MOONRAY-01, a phase 1 study of LY3962673, a potent, orally bioavailable, and selective KRAS G12D inhibitor in KRAS G12D -mutant solid tumors.

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TPS845 Background: KRAS G12D mutations occur in ~35%, 13%, and 4% of pancreatic, colorectal, and non-small cell lung cancers, respectively and less commonly in other cancers. Currently, there are no approved therapies for patients with KRAS G12D -mutant solid tumors. LY3962673 is a potent and orally bioavailable inhibitor of GDP-bound KRAS G12D that is highly selective for KRAS G12D against wild-type KRAS and other RAS mutations or amplifications. Preclinically, LY3962673 demonstrated robust anti-tumor activity in vivo as a single-agent and in combination with other agents in multiple KRAS G12D PDX models (Gong X, et al. Poster presented at AACR 2024). Methods: MOONRAY-01 is a global, open-label, multicenter, first-in-human phase 1 study of oral LY3962673 in participants (pts) with KRAS G12D -mutant solid tumors conducted in 2 phases: phase 1a dose escalation (Part A) to evaluate LY3962673 monotherapy and phase 1b dose expansion/randomized dose optimization (Parts B-E) to evaluate LY3962673 monotherapy and in combination with other anticancer therapies (Table). In phase 1a, additional pts will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. In phase 1b, each combination cohort will include a safety lead-in of 3-6 pts. Phase 1a/b escalation will utilize the mTPI-2 method. The DLT evaluation period will be 28 days. Eligible pts (≥18 years) must have locally advanced, unresectable, and/or metastatic cancer, measurable disease per RECIST v1.1, evidence of KRAS G12D mutation in tumors or ctDNA, and an ECOG PS of 0-1; asymptomatic CNS disease is allowed. In phase 1a, pts must have received ≥1 prior line of systemic chemotherapy for advanced or metastatic disease. In phase 1b, prior KRAS therapy is not allowed; other eligibility requirements are outlined in the Table. Key exclusion criteria include known active CNS metastases and/or carcinomatous meningitis, or significant cardiovascular disease. Key objectives are to determine the RP2D/optimal dose and assess the safety, tolerability, PK properties, and antitumor activity of LY3962673 per RECIST v1.1. The study is currently enrolling pts. Clinical trial information: NCT06586515 . Phase 1b Parts Key Eligibility Cohorts B: PDAC · B1: ≥1 prior systemic therapy· B2, B3, B4: treatment naïve allowed· B5: treatment naïve only · *B1: LY3962673· B2: LY3962673 + gemcitabine (G) + nab-paclitaxel (P)· *B3: LY3962673 + G + P· B4: LY3962673 + mFOLFIRINOX· *B5: LY3962673 + mFOLFIRINOX C: CRC · C1, C2: ≥1 prior systemic therapy· C3, C4, C5: treatment naïve allowed · C1: LY3962673 + cetuximab (C)· *C2: LY3962673 + C· C3: LY3962673 + C + FOLFOX· C4: LY3962673 + C + FOLFIRI· *C5: LY3962673 + C + FOLFIRI / FOLFOX D: NSCLC · ≥1 prior systemic therapy · *D1: LY3962673 E: Other solid tumors · ≥1 prior systemic therapy · E1: LY3962673 * Cohorts randomized to various LY3962673 doses.