Phase 1 Trial of VS-6766, a Dual RAF-MEK Inhibitor, and Defactinib, an FAK Inhibitor

In patients with non–small-cell lung cancer and KRAS G12V mutations who were pretreated with chemotherapy and immunotherapy, the combination of VS-6766 and defactinib is active with an acceptable tolerability profile.

KRAS is a known oncogenic driver in non–small-cell lung cancer (NSCLC), with KRAS G12C and KRAS G12V mutations occurring in approximately 13% and approximately 7% of NSCLC adenocarcinomas, respectively.1 As reported by Guo et al, VS-6766, a dual RAF-MEK inhibitor, has shown single-agent activity against KRAS G12V–mutated NSCLC.2

Based on preclinical data, researchers hypothesized that augmented focal adhesion kinase (FAK) signaling is a mechanism of resistance to MEK inhibition. They then devised the current clinical trial.1 These scientists had previously reported safety data for an intermittent schedule of the combination of VS-6766 and defactinib, as well as its efficacy in low-grade serous ovarian cancer.3 At the American Association of Cancer Research Annual Meeting 2021, they reported the activity of the combination in KRAS-mutated NSCLC.1

In the dose-escalation and expansion cohorts of the study, patients were treated with an intermittent dose of VS-6766 (3.2-4 mg twice a week) and defactinib (200 mg twice daily). Both drugs were administered 3 weeks on, 1 week off in 28-day cycles. The study aims to recruit 20 patients with KRAS-mutated NSCLC in an expansion cohort.1

As of data cutoff, 19 patients with KRAS-mutated NSCLC were treated in the dose-escalation and expansion cohorts. All patients had been previously treatment with a PD-1 or PD-L1 targeting immune checkpoint inhibitor. Their median age was 64 years (range, 22-73 years), and the median number of prior lines of treatment received was 3. Seventeen of 19 patients have had at least 1 restaging assessment, 2 of 17 (12%) patients had a partial response, and 10 of 17 (59%) had a best response of stable disease. The researchers reported that 11 of 17 (65%) patients had a degree of reduction in the size of their tumors, while 5 of 17 (29%) patients have been treated for ≥6 months. Both patients with KRAS G12V–mutated NSCLC achieved a partial response.1

The combination of VS-6766 and defactinib treatment in patients with non-G12C KRAS-mutated NSCLC who were pretreated with chemotherapy and immunotherapy has shown antitumor activity, particularly in patients whose tumors harbor KRAS G12V mutations. A registration-directed study of VS-6766 with or without defactinib in patients with recurrent NSCLC with KRAS G12V mutation is underway.1

1. Krebs MG, Shinde R, Rahman RA, et al. A phase I trial of the combination of the dual RAF-MEK inhibitor VS-6766 and the FAK inhibitor defactinib: evaluation of efficacy in KRAS mutated NSCLC. Presented at: American Association of Cancer Research Annual Meeting 2021; April 10-15, 2021. Abstract CT019.
2. Guo C, Chénard-Poirier M, Roda D, et al. Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. Lancet Oncol. 2020;21:1478-1488.
3. Shinde R, Terbuch A, Little M, et al. Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers. Presented at: American Association of Cancer Research 2020; April 24-29, 2020. Abstract CT143.