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Ref Type Journal Article
PMID (31739184)
Authors Gerber DE, Camidge DR, Morgensztern D, Cetnar J, Kelly RJ, Ramalingam SS, Spigel DR, Jeong W, Scaglioni PP, Zhang S, Li M, Weaver DT, Vaikus L, Keegan M, Horobin JC, Burns TF
Title Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer.
Journal Lung cancer (Amsterdam, Netherlands)
Vol 139
Issue
Date 2020 Jan
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Defactinib VS-6063|PF-04554878 FAK inhibitor 13 Defactinib (VS-6063) inhibits FAK, resulting in decreased downstream signaling, and potentially leading to reduced tumor cell proliferation and survival (PMID: 31739184).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown lung non-small cell carcinoma not applicable Defactinib Phase I Actionable In a Phase I trial, 31% (17/55) of KRAS-mutant patients with non-small cell lung cancer demonstrated progression-free survival at 12 weeks and one patient experienced a partial response and eight patients had stable disease as a best overall response when treated with Defactinib (VS-6063) (PMID: 31739184; NCT01778803). 31739184