Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy

Our plain-English summary of Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy, by S. Papa, S. Popat, R. Shah, et al (Journal of Thoracic Oncology, 2013).

The study

• Authors: S. Papa, S. Popat, R. Shah, A.T. Prevost, R. Lal, B. McLennan, P. Cane, L. Lang-Lazdunski, Z. Viney, J.T. Dunn, S. Barrington, D. Landau, J. Spicer
• Journal: Journal of Thoracic Oncology
• Published: 2013;8(6):783-7
• Cited by: 61 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including receptors for vascular endothelial growth factor, which are implicated in mesothelioma pathogenesis by preclinical and clinical data.

Methods: Sorafenib, at 400 mg twice daily, was assessed in a single-arm multicenter phase 2 study, using Simon's two-stage design. Eligible patients had received platinum combination chemotherapy earlier. The primary endpoint was PFS at 6 months, with secondary endpoints, including response rate and metabolic response, assessed using fluorodeoxyglucose positron emission tomography. Published reference values for PFS in mesothelioma provide a benchmark for the null hypothesis of 28% progression-free at 6 months, and for moderate or significant clinical activity of 35% or 43% progression-free at 6 months, respectively.

Results: Fifty-three patients (72%) were treated. Most had epithelioid histology. Ninety-three percent of patients had a performance status 0 or 1. Treatment was well tolerated with few grade 3 or 4 toxicities. Median PFS was 5.1 months, with 36% of patients being progression-free at 6 months. Nine percent of patients remained on study beyond 1 year. Changes in fluorodeoxyglucose positron emission tomography parameters did not predict clinical outcome.

Conclusions: Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.

In plain English

This single-arm phase 2 trial, with no comparison group, tested sorafenib 400 mg twice daily in people with malignant pleural mesothelioma previously treated with pemetrexed and platinum chemotherapy. Of 56 patients recruited at three centers between November 2008 and April 2011, three were ineligible, leaving 53. The study did not examine asbestos exposure. Median progression-free survival (time alive without the disease worsening) was 5.1 months (95% confidence interval 3.5 to 6.7), and 36% of patients (95% confidence interval 22% to 49%) were progression-free at 6 months. Median overall survival was 9.0 months (95% confidence interval 6.7 to 11.3). Three patients (6%) had a partial response and 30 (56%) had stable disease at 8 weeks. The most common severe side effects were fatigue (15%), a hand-foot skin reaction called palmar-plantar erythrodysesthesia (13%) and rash (9%). Eleven patients (21%) stopped treatment because of side effects. PET scan changes in 14 patients did not significantly correlate with outcome. The authors concluded that sorafenib was well tolerated and showed moderate activity compared with pooled historical data. They named the lack of randomization as the main limitation.

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 multicenter phase 2 clinical trial using a two-stage design
• Who was studied: Patients with malignant pleural mesothelioma not suitable for surgery, all previously treated with first-line pemetrexed and platinum chemotherapy. 56 were recruited at three centers (UK ethics approval) between November 2008 and April 2011; 3 were excluded as ineligible, leaving 53.
• Exposure: Treatment with sorafenib 400 mg twice daily continuously, in 28-day cycles. Asbestos exposure was not studied.
• Main results:
  • Among the 53 patients, median progression-free survival was 5.1 months (95% CI: 3.5–6.7 months), and 36% (95% CI: 22%–49%) were progression-free at 6 months
  • 9% of patients were still receiving the study drug at 1 year
  • Median overall survival was 9.0 months (95% CI: 6.7–11.3 months)
  • In the first stage, 6 of 19 patients were progression-free after 6 months, so the trial continued
  • 3 patients had a partial response (6%) and 30 had stable disease (56%) at 8 weeks, a disease control rate of 62%; 8 progressed (15%) and 12 were not evaluable
  • Most common grade 3/4 side effects: fatigue (15%), palmar-plantar erythrodysesthesia (13%), rash (9%)
  • Only one grade 4 event was recorded: a myocardial infarction in a patient previously treated for coronary artery disease
  • 39% of patients needed at least one dose reduction and 32% a dosage interruption
  • 11 patients (21%) discontinued treatment because of toxicity
  • In the 14 patients with paired FDG-PET-CT scans, no FDG measure correlated significantly with progression-free or overall survival
• The authors' conclusion: The authors concluded that sorafenib is well tolerated in mesothelioma and has moderate clinical activity when benchmarked against pooled historical data. They also concluded that its median progression-free survival of 5.1 months compares favorably with other VEGFR inhibitors in patients previously treated with platinum chemotherapy.
• Limitations the authors state:
  • The authors called the absence of randomization the main limitation
  • With only 14 patients in the PET analysis, the power to detect a correlation was only 46%
  • The comparison benchmarks came from chemotherapy-naive patients, which the authors describe as a high hurdle for this second-line study

Topics

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

Medical terms in this study, explained in our Lexicon: Sorafenib (Nexavar), Malignant Mesothelioma, Chemotherapy, Mesothelioma, Cisplatin, Pemetrexed (Alimta), Progression-Free Survival, Epithelioid.

Related studies

• Successful salvage chemotherapy with gemcitabine and vinorelbine in a malignant pleural mesothelioma patient previously treated with pemetrexed — T. Agatsuma, T. Koizumi, et al. (2010)
• Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients — T. Powrózek, D.M. Kowalski, et al. (2014)
• Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial — L. Calabrò, A. Morra, et al. (2013)
• DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy — N. Erčulj, V. Kovač, et al. (2012)
• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma — S. Ting, F.D. Mairinger, et al. (2013)
• Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience — G. Pasello, S. Nicotra, et al. (2011)

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