A phase 2 study of VS-6766 (RAF/MEK clamp) RAMP 202, as a single agent and in combination with defactinib (FAK inhibitor) in recurrent KRAS mutant (mt) and BRAF mt non–small cell lung cancer (NSCLC).

TPS9147 Background: KRAS is mutated (mt) in 25% of NSCLC adenocarcinoma, with KRAS G12V and G12C mt occurring in ̃7% and ̃13% of patients (pts), respectively. Whereas G12C inhibitors have demonstrated promising activity in pts with KRAS G12C NSCLC, KRAS G12V NSCLC remains an unmet need. BRAF mt occurs in ̃4% of NSCLC with roughly equal split between BRAF V600E and non-V600E. VS-6766 is a small molecule RAF/MEK clamp that inhibits BRAF, CRAF and MEK, enabling VS-6766 to block MEK signaling without compensatory activation of MEK observed with MEK-only inhibitors. VS-6766 potently inhibits proliferation of KRAS and BRAF mt cell lines. Focal adhesion kinase (FAK) activation is a putative resistance mechanism to RAF and MEK inhibition, and defactinib, a small molecule FAKi, has shown synergistic anti-tumor activity with VS-6766 in KRAS mt NSCLC models. In a KRAS G12V mt NSCLC mouse model, which was shown to be especially dependent on CRAF, VS-6766 induced strong tumor regressions both as monotherapy and in combination with FAKi (Coma AACR 2021). Clinically, VS-6766 monotherapy has shown responses in KRAS mt NSCLC including pts with KRAS G12V and in pts with BRAF V600E solid tumors (Guo 2020; Martinez-Garcia 2012). The combination of VS-6766 + defactinib is currently being evaluated in the Investigator Sponsored FRAME study. In an updated analysis of response in 20 pts with KRAS mt NSCLC, there were 2 confirmed PRs, 1 unconfirmed PR and 10 SDs (ORR = 15%; DCR = 65%) with 7/20 pts remaining on treatment for ≥24 weeks. The 2 pts with KRAS G12V NSCLC both had confirmed PRs (ORR = 100%). This combination regimen exhibited a manageable safety profile with no NSCLC pts discontinuing for adverse events (Krebs AACR 2021). Methods: This is an international phase 2, adaptive, multicenter, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 vs. VS-6766 + defactinib in pts with recurrent KRAS or BRAF mt NSCLC (NCT04620330). Part A will determine the optimal regimen, either VS-6766 monotherapy or VS-6766 + defactinib based on pts with KRAS G12V. Part A will consist of 5 NSCLC arms: Arm 1 VS-6766 monotherapy in KRAS G12V, Arm 2 VS-6766 + defactinib in KRAS G12V, Arm 3 the combination in KRAS non-G12V, Arm 4 the combination in BRAF V600E and Arm 5 the combination in BRAF non-V600E. Part B will determine the efficacy of the optimal regimen identified in Part A. Pts must have histologic or cytologic evidence of NSCLC, measurable disease according to RECIST V1.1, known KRAS or BRAF mt and at least 1 prior systemic therapy (appropriate therapy for activating mutation and/or platinum-based therapy). Part A will enroll 102 pts Arms 1 and 2 (KRAS G12V), and Arms 4 and 5 (BRAF V600E and non-V600E) are currently open. Arm 3 (KRAS non-G12V) enrollment is completed. The total number of pts in Part B will be determined by results from Part A. Clinical trial information: NCT04620330.