Verastem Shifts Focus from KRAS G12C to G12D in NSCLC, Discontinues Phase 1/2 Trial

Verastem Oncology has announced a strategic pivot in its non-small cell lung cancer (NSCLC) program, discontinuing its phase 1/2 trial targeting KRAS G12C mutations and redirecting resources towards the development of VS-7375, an oral KRAS G12D inhibitor. This decision comes in the wake of emerging next-generation KRAS G12C inhibitors that have set new benchmarks for efficacy in the field.

Ramp 203 Trial Results and Discontinuation

The phase 1/2 Ramp 203 trial, which evaluated combinations including Verastem's RAF/MEK inhibitor Avmapki (avutometinib) and Amgen's KRAS G12C inhibitor Lumakras (sotorasib), has been terminated following an interim data analysis. The trial explored both doublet and triplet regimens, with the latter also incorporating Verastem's FAK inhibitor Fakzynja (defactinib).

As of November 26, 2025, the trial had yielded mixed results:

• In G12C inhibitor-naïve patients, the doublet combination showed an overall response rate (ORR) of 40% and a median progression-free survival (PFS) of 11.1 months.
• The triplet regimen demonstrated a 50% ORR in treatment-naïve patients.
• For G12C-experienced patients, the doublet achieved a 9.5% ORR and 3.7-month median PFS, while the triplet resulted in tumor reductions exceeding 30% in 36% of patients, with a 3.6-month median PFS.

Despite these outcomes and a manageable safety profile, Verastem's Chief Medical Officer, John Hayslip, M.D., cited the superior performance of newer G12C inhibitors as the primary reason for discontinuing the trial.

Strategic Shift to KRAS G12D Inhibition

Verastem is now concentrating its efforts on VS-7375, a potentially best-in-class KRAS G12D inhibitor. Early data for VS-7375 has shown promise, with a reported 69% response rate among 16 patients with KRAS G12D NSCLC.

The company's focus on G12D is strategic, as this mutation is the most prevalent KRAS mutation across all human cancers. It occurs in 37% of pancreatic cancers, 12.5% of colorectal cancers, 8% of endometrial cancers, and 5% of NSCLC cases.

VS-7375, in-licensed from China's GenFleet Therapeutics in early 2025, is distinguished as a KRAS (on/off) inhibitor. This means it targets the RAS protein in both its inactive GDP-bound form and active GTP-bound form, potentially offering advantages over current marketed KRAS G12C inhibitors that only target the "off" state.