Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer

• Type of Material: Article
• Authors: David E. Gerber, University of Texas Southwestern Medical Center; D. Ross Camidge, University of Colorado; Daniel Morgensztern, Washington University; Jeremey Cetnar, Oregon Health and Science University; Ronan J. Kelly, Johns Hopkins University; Suresh Ramalingam, Emory University; David R. Spigel, Sarah Cannon Research Institute; Woondong Jeong, University of Texas Health Science Center; Pier P. Scaglioni, University of Texas Southwestern Medical Center; Song Zhang, University of Texas Southwestern Medical Center; Marilyn Li, Baylor College of Medicine; David T. Weaver, Verastem Inc; Louis Vaikus, Verastem Inc; Mitchell Keegan, Verastem Inc; Joanna Horobin, Verastem Inc; Timothy F. Burns, University of Pittsburgh
• Language: English
• Date: 2020-01-01
• Publisher: Elsevier Ireland Ltd.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.lungcan.2019.10.033
• Title of Journal or Parent Work: Lung Cancer
• Volume: 139
• Start Page: 60
• End Page: 67
• Grant/Funding Information: Cancer Prevention and Research Institute of Texas (RP150596).; This work was supported by Verastem, Inc., by a National Cancer Institute (NCI) Midcareer Investigator Award in Patient-Oriented Research (K24 CA201543-01, to D.E.G.),; Biostatistics Shared Resource of the Harold C. Simmons Comprehensive Cancer Center, which is supported in part by National Cancer Institute Cancer Center Support Grant 1P30CA142543-01
• Keywords: Affinity; Biology; Adenocarcinoma; Selumetinib; KRAS; FAK; Targeted therapy; Tyrosine kinase inhibitor; Pooled analysis; Science & Technology; Gefitinib; TP53; 4 trials; Mutations; CDKN2A; Oncology; Respiratory System; Life Sciences & Biomedicine; Resistance
• Research Categories: Biology, Cell; Health Sciences, Public Health; Health Sciences, Oncology

Abstract

Objectives: KRAS mutations, which occur in approximately 25% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A (INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK. Materials and Methods: Patients with previously treated advanced KRAS mutant NSCLC were prospectively assigned to one of four molecularly defined cohorts based on the presence or absence of TP53 or CDKN2A alterations and received treatment with defactinib 400 mg orally BID until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 12 weeks. Results: Fifty-five patients were enrolled. Mean age was 62 years; 51% were female. The median number of prior lines of therapy was 4 (range 1–8). Fifteen (28%) patients met the 12-week PFS endpoint, with one patient achieving a partial response. Median PFS was 45 days. Clinical efficacy did not correlate with TP53 or CDKN2A status. The most common adverse events were fatigue, gastrointestinal, and increased bilirubin, and were generally grade 1 or 2 in severity. Conclusion: In heavily pretreated patients with KRAS mutant NSCLC, defactinib monotherapy demonstrated modest clinical activity. Efficacy was not associated with TP53 and CDKN2A status. Defactinib was generally well tolerated.