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

David E. Gerber, D. Ross Camidge, Daniel Morgensztern, Jeremey Cetnar, Ronan J. Kelly, Suresh S. Ramalingam, David R. Spigel, Woondong Jeong, Pier P. Scaglioni, Song Zhang, Marilyn Li, David T. Weaver, Louis Vaikus, Mitchell Keegan, Joanna C. Horobin, Timothy F. Burns

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)60-67
Number of pages8
JournalLung Cancer
Volume139
DOIs
StatePublished - Jan 2020

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Focal Adhesion Kinase 2
Non-Small Cell Lung Carcinoma
Disease-Free Survival
Focal Adhesion Protein-Tyrosine Kinases
Bilirubin
Heterografts
Fatigue
Disease Progression
Thorax
defactinib
Cell Line
Mutation
Therapeutics

Keywords

  • Adenocarcinoma
  • CDKN2A
  • KRAS
  • Targeted therapy
  • TP53
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer. / Gerber, David E.; Camidge, D. Ross; Morgensztern, Daniel; Cetnar, Jeremey; Kelly, Ronan J.; Ramalingam, Suresh S.; Spigel, David R.; Jeong, Woondong; Scaglioni, Pier P.; Zhang, Song; Li, Marilyn; Weaver, David T.; Vaikus, Louis; Keegan, Mitchell; Horobin, Joanna C.; Burns, Timothy F.

In: Lung Cancer, Vol. 139, 01.2020, p. 60-67.

Research output: Contribution to journalArticle

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 2020, '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, vol. 139, pp. 60-67. https://doi.org/10.1016/j.lungcan.2019.10.033
Gerber, David E. ; Camidge, D. Ross ; Morgensztern, Daniel ; Cetnar, Jeremey ; Kelly, Ronan J. ; Ramalingam, Suresh S. ; Spigel, David R. ; Jeong, Woondong ; Scaglioni, Pier P. ; Zhang, Song ; Li, Marilyn ; Weaver, David T. ; Vaikus, Louis ; Keegan, Mitchell ; Horobin, Joanna C. ; Burns, Timothy F. / Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer. In: Lung Cancer. 2020 ; Vol. 139. pp. 60-67.
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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.",
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T1 - Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer

AU - Gerber, David E.

AU - Camidge, D. Ross

AU - Morgensztern, Daniel

AU - Cetnar, Jeremey

AU - Kelly, Ronan J.

AU - Ramalingam, Suresh S.

AU - Spigel, David R.

AU - Jeong, Woondong

AU - Scaglioni, Pier P.

AU - Zhang, Song

AU - Li, Marilyn

AU - Weaver, David T.

AU - Vaikus, Louis

AU - Keegan, Mitchell

AU - Horobin, Joanna C.

AU - Burns, Timothy F.

PY - 2020/1

Y1 - 2020/1

N2 - 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.

AB - 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.

KW - Adenocarcinoma

KW - CDKN2A

KW - KRAS

KW - Targeted therapy

KW - TP53

KW - Tyrosine kinase inhibitor

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