Verastem (VSTM) Study update summary

Program Overview and Rationale

• VS-7375 is a highly selective, oral KRAS G12D on-off inhibitor designed for deep and durable pathway suppression in KRAS G12D-mutated cancers, aiming to avoid toxicities seen with pan-RAS inhibitors.

• The molecule demonstrates strong oral bioavailability, dose-dependent exposure, and a differentiated safety profile, supporting its use in combination regimens.

• The addressable U.S. market exceeds $2.5 billion, with high unmet need in pancreatic, colorectal, and lung cancers harboring KRAS G12D mutations; annual incidence is estimated at ~29K for pancreatic, ~22K for colorectal, and ~10K for lung cancer.

• VS-7375 is being advanced rapidly through phase I/II and registration-directed phase II trials, with pivotal phase III trials planned for 2027.

Clinical Activity and Efficacy

• Over 150 patients have been enrolled in the TARGET-D 101 phase I/II trial, with broad anti-tumor activity seen in pancreatic, colorectal, and lung cancers.

• At 900 mg, 93% of pancreatic cancer patients with elevated CA 19-9 achieved at least a 50% reduction, with several exceeding 90%, correlating with improved outcomes.

• Combination with cetuximab or anti-EGFR therapy in pancreatic and colorectal cancer cohorts has shown deeper and more rapid responses than monotherapy.

• Confirmed and unconfirmed partial responses, including complete resolution of target lesions and rapid symptom improvement, were observed even in heavily pretreated patients.

• In non-small cell lung cancer, single-agent VS-7375 at 600 mg led to confirmed partial responses and symptom improvement, with ongoing evaluation at 900 mg.

Safety and Tolerability

• VS-7375 is primarily associated with low-grade gastrointestinal adverse events (nausea, vomiting, diarrhea), which attenuate after the first cycle; no Grade 4 or 5 events attributed to the drug.

• No significant cytopenias, liver function abnormalities, or cumulative toxicities observed; GI side effects decrease by over 50% after cycle one.

• Most side effects resolved with standard supportive care, and nearly all responded to prophylactic treatment.

• Combination with cetuximab or anti-EGFR therapy does not exacerbate VS-7375 side effects; cetuximab-related rash is common but manageable.

• Grade 3 adverse events were rare and manageable; Grade 4 events were attributed to underlying disease, not VS-7375.