The emergence of next-generation KRAS G12C inhibitors has led Verastem Oncology to change course.
The Boston biotech has decided to discontinue a phase 1/2 trial in advanced KRAS G12C-mutated non-small cell lung cancer (NSCLC) following an interim data analysis.
Explaining the move in a Dec. 29 statement, Verastem’s chief medical officer, John Hayslip, M.D., said newer G12C inhibitors are “establishing a new benchmark with higher response rates.”
The phase 1/2 Ramp 203 trial had been testing a two-drug combination of Verastem’s RAF/MEK inhibitor Avmapki (avutometinib) with Amgen’s KRAS G12C inhibitor Lumakras (sotorasib) and a triplet regimen that also included Verastem’s FAK inhibitor Fakzynja (defactinib). Patients had KRAS G12C NSCLC that was either experienced or new to a G12C drug.
As of a Nov. 26 data cutoff, 66 patients in Ramp 203 treated with the recommended phase 2 dose were evaluable for efficacy. For 30 G12C inhibitor-naïve patients, the doublet showed an overall response rate (ORR) of 40% and a median progression-free survival (PFS) of 11.1 months, according to Verastem. The ORR was 50% for four treatment-naïve patients who got the triplet.
For G12C-experienced patients, the doublet triggered an ORR of 9.5% and a median PFS of 3.7 months among four patients, while four patients (36%) who received the triplet saw a greater-than-30% tumor reduction—which typically meets the bar of a partial response—and a median PFS of 3.6 months.
Verastem reported no dose-limiting toxicities across the doublet and triplet combinations and “generally manageable” treatment-related adverse events.
As Verastem’s Hayslip noted, rival KRAS G12C inhibitors have shown better responses in NSCLC. Eli Lilly’s second-generation olomorasib recently logged a 73.9% ORR when combined with Merck’s Keytruda in first-line KRAS G12C NSCLC. Revolution Medicines’ elironrasib has also demonstrated a 42% ORR in G12C inhibitor-pretreated patients.
The Avmapki-Fakzynja duo was first approved by the FDA in May to treat KRAS-mutated recurrent low-grade serous ovarian cancer. Investor confidence in the program recently took a beating after Verastem disclosed in November that an independent data monitoring committee recommended that the ongoing phase 3 Ramp 301 confirmatory trial add another 29 patients. Although investors feared for the trial’s outcome, analysts suggested the expansion could increase the likelihood of statistical significance.
With the end of the G12C NSCLC program, Verastem said it will now focus its resources on clinical development of VS-7375, an oral KRAS G12D inhibitor, in NSCLC and other solid tumors. In his statement, Hayslip touted VS-7375 as a potentially best-in-class molecule that had shown a 69% response rate—including confirmed and unconfirmed responses—among 16 patients with KRAS G12D NSCLC.
Verastem officially in-licensed VS-7375 in early 2025 as part of a RAS-focused options deal with China’s GenFleet Therapeutics. While KRAS G12C is the most frequent variant of all KRAS mutations in NSCLC, KRAS G12D is the most prevalent KRAS mutation across all human cancers. The G12D mutation occurs most commonly in pancreatic (37%), colorectal (12.5%), endometrial (8%) and non-small cell lung (5%) cancers, according to Verastem.
VS-7375 is a KRAS (on/off) inhibitor as it targets the RAS protein in both its inactive GDP-bound form (off) and and an active GTP-bound form (on). The two marketed KRAS G12C inhibitors, Amgen’s Lumakras and Bristol Myers Squibb’s Krazati, target the “off” state.