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 12week 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.

Current therapy of KRAS-mutant lung cancer

“…4 vs. 2.3; p = NS KRAS mut pts. 10.5 vs. 21.8; p = NS RO5126766 Chenard-Poirier et al [ 132 ] 2017 Phase I, OL, SC MEK/RAF 10 mut Response NA NA Selumetinib Jänne et al [ 133 ] 2017 Phase III, R, DB, MC MEK 510 mut PFS 3.9 vs. 2.8; p = NS 8.7 vs. 7.9; p = NS Defactinib Gerber et al [ 134 ] 2019 Phase II, OL, SC FAK 55 mut PFS at 12 wks 45 days NA DB , double blind; DCR , disease control rate; DPE , disease progression event count; FAK , focal adhesion kinase; KRAS , Kirsten rat sarcoma viral oncogene homolog; MC , multicenter; MEK , MAPK/ERK kinase; mTOR , mammalian target of rapamycin; mut , mutant; NS , non-significant; NA , not announced; OL , open label; OS , overall survival; PFS , progression-free survival; pt , patient; R , randomized; RAF , rapidly accelerated fibrosarcoma; RAS , rat sarcoma virus; SC , single-center; wks , weeks; wt , wild type *Patients with non-small cell lung cancer #In months unless otherwise stated …”

Focal adhesion kinase—An emerging viable target in cancer and development of focal adhesion kinase inhibitors

“…Studies revealed that defactinib inhibited FAK phosphorylation at Y397 and a combination of defactinib with paclitaxel showed decreased cell proliferation and apoptosis in ovarian cancer cells (Kang et al, 2013). In phase 2 trials, defactinib has moderate activity in KRAS mutant non-small cell lung carcinoma but failed to boost the clinical trial outcomes as a maintenance therapy (Gerber et al 2020). Verastem screened a combination of defactinib and paclitaxel in women with ovarian cancer in a phase I/Ib clinical trial (#NCT01778803).…”

Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer

“…Our initial analysis showed that tumor cell viability decreased by approximately 40%, when treated with ≤5.0 μM, VS-6063, a chemical inhibitor of active FAK which blocks its Y 397 autophosphorylation ( Supplementary Figure S2A ). Given the limitation of clinical efficacy of this FAK inhibitor against epithelia-origin human cancers ( Jones et al, 2015 ; Xu et al, 2017 ; Gerber et al, 2020 ), we examined the combinatorial inhibition strategy for this inhibitor-based targeting by performing cell viability-based chemical inhibitor screening. As shown in Supplementary Figure S2 , two out of more than 30 anti-tumor chemical agents screened, the pharmacological agents of epigenetic drivers BRD4 (JQ1) and histone deacetylase (HDAC, LBH589) ( Filippakopoulos et al, 2010 ), and the pro-survival Akt (MK-2206) and Bcl-2 (ABT-737), exhibited strong cooperative effects with VS-6063 in terms of cell viability inhibition.…”