did not evaluate the effect of sorafenib on phospho-ERK1/2 after treatment.
  • The authors noted that the variety within mesothelioma can confound the results of a single-arm study such as this one.

Topics

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

Medical terms in this study, explained in our Lexicon: Sorafenib (Nexavar), Malignant Mesothelioma, Platelet-Derived Growth Factor (PDGF), Unresectable, Mesothelioma, Chemotherapy, confidence interval, Progression-Free Survival.

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