Dataset Information

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

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.

SUBMITTER: Gerber DE

PROVIDER: S-EPMC6942685 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

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 DE Camidge D Ross DR Morgensztern Daniel D Cetnar Jeremey J Kelly Ronan J RJ Ramalingam Suresh S SS Spigel David R DR Jeong Woondong W Scaglioni Pier P PP Zhang Song S Li Marilyn M Weaver David T DT Vaikus Louis L Keegan Mitchell M Horobin Joanna C JC Burns Timothy F TF

Lung cancer (Amsterdam, Netherlands) 20191104

<h4>Objectives</h4>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.<h4>Materials and methods</h4>Patients with previously treated advance ...[more]

PMID: 31739184

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Project description:ImportanceDetermining the risk of relapse after neoadjuvant chemotherapy in patients with locally advanced breast cancer is required to offer alternative therapeutic strategies.ObjectiveTo examine whether endothelial cell phosphorylated-focal adhesion kinase (EC-pY397-FAK) expression in patients with treatment-naive locally advanced breast cancer is a biomarker for chemotherapy sensitivity and is associated with survival after neoadjuvant chemotherapy.Design, setting, and participantsIn this prognostic study, expression levels of EC-pY397-FAK and tumor cell (TC)-pY397-FAK were determined by immunohistochemistry in prechemotherapy core biopsies from 82 female patients with locally advanced breast cancer treated with anthracycline-based combination neoadjuvant chemotherapy at Nottingham City Hospital in Nottingham, UK. Median follow-up time was 67 months. The study was conducted from December 1, 2010, to September 28, 2019, and data analysis was performed from October 2, 2019, to March 31, 2020.ExposuresAll women underwent surgery followed by adjuvant radiotherapy and, if tumors were estrogen receptor-positive, 5-year tamoxifen treatment.Main outcomes and measuresOutcomes were pathologic complete response and 5-year relapse-free survival examined using Kaplan-Meier, univariable logistic, multivariable logistic, and Cox proportional hazards models.ResultsA total of 82 women (age, 29-76 years) with locally advanced breast cancer (stage IIA-IIIC) were included. Of these, 21 women (26%) had high EC-pY397-FAK expression that was associated with estrogen receptor positivity (71% vs 46%; P = .04), progesterone receptor positivity (67% vs 39%; P = .03), high Ki67 (86% vs 41%; P < .001), 4-immunohistochemically stained luminal-B (52% vs 8%; P < .001), higher tumor category (T3/T4 category: 90% vs 59%; P = .01), high lymph node category (N2-3 category: 43% vs 5%; P < .001), and high tumor node metastasis stage (IIIA-IIIC: 90% vs 66%; P = .03). Of 21 patients with high EC-pY397-FAK expression levels, none showed pathologic complete response, compared with 11 of 61 patients with low EC-pY397-FAK expression levels who showed pathologic complete response (odds ratio, 0.70; 95% CI, 0.61-0.82; P = .04). High EC-pY397-FAK expression levels and high blood vessel density (BVD) were associated with shorter 5-year relapse-free survival compared with those with low EC-pY397-FAK expression levels (hazard ratio [HR], 2.21; 95% CI, 1.17-4.20; P = .01) and low BVD (HR, 2.2; 95% CI, 1.15-4.35; P = .02). High TC-pY397-FAK expression levels in 15 of 82 women (18%) were not associated significantly with pathologic complete response or 5-year relapse-free survival. A multivariable Cox regression model for 5-year relapse-free survival indicated that high EC-pY397-FAK expression levels was an independent poor prognostic factor after controlling for other validated prognostic factors (HR, 3.91; 95% CI, 1.42-10.74; P = .01). Combined analysis of EC-pY397-FAK expression levels, TC-pY397-FAK expression levels, and BVD improved prognostic significance over individually tested features.Conclusions and relevanceThe findings of this study suggest that low EC-pY397-FAK expression levels are associated with chemotherapy sensitivity and improved 5-year relapse-free survival after systemic therapy. Combined analysis of high EC-pY397-FAK expression levels, high TC-pY397-FAK expression levels, and high BVD appeared to identify a high-risk population.

Dataset Information

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

Objectives

Materials and methods

Results

Conclusion

Publications

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

Similar Datasets

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