LY3962673 / Eli Lilly - LARVOL DELTA

Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies. (PubMed, Future Med Chem) - "Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805...Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment."

IO biomarker • Journal • Review • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS

LY4050784, a selective inhibitor of SMARCA2, demonstrates synergistic activity in combinations with pembrolizumab or KRAS inhibitors (AACR 2025) - P1 | "LY4050784 demonstrated robust activity in vitro and in vivo when combined with standard lung cancer chemotherapies (paclitaxel, cisplatin, and pemetrexed)...Finally, we explored the activity of LY4050784 in combination with both mutant-selective KRAS G12C and G12D inhibitors (olomorasib and LY3962673, respectively) and the isoform-selective pan-KRAS inhibitor LY4066434...These results demonstrate that LY4050784 exhibits robust antitumor activity in combination with chemotherapy, pembrolizumab, and multiple KRAS inhibitors in preclinical models of SMARCA4-mutant cancers. Investigation of these combinations clinically is warranted"

IO biomarker • Colon Cancer • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • SMARCA2 • SMARCA4

Acquired resistance to Tri-complex inhibitors in colorectal cancer (AACR 2026) - "For patients with advanced solid tumors harboring a KRAS G12D mutation, several selective inhibitors have entered clinical trials (MRTX1133, RMC-9805, QTX3034/46, LY3962673...) and RMC-6236, a pan-RAS inhibitor from Revolution Medicines, has recently shown promising early clinical data. This resistance can still be addressed by other KRAS G12D inhibitors, opening options for patients harboring this characteristic post RMC-therapy. Future investigations may focus on characterizing tumors from patients who relapse on RMC-6236 and RMC-9805 to validate these findings clinically."

Preclinical • Colorectal Cancer • Oncology • Solid Tumor • KRAS

LY3962673, an oral, highly potent, mutant-selective, and non-covalent KRAS G12D inhibitor demonstrates robust anti-tumor activity in KRAS G12D models (AACR 2024) - "Furthermore, in multiple KRAS G12D-mutant PDX models representing diverse tumor types, LY3962673 demonstrated anti-tumor activities, ranging from tumor growth inhibition to robust tumor regression. LY3962673 also showed enhanced efficacy when combined with other anti-cancer agents.Taken together, the findings underscore the potential of LY3962673 as a monotherapy or in combination with other anti-cancer agents, as a promising oral therapeutic option for a range of cancer types with KRAS G12D mutations."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

MOONRAY-01, a phase 1 study of LY3962673, a potent, orally bioavailable, and selective KRAS G12D inhibitor in KRAS G12D-mutant solid tumors. (ASCO-GI 2025) - P1 | "The study is currently enrolling pts. *Cohorts randomized to various LY3962673 doses."

P1 data • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

A Study of LY3962673 in Participants With KRAS G12D-Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=530 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

A Study of LY3962673 in Participants With KRAS G12D-Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=530 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Lilly Announces Details of Presentations at 2024 American Association for Cancer Research (AACR) Annual Meeting (PRNewswire) - "Eli Lilly and Company...announced that preclinical data for agents targeting Nectin-4, KRAS G12D, and BRM (SMARCA2) will be presented at the American Association for Cancer Research (AACR) Annual Meeting....The presentations will include new preclinical data for a fully human monoclonal anti-Nectin-4 antibody conjugated to a novel topoisomerase I inhibitor and a highly potent and orally administered inhibitor of KRAS G12D that is selective against wild-type KRAS. In addition, preclinical data on a potent and selective BRM (SMARCA2) inhibitor for the treatment of BRG1 (SMARCA4) mutated cancers will be presented in collaboration with Foghorn Therapeutics. Investigational New Drug (INDs) applications are planned for all three programs in 2024."

IND • Preclinical • Solid Tumor

Loxo@Lilly Unveils Three New Oncology Programs at 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (PRNewswire) - "[email protected] that preclinical data for agents targeting KRAS G12D, multiple oncogenic KRAS mutations and Nectin-4, will be presented at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics...These programs are among the next slate of new oncology agents planned to enter clinical trials for Loxo@Lilly in 2024. The poster presentations will include preclinical characterization data for a highly potent inhibitor of KRAS G12D that is selective against wild-type KRAS, a highly potent and isoform-selective pan-KRAS inhibitor with activity against a broad spectrum of the most common activating KRAS mutations and high selectivity over wild-type HRAS and NRAS, and a fully human monoclonal anti-Nectin-4 antibody conjugated to a topoisomerase I (TOPO 1) inhibitor."

New trial • Preclinical • Oncology