Verastem Oncology announced preliminary clinical data from the RAMP 203 Phase 1/2 study, evaluating the triplet combination of avutometinib, sotorasib, and defactinib in patients with KRAS G12C mutant advanced non-small cell lung cancer (NSCLC). The initial data showed no dose-limiting toxicities and encouraging anti-tumor activity in patients previously treated with a G12C inhibitor. The company plans to present an interim update at a medical meeting in the second half of 2025.
RAMP 203 Trial Design and Initial Findings
The RAMP 203 trial is a Phase 1/2 open-label study assessing the efficacy and safety of avutometinib and sotorasib, with or without defactinib, in KRAS G12C mutant NSCLC patients. The study includes both patients who have not been previously treated with a KRAS G12C inhibitor and those who have progressed on such therapies.
As of the data cutoff on November 21, 2024, three patients whose cancer had progressed on a G12C inhibitor were treated with sotorasib 960 mg daily, avutometinib 3.2 mg twice-weekly (BIW), and defactinib 200 mg twice-daily (BID). Avutometinib and defactinib were administered on a three-out-of-four-week schedule. Two of the three patients demonstrated initial tumor reductions of at least 20% at the first scan. All three patients remained on treatment at the time of the data cutoff. No dose-limiting toxicities (DLTs) were observed in the first triplet combination cohort.
Clinical Significance and Future Plans
"We are encouraged by the initial data from the triplet combination of avutometinib and sotorasib plus defactinib in the RAMP 203 trial, which shows early evidence of tumor reductions for patients who have limited treatment options," said John Hayslip, M.D., chief medical officer at Verastem Oncology. He further noted that the triplet combination builds on the experience from the RAMP 201 study in recurrent low-grade serous ovarian cancer, where adding defactinib showed a clear advantage.
The company anticipates enrolling additional patients in the triplet combination cohort. Enrollment in the doublet combination of avutometinib with sotorasib has been completed (n=28) in the G12C inhibitor treatment-naïve Stage 1 Part B cohort. Enrollment in the KRAS G12C inhibitor prior-treated Stage I Part B cohort is expected to be completed in early 2025. Patients in both cohorts continue to be monitored for safety and efficacy to determine if observed efficacy supports expanded enrollment.
About Avutometinib and Defactinib
Avutometinib is an oral RAF/MEK clamp that inhibits MEK1/2 kinase activities and induces inactive complexes of MEK with ARAF, BRAF, and CRAF. This mechanism potentially creates a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition.
Defactinib is an oral, selective inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). FAK and Pyk2 integrate signals from integrin and growth factor receptors to regulate cell proliferation, survival, migration, and invasion. FAK activation has been shown to mediate resistance to multiple anti-cancer agents, including RAF and MEK inhibitors.
