Sotorasib

With the end of the G12C lung cancer program, Verastem Oncology said it will now focus its resources on clinical development of VS-7375, an oral KRAS G12D inhibitor. 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.

Verastem Oncology is ending an early-stage trial of its MEK inhibitor Avmapki in lung cancer and pivoting to another program that it says could have a greater impact on patients. The biotech said Monday it will discontinue the Phase 1/2 RAMP 203 study testing Avmapki, which has the generic name avutometinib, following a look at some interim data. The trial is assessing a doublet regimen of Avmapki with Amgen’s Lumakras and a triplet with Lumakras and Verastem’s FAK inhibitor Fakzynja (defactinib). The trial had been enrolling patients with advanced KRAS G12C-mutated non-small cell lung cancer. Avmapki acts on the MAPK pathway, which is overactivated in KRAS-mutated cancers. Verastem will now stop recruitment, but those already in the trial can continue treatment at the investigator’s discretion. The decision “reflects the evolving treatment landscape for KRAS G12C inhibitors,” Verastem said in a release. Lumakras and Bristol Myers Squibb’s Krazati are the only KRAS G12C inhibitors currently approved for NSCLC, but several investigational second-generation candidates targeting this oncogene are already showing potential for better efficacy. These include Roche’s divarasib, which achieved a 59% ORR in 44 patients enrolled in a Phase 1 trial — higher than the 36% ORR cited on Lumakras’ label . Divarasib is currently going head-to-head with Lumakras and Krazati in a Phase 3 study. In RAMP 203, Avmapki and Lumakras attained a 40% ORR in 30 patients who had not been treated with a KRAS G12C inhibitor before. The triplet of Avmapki, Lumakras and Fakzynja produced a 50% ORR in the same setting, although there were only four evaluable patients in that cohort. Verastem said it is “assessing opportunities” to share more data from the study. In May, the FDA approved a combination of Avmapki capsules and Fakzynja tablets, packaged together, for KRAS-mutated recurrent low-grade serous ovarian cancer. The treatment pulled $11.2 million in its first full quarter of launch. The Avmapki-Fakzynja combination is also in an open-label Phase 2 study in pancreatic cancer, on top of standard of care chemotherapy. Data could come next year. Instead of pursuing Avmapki in lung cancer, Verastem plans to advance a pill that targets a different KRAS mutation. VS-7375, which inhibits KRAS G12D, is being evaluated in a Phase 1/2a study in patients with solid tumors harboring this mutation, including NSCLC as well as pancreatic and colorectal cancers. The drug has demonstrated a 69% response rate in 16 NSCLC patients, Verastem said Monday. Several large drugmakers have recently inked deals focused on drugs targeting KRAS, including AstraZeneca and Bayer . In May 2024, Novartis ended development of a Phase 3 KRAS candidate, citing “increasing options” available for patients with KRAS G12C-mutated cancers.