Abstract CT204: A phase 1/2 study of VS-6766 in combination with sotorasib in patients with KRAS G12C mutant non-small cell lung cancer (NSCLC) (RAMP 203)

Abstract Background: KRAS is mutated (mt) in 25% of non-small cell lung cancer (NSCLC) adenocarcinoma, with KRAS G12C mt occurring in ~13% of patients. The G12C inhibitor (G12Ci) sotorasib has recently received FDA approval for patients with KRAS G12C mt NSCLC, however emerging data suggest that combinations may be necessary for maximal depth and duration of response. Unlike MEK-only inhibitors (MEKi), the dual RAF/MEK inhibitor VS-6766 is a potent allosteric inhibitor of MEK kinase activity and promotes a dominant negative RAF/MEK complex preventing phosphorylation of MEK by BRAF and CRAF. Thus, VS-6766 blocks MEK signaling without compensatory activation of MEK which limits the efficacy of MEKi. In vitro 3D proliferation and in vivo tumor models were used to assess anti-tumor efficacy of VS-6766 ± G12Ci. In KRAS G12C mt NSCLC cell lines, VS-6766 was synergistic with both sotorasib and adagrasib (G12Ci) in reducing tumor cell viability which correlated with deeper inhibition of RAS pathway signaling. In vivo, combination of VS-6766 with sotorasib induced strong tumor regressions in contrast to sotorasib monotherapy or sotorasib plus trametinib. Initial clinical activity of VS-6766 in KRAS G12C mt NSCLC is supported by the FRAME study [NCT03875820] results in which 4/6 patients with KRAS G12C mt NSCLC showed tumor reduction including 1 PR. These results support the clinical evaluation of VS-6766 in combination with a G12Ci for treatment of KRAS G12C mt NSCLC. Methods: This is a Phase 1/2, multicenter, open label, dose evaluation/dose expansion study designed to evaluate the efficacy and safety of VS-6766 in combination with sotorasib in patients with KRAS G12C mt NSCLC who have not previously been treated with a KRAS G12Ci or have experienced disease progression while undergoing therapy with a KRAS G12Ci [NCT05074810]. The study will be conducted in two parts: Part A (dose evaluation) and Part B (dose expansion). Up to 3 dose levels will be evaluated in Part A to determine the Recommended Phase 2 Dose (RP2D) for Part B. Part B will assess the efficacy of the RP2D and will be conducted in 2 cohorts: patients who are G12Ci treatment naïve (cohort 1) and patients who have experienced disease progress during G12Ci therapy (Cohort 2). Patients enrolled must have histologic or cytologic evidence of NSCLC, measurable disease according to RECIST V1.1 and known KRAS G12C mutation. The study will enroll up to 121 patients with a minimum of 6 and a maximum of 12 patients (dose levels 1 and -1 have >1 DLT in first 3 patients or dose levels 1 and 2 each enroll 6 patients) in Part A and an additional 109 patients in Part B (minimum of 41 patients RP2D stage 1 for cohort 1 and 2 or RP2D stages 1 and 2 in both cohorts). Citation Format: Ramaswamy Govindan, Jonathan A. Pachter, Andrew G. Koustenis, Gloria Patrick, Louis J. Denis. A phase 1/2 study of VS-6766 in combination with sotorasib in patients with KRAS G12C mutant non-small cell lung cancer (NSCLC) (RAMP 203) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT204.