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Published on: December 21, 2019
Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural
Dean A Fennell1, Paul Baas2, Paul Taylor3
11 University of Leicester, Leicester, United Kingdom.
Purpose:
Inhibition of focal adhesion kinase has been shown to selectively kill mesothelioma cells that express low levels of moesin-ezrin-radixin-like protein (merlin). On this basis, we designed a randomized, phase II trial to investigate whether defactinib as maintenance therapy after standard first-line chemotherapy could improve progression-free survival (PFS) in patients with malignant pleural mesothelioma (MPM).
Methods:
This global, double-blind, randomized, placebo-controlled trial was conducted in patients with advanced MPM and disease control after at least four cycles of first-line chemotherapy. Patients were stratified for merlin and then randomly assigned (in a 1:1 fashion) to receive either oral defactinib or placebo until disease progression, unacceptable toxicity, or withdrawal occurred. The coprimary end points were PFS and overall survival (OS). Quality of life (QoL) was assessed using the Lung Cancer Symptom Scale for Mesothelioma tool.
Results:
Three hundred forty-four patients were randomly assigned to receive either defactinib (n = 173) or placebo (n = 171). The median PFS was 4.1 months (95% CI, 2.9 to 5.6 months) for defactinib versus 4.0 months (95% CI, 2.9 to 4.2 months) for placebo. The median OS was 12.7 months (95% CI, 9.1 to 21 months) for defactinib versus 13.6 months (95% CI, 9.6 to 21.2 months) for placebo (hazard ratio, 1.0; 95% CI, 0.7 to 1.4). Although shorter survival for both defactinib- and placebo-treated patients was observed, in the patients who had merlin-low MPM compared with the patients who had merlin-high MPM, there were no statistical differences in response rate, PFS, OS, or QoL between the treatment groups. The most common grade 3 or worse adverse events were nausea, diarrhea, fatigue, dyspnea, and decreased appetite.
Conclusion:
Neither PFS nor OS was improved by defactinib after first-line chemotherapy in patients with merlin-low MPM. Defactinib cannot be recommended as maintenance therapy for advanced MPM.
Insights
Defactinib maintenance therapy did not improve progression-free survival or overall survival in patients with merlin-low malignant pleural mesothelioma. This study suggests defactinib is not recommended for advanced MPM maintenance treatment.
Area of Science:
- Oncology
- Clinical Trials
- Cancer Therapeutics
Background:
- Malignant pleural mesothelioma (MPM) is an aggressive cancer.
- Focal adhesion kinase (FAK) inhibition shows promise in selectively targeting mesothelioma cells with low merlin expression.
- Merlin (moesin-ezrin-radixin-like protein) is a tumor suppressor protein implicated in MPM progression.
Purpose of the Study:
- To evaluate defactinib as maintenance therapy after first-line chemotherapy in advanced MPM.
- To determine if defactinib improves progression-free survival (PFS) and overall survival (OS) in patients with merlin-low MPM.
- To assess the impact of defactinib on quality of life (QoL) in MPM patients.
Main Methods:
- A global, double-blind, randomized, placebo-controlled, phase II trial.
- 344 patients with advanced MPM and disease control after chemotherapy were randomized (1:1) to defactinib or placebo.
- Stratification by merlin expression, with PFS and OS as coprimary end points; QoL assessed using the Lung Cancer Symptom Scale for Mesothelioma.
Main Results:
- Defactinib (n=173) showed median PFS of 4.1 months vs. 4.0 months for placebo (n=171).
- Median OS was 12.7 months for defactinib vs. 13.6 months for placebo (HR 1.0).
- No significant differences in response rate, PFS, OS, or QoL were observed between treatment groups, irrespective of merlin status.
Conclusions:
- Defactinib maintenance therapy following first-line chemotherapy did not improve PFS or OS in patients with merlin-low MPM.
- Defactinib is not recommended as a maintenance treatment for advanced malignant pleural mesothelioma.
- Further research may be needed to identify specific patient subgroups who could benefit from FAK inhibition in MPM.
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