Verastem Oncology (NASDAQ: VSTM) announced a strategic pivot in its clinical development program for advanced non-small cell lung cancer (NSCLC) on Monday, unveiling plans to terminate enrollment in its RAMP 203 trial. This Phase 1/2 study centered on treating patients with KRAS G12C mutations, a specific oncogenic driver in NSCLC. The decision comes after an interim data assessment highlighted heightened competition and the need to meet rising efficacy benchmarks in this therapeutic niche.
Under the revised strategy, Verastem will cease enrollment in RAMP 203, with patients already participating allowed to continue on treatment at the discretion of their investigators. This adjustment reflects an evolving landscape in KRAS G12C-targeted therapies, where next-generation inhibitors have delivered improved response rates, raising the bar for emerging candidates.
RAMP 203 was a collaborative effort with Amgen Inc. (NASDAQ: AMGN), designed to evaluate combinations of Verastem's avocatometinib with Amgen's Lumakras (sotorasib), a first-in-class KRAS G12C inhibitor. Specifically, the trial explored doublet regimens pairing avocatometinib with Lumakras as well as triplet regimens adding defactinib, assessing tolerability and therapeutic benefit in patients harboring advanced KRAS G12C-mutated NSCLC.
Rather than continuing RAMP 203, Verastem is opting to redirect resources toward advancing VS-7375, its oral KRAS G12D (ON/OFF) inhibitor. This agent has exhibited compelling activity, including a reported 69% response rate among patients with advanced KRAS G12D-mutated NSCLC, encompassing both confirmed and unconfirmed responses across 16 evaluable patients. The company sees VS-7375 as having greater strategic promise in this setting.
Further development plans include continued progress on RAMP 205, a trial assessing a combination of avocatometinib and defactinib alongside chemotherapy in patients with first-line metastatic pancreatic cancer.
The decision to halt RAMP 203 enrollment underscores intensifying competition in the KRAS inhibitor space. In May 2025, Merck & Co. Inc. (NYSE: MRK) released results from its Phase 1 KANDLELIT-001 study of MK-1084, a KRAS G12C covalent inhibitor designed for monotherapy and combination use in advanced colorectal cancer (CRC) and NSCLC with this mutation. The agent demonstrated a manageable safety profile along with antitumor effects.
Additionally, in September 2025, the US Food and Drug Administration granted Breakthrough Therapy designation to Eli Lilly and Co.'s (NYSE: LLY) olomorasib. This second-generation KRAS G12C inhibitor, combined with Merck's checkpoint inhibitor Keytruda (pembrolizumab), targets first-line treatment for unresectable advanced or metastatic NSCLC patients with KRAS G12C mutations and high PD-L1 expression (≥ 50%). Olomorasib notably also shows preliminary activity in the central nervous system.
These developments reflect a highly dynamic marketplace for KRAS-directed therapies where Verastem's prior RAMP 203 approach, although innovative, faces challenges in establishing a differentiated clinical benefit.
Stock market reaction to Verastem's announcement was negative, with shares falling approximately 4.34% to $7.75 as of Friday's trading session, based on Benzinga Pro data. This decline likely reflects investor uncertainty regarding the competitive position of Verastem's pipeline and the impact of halting a late-stage lung cancer trial.
Strategic Implications
Verastem's move to emphasize VS-7375 indicates a focused approach toward the KRAS G12D subset, an area with potentially less crowded competition compared to KRAS G12C. The reported response rate of 69% in a small cohort is a promising signal, suggesting that VS-7375 may provide meaningful clinical benefit if results are confirmed in larger studies.
Simultaneously, the continued investigation of RAMP 205 in metastatic pancreatic cancer, combining avocatometinib and defactinib with chemotherapy, suggests that Verastem remains committed to leveraging its core assets in difficult-to-treat cancers beyond lung malignancies.
Key Points
- Enrollment for the RAMP 203 Phase 1/2 trial in KRAS G12C-mutated NSCLC is discontinued following interim data review.
- Verastem will prioritize development of VS-7375, an oral KRAS G12D inhibitor with a reported 69% response rate in advanced NSCLC.
- RAMP 203 involved combination regimens with Amgen’s Lumakras and defactinib but faces intensified competition from newer KRAS G12C inhibitors.
- Ongoing clinical focus includes RAMP 205 trial for metastatic pancreatic cancer using avocatometinib and defactinib with chemotherapy.
Risks and Uncertainties
- The competitive environment for KRAS G12C inhibitors is robust, with several advanced-stage programs potentially surpassing RAMP 203's efficacy benchmarks.
- Changes in clinical trial priorities introduce execution risks, including potential delays or unmet expectations with VS-7375’s further development.
- Market sentiment may remain volatile given RAMP 203's enrollment halt and ongoing competitive pressure from major pharmaceutical companies' agents.
- Limited data on VS-7375 and its translation to broader patient populations introduce uncertainty regarding its ultimate clinical and commercial success.