Verastem Discontinues KRAS G12C Trial to Focus on Promising G12D Inhibitor with 69% Response Rate
核心洞察
Verastem Oncology announced discontinuation of the RAMP 203 Phase 1/2 trial testing combination therapy in KRAS G12C-mutated non-small cell lung cancer (搜索) following interim data evaluation.
The company will redirect resources to VS-7375, an oral KRAS G12D (搜索) inhibitor that demonstrated a 69% response rate in advanced KRAS G12D NSCLC (搜索) patients.
RAMP 203 showed modest efficacy with 40% response rate in treatment-naïve patients but only 9.5% in previously treated patients with existing G12C inhibitors.
Verastem Oncology has announced the discontinuation of its RAMP 203 Phase 1/2 clinical trial in advanced KRAS G12C-mutated non-small cell lung cancer (搜索) (NSCLC) following evaluation of interim data. The biopharmaceutical company will redirect resources toward the clinical development of VS-7375, an oral KRAS G12D (搜索) (ON/OFF) inhibitor that has demonstrated promising efficacy in advanced NSCLC and other solid tumors.
The decision reflects the evolving treatment landscape for KRAS G12C (搜索) inhibitors and strategic prioritization of programs with the greatest potential impact for patients with advanced lung cancer. "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," said John Hayslip, chief medical officer at Verastem Oncology.
RAMP 203 Trial Results
RAMP 203 was conducted in collaboration with Amgen, evaluating avutometinib (an oral RAF (搜索)/MEK (搜索) clamp) and LUMAKRAS (sotorasib) in a doublet combination, and also with defactinib (an oral FAK (搜索) inhibitor) as a triplet combination in patients naïve to or previously treated with a KRAS G12C (搜索) inhibitor.
As of the November 26, 2025 data cutoff, 66 patients were treated at the recommended Phase 2 dose, had at least one tumor scan, and were evaluable for efficacy. The doublet combination showed differential efficacy based on prior treatment status:
- In 30 G12C-inhibitor treatment-naïve patients, the overall response rate (ORR) was 40% (12/30) with a median progression-free survival (mPFS) of 11.1 months and median follow-up of 15.9 months
- In 21 previously G12C-inhibitor treated patients, the ORR was 9.5% (2/21) with an mPFS of 3.7 months and median follow-up of 10.8 months
The triplet combination showed preliminary promise in the limited patient cohort evaluated. Among six G12C-inhibitor treatment-naïve patients, four were evaluable for efficacy and achieved an ORR of 50% (2/4), with one confirmed and one unconfirmed response. Among 12 patients previously treated with a KRAS G12C (搜索) inhibitor, 11 were efficacy evaluable and four (36%) showed greater than 30% tumor reduction, with seven still ongoing as of the data cutoff.
Safety Profile
Across both doublet and triplet combinations, no dose-limiting toxicities were observed. Treatment-related adverse events were generally manageable, with the most common being nausea (56.8%), diarrhea (52.7%), and fatigue (45.9%).
Strategic Pivot to VS-7375
The company's strategic shift prioritizes VS-7375, which demonstrated a 69% response rate (11 of 16, both confirmed and unconfirmed) in advanced KRAS G12D NSCLC (搜索). Hayslip emphasized that this "potentially best-in-class oral KRAS G12D (搜索) (ON/OFF) inhibitor" has the potential to help more patients with its differentiated approach in multiple solid tumors.
Verastem will also continue the RAMP 205 clinical trial evaluating avutometinib plus defactinib in combination with chemotherapy in first-line metastatic pancreatic cancer (搜索). Patients currently enrolled in RAMP 203 will have the option to continue treatment per investigator discretion, though no further enrollment will occur.
Mechanism of Action
AVMAPKI (搜索) (avutometinib) inhibits MEK (搜索) kinase activity while blocking the compensatory reactivation of MEK by upstream RAF (搜索). RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway. Blocking RAF and/or MEK activates FAK (搜索), a key mediator of drug resistance. FAKZYNJA (搜索) (defactinib) is a FAK inhibitor, and together, the combination was designed to provide more complete blockade of signaling that drives growth and drug resistance of RAS/MAPK pathway-dependent tumors.
The FDA approved AVMAPKI (搜索) FAKZYNJA (搜索) CO-PACK for treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (搜索) who have received prior systemic therapy on May 8, 2025, under accelerated approval based on tumor response rate and duration of response.