RAMP 205 Data Update - Dose Level 1 in RAMP 205 demonstrated an 83% unconfirmed ORR (10/12 patients) and a 66.7% confirmed ORR (8/12 patients) in frontline metastatic PDAC[48] - Dose Level 1 also showed a 92% disease control rate (11/12 patients) for at least 4 cycles[48] - In RAMP 205, 92% (48/52) of patients showed tumor reduction across all dose cohorts[57] - Approximately 180,000 total incident PDAC patients globally represent a high unmet need, with a 5-year relative survival rate of 13.3%[20, 22] VS-7375 KRAS G12D Inhibitor - VS-7375 is a KRAS G12D (ON/OFF) inhibitor with IC50 values of 2 nM for GppNp-bound (ON/active) and 6 nM for GDP-bound (OFF/inactive) KRAS G12D[68] - Preclinical data indicates that VS-7375 is more efficacious than KRAS ON inhibitors in reducing tumor growth in KRAS G12D models[73] - In a KRAS G12D colorectal cancer model, the addition of Cetuximab with VS-7375 induced complete responses in all mice[78] - KRAS G12D mutations account for 26% of all KRAS mutations and are prevalent in pancreatic and colorectal cancers[84] Clinical Development Plans - The company plans to launch a Phase 3 study in 1L mPDAC in 2026[103, 113] - The company is initiating enrollment for the Phase 1/2a trial of VS-7375 in advanced solid tumors in the US, starting with an efficacious dose level of 400 mg QD[108, 113]

Core Insights - Erasca, Inc. presented new preclinical data at the AACR Annual Meeting, highlighting the best-in-class potential of its RAS-targeting compounds ERAS-0015 and ERAS-4001, which show robust anti-tumor activity as both monotherapy and in combination therapy [1][2] Group 1: ERAS-0015 - ERAS-0015 is a pan-RAS molecular glue that demonstrated favorable pharmacokinetic properties, including longer residence time and greater tissue exposure, leading to robust anti-tumor activity at lower doses compared to leading competitors [3][5] - The compound forms a ternary complex with active state RAS and cyclophilin A (CypA), effectively blocking downstream effector complex formation and showing potent inhibition of proliferation across diverse tumor tissues and RAS mutations [5] Group 2: ERAS-4001 - ERAS-4001 is a pan-KRAS inhibitor that selectively targets both mutant and wildtype KRAS, potentially offering an expanded therapeutic index and addressing resistance mechanisms associated with mutant-selective KRAS inhibitors [4][6] - The compound exhibited significant tumor growth inhibition and anti-tumor efficacy in KRAS mutant xenograft models, with single-digit nanomolar IC50s observed in various cell lines [6][10] Group 3: SHOC2 Modulators - The company identified direct SHOC2 binders that inhibit the assembly of the SHOC2-MRAS-PP1C complex, representing a novel approach to attenuate RAS/MAPK pathway signaling [7][10] - These compounds are the first examples of direct modulators of the SMP complex, with ongoing optimization for potential protein-protein inhibitors and degrader modalities [10] Group 4: Company Overview - Erasca is a clinical-stage precision oncology company focused on developing therapies for RAS/MAPK pathway-driven cancers, with a strong pipeline and collaboration with leading experts in the field [8]