Investigators Will Discontinue Phase 1/2 Avutometinib Combo Trial in NSCLC

Investigators will discontinue the phase 1/2 RAMP 203 trial (NCT05074810) evaluating avutometinib/defactinib (Avmapki Fakzynja Co-pack) in combination with sotorasib (Lumakras) for patients with KRAS G12C-mutated non–small cell lung cancer (NSCLC), according to a press release from the developer, Verastem Oncology.¹

Developers noted that the trial will be discontinued so that they can dedicate resources to developing VS-7375, an orally available KRAS G12D inhibitor, for those with NSCLC and other solid tumors. No additional patients will be able to enroll on the trial; those currently enrolled on the study may continue treatment with the investigational combination based on investigator discretion.

“RAMP 203 has provided important insights into treatment strategies and demonstrated proof-of-concept. While avutometinib plus defactinib combined well with a G12C inhibitor to drive early and sustained anti-tumor responses, next generation G12C inhibitors are establishing a new benchmark with higher response rates,” John Hayslip, MD, chief medical officer at Verastem Oncology, stated in the press release.¹ “Accordingly, we are prioritizing our clinical development of VS-7375, a potentially best-in-class oral KRAS G12D (ON/OFF) inhibitor, that demonstrated a 69% response rate (11 of 16, both confirmed and unconfirmed) in advanced [KRAS G12D-mutated] NSCLC and has the potential to help more patients with its differentiated approach in multiple solid tumors.”

With a data cutoff of November 26, 2025, the RAMP 203 trial included 66 evaluable patients who received the recommended phase 2 dose (RP2D). Among patients who received no prior G12C inhibitors (n = 30), avutometinib plus sotorasib produced an overall response rate (ORR) of 40% and a median progression-free survival (PFS) of 11.1 months. Among those who previously received a G12C inhibitor (n = 21), the doublet combination yielded an ORR of 9.5% and a median PFS of 3.7 months.

In a cohort of evaluable patients without prior G12C inhibitor therapy (n = 4), the triplet regimen elicited an ORR of 50%, which included 1 confirmed and 1 unconfirmed response. Additionally, among patients with prior receipt of KRAS G12C inhibitors (n = 11), a tumor reduction of more than 30% occurred in 36%; 7 patients were continuing therapy at the time of analysis. Investigators could not determine the median PFS for patients without prior G12C inhibitors who received the triplet regimen; those who had prior G12C inhibitors experienced a median PFS of 3.6 months.

Data showed no dose-limiting toxicities (DLTs) across the doublet and triplet cohorts. The most common adverse effects (AEs) included nausea (56.8%), diarrhea (52.7%), and fatigue (45.9%).

Investigators of the open-label, multi-center RAMP 203 trial assessed the efficacy and safety of avutometinib plus sotorasib with or without defactinib among patients with KRAS G12C-mutated NSCLC.² The trial’s primary end points included DLTs in part A as well as the confirmed ORR per RECIST v1.1 guidelines in part B. Secondary end points across all portions of the trial included the frequency and severity of AEs, duration of response, disease control rate, PFS, overall survival, and pharmacokinetics.

Patients 18 years and older with histologically or cytologically confirmed NSCLC harboring known KRAS G12C mutations, measurable disease per RECIST v1.1 guidelines, and an ECOG performance status of 0 or 1 were eligible for enrollment on the trial. Other eligibility criteria included having adequate organ function and adequate recovery from toxicities associated with prior therapies. Those with systemic anti-cancer treatment within 4 weeks of initiating study therapy, symptomatic brain metastases requiring steroids or other local interventions, or a history of rhabdomyolysis were ineligible for enrollment.

References

1. Verastem Oncology provides update on RAMP 203 phase 1/2 clinical trial for advanced KRAS G12C mutant non-small cell lung cancer. News release. Verastem Oncology. December 30, 2025. Accessed January 2, 2026. https://tinyurl.com/mrx292an
2. Phase 1/​2 study of avutometinib (VS-6766) + sotorasib with or without defactinib in KRAS G12C NSCLC patients (RAMP203). ClinicalTrials.gov. Updated September 12, 2025. Accessed January 2, 2026. https://tinyurl.com/2cfd7h5t