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

Lung Cancer. 2020 Jan:139:60-67. doi: 10.1016/j.lungcan.2019.10.033. Epub 2019 Nov 4.

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.

Keywords: Adenocarcinoma; CDKN2A; KRAS; TP53; Targeted therapy; Tyrosine kinase inhibitor.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma of Lung / drug therapy*
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / pathology
  • Benzamides / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Follow-Up Studies
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Prognosis
  • Prospective Studies
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Pyrazines / therapeutic use*
  • Salvage Therapy
  • Sulfonamides / therapeutic use*
  • Survival Rate

Substances

  • Benzamides
  • KRAS protein, human
  • Pyrazines
  • Sulfonamides
  • defactinib
  • Focal Adhesion Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins p21(ras)