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J Clin Oncol. 2019 Feb 20:JCO2018790543. doi: 10.1200/JCO.2018.79.0543. [Epub ahead of print]

Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study.

Author information

1
1 University of Leicester, Leicester, United Kingdom.
2
2 Netherlands Cancer Institute, Amsterdam, the Netherlands.
3
3 Wythenshawe Hospital, Manchester, United Kingdom.
4
4 University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia.
5
5 Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke's Hospital, Cambridge, United Kingdom.
6
6 Hyogo College of Medicine, Hyogo, Japan.
7
7 Verastem, Boston, MA.
8
8 Calmette Hospital, Regional University Hospital of Lille, Lille Cedex, France.
9
9 Northern Cancer Institute, St Leonards, NSW, Australia.
10
10 Universitair Ziekenuis, Antwerp, Belgium.
11
11 Karolinska University Hospital, Stockholm, Sweden.
12
12 University Hospital, Southampton, United Kingdom.
13
13 University of Chicago Medical Center, Chicago, IL.
14
14 Erasmus Medical College, Rotterdam, the Netherlands.

Abstract

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.

PMID:
30785827
DOI:
10.1200/JCO.2018.79.0543

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