Elisrasib (D3S-001) GDP-bound KRAS G12C inhibitor drives 62% ORR in mCRC with cetuximab—and 68% ORR as monotherapy in PDAC

Elisrasib (D3S-001) is an oral, next-generation KRAS G12C inhibitor engineered to bind the GDP-bound state and resist growth factor–driven nucleotide exchange; in KRAS G12C–mutant mCRC it was also combined with cetuximab (EGFR blockade) to blunt MAPK rebound. In this ongoing Phase 1/2 study (NCT05410145) in previously treated, G12Ci-naïve metastatic CRC and PDAC, elisrasib monotherapy delivered ORR 47.2% (17/36; 1 CR), mPFS 8.5mo and mDOR 13.1mo in evaluable mCRC; in PDAC, ORR was 68.2% (15/22) with mPFS 11.1mo (at 600mg: ORR 63.2% and mPFS 13.5mo). In mCRC combination (elisrasib 600mg + cetuximab), ORR was 62.1% (18/29; 1 CR) with mPFS 8.2mo; safety showed no G4/5 TRAEs across 101 treated patients, with G3 TRAEs in 17.0% (mCRC mono), 8.7% (PDAC mono), and 48.4% (mCRC combo)—largely cetuximab-related skin toxicity; by comparison, approved KRAS G12C mCRC regimens typically post ORR ~30–34% and mPFS ~5.6–6.9mo for KRAS/EGFR combinations (e.g., sotorasib+panitumumab; adagrasib+cetuximab), and KRAS G12C PDAC experience with first-gen inhibitors has been modest (e.g., sotorasib ORR ~21% in heavily pretreated cohorts).