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

Dean A. Fennell, Paul Baas, Paul Taylor, Anna K. Nowak, David Gilligan, Takashi Nakano, Jonathan A. Pachter, David T. Weaver, Arnaud Scherpereel, Nick Pavlakis, Jan P. van Meerbeeck, Susana Cedres, Luke Nolan, Hedy Kindler, Joachim G. J. V. Aerts

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 M PM 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. (C) 2019 by American Society of Clinical Oncology

Original languageEnglish
Pages (from-to)790-798
Number of pages10
JournalJournal of Clinical Oncology
Volume37
Issue number10
DOIs
Publication statusPublished - 1 Apr 2019

Cite this

Fennell, Dean A. ; Baas, Paul ; Taylor, Paul ; Nowak, Anna K. ; Gilligan, David ; Nakano, Takashi ; Pachter, Jonathan A. ; Weaver, David T. ; Scherpereel, Arnaud ; Pavlakis, Nick ; van Meerbeeck, Jan P. ; Cedres, Susana ; Nolan, Luke ; Kindler, Hedy ; Aerts, Joachim G. J. V. / Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma : COMMAND-A Double-Blind, Randomized, Phase II Study. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 10. pp. 790-798.
@article{0b497fa8cbc542308a998d6bbe961de9,
title = "Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study",
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 M PM 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. (C) 2019 by American Society of Clinical Oncology",
keywords = "ADHESION KINASE INHIBITOR, ARGININOSUCCINATE SYNTHETASE, OPEN-LABEL, MUTATIONS, GENE, FAK, NF2, EXPRESSION, CISPLATIN, CELLS",
author = "Fennell, {Dean A.} and Paul Baas and Paul Taylor and Nowak, {Anna K.} and David Gilligan and Takashi Nakano and Pachter, {Jonathan A.} and Weaver, {David T.} and Arnaud Scherpereel and Nick Pavlakis and {van Meerbeeck}, {Jan P.} and Susana Cedres and Luke Nolan and Hedy Kindler and Aerts, {Joachim G. J. V.}",
year = "2019",
month = "4",
day = "1",
doi = "10.1200/JCO.2018.79.0543",
language = "English",
volume = "37",
pages = "790--798",
journal = "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "10",

}

Fennell, DA, Baas, P, Taylor, P, Nowak, AK, Gilligan, D, Nakano, T, Pachter, JA, Weaver, DT, Scherpereel, A, Pavlakis, N, van Meerbeeck, JP, Cedres, S, Nolan, L, Kindler, H & Aerts, JGJV 2019, 'Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study' Journal of Clinical Oncology, vol. 37, no. 10, pp. 790-798. https://doi.org/10.1200/JCO.2018.79.0543

Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma : COMMAND-A Double-Blind, Randomized, Phase II Study. / Fennell, Dean A.; Baas, Paul; Taylor, Paul; Nowak, Anna K.; Gilligan, David; Nakano, Takashi; Pachter, Jonathan A.; Weaver, David T.; Scherpereel, Arnaud; Pavlakis, Nick; van Meerbeeck, Jan P.; Cedres, Susana; Nolan, Luke; Kindler, Hedy; Aerts, Joachim G. J. V.

In: Journal of Clinical Oncology, Vol. 37, No. 10, 01.04.2019, p. 790-798.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma

T2 - COMMAND-A Double-Blind, Randomized, Phase II Study

AU - Fennell, Dean A.

AU - Baas, Paul

AU - Taylor, Paul

AU - Nowak, Anna K.

AU - Gilligan, David

AU - Nakano, Takashi

AU - Pachter, Jonathan A.

AU - Weaver, David T.

AU - Scherpereel, Arnaud

AU - Pavlakis, Nick

AU - van Meerbeeck, Jan P.

AU - Cedres, Susana

AU - Nolan, Luke

AU - Kindler, Hedy

AU - Aerts, Joachim G. J. V.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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 M PM 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. (C) 2019 by American Society of Clinical Oncology

AB - 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 M PM 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. (C) 2019 by American Society of Clinical Oncology

KW - ADHESION KINASE INHIBITOR

KW - ARGININOSUCCINATE SYNTHETASE

KW - OPEN-LABEL

KW - MUTATIONS

KW - GENE

KW - FAK

KW - NF2

KW - EXPRESSION

KW - CISPLATIN

KW - CELLS

U2 - 10.1200/JCO.2018.79.0543

DO - 10.1200/JCO.2018.79.0543

M3 - Article

VL - 37

SP - 790

EP - 798

JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology

JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology

SN - 0732-183X

IS - 10

ER -