RMC-5127 / Revolution Medicines - LARVOL DELTA

First disclosure of a highly potent and selective oral KRAS G12V inhibitor PSTA-6208 (AACR 2026) - "In head-to-head comparisons, PSTA-6208 was 17-fold more potent than RMC-5127. PSTA-6208 is a potent, highly selective, and orally bioavailable KRAS G12V inhibitor. Its compelling preclinical profile—including sub-nanomolar cellular potency, exceptional selectivity, favorable pharmacokinetics, and robust in vivo efficacy culminating in tumor regression at low doses—strongly supports its further development as a clinical candidate for KRAS G12V-driven cancers."

Oncology • KRAS

RCZY-698: An orally bioavailable, highly potent, and selective reversible KRASG12V (ON)-state inhibitor with robust antitumor activity in preclinical models of KRASG12V-driven solid tumors (AACR 2026) - "In a panel of KRASG12V-mutant tumor cell lines, RCZY-698 elicits potent antiproliferative effects, demonstrating superior in vitro growth inhibition compared with RMC-5127. Collectively, these data delineate the discovery and preclinical profiling of RCZY-698 as a novel oral non-covalent KRASG12V(ON)-selective tri-complex inhibitor with compelling in vitro potency and in vivo efficacy. Further efforts and characterization work are being implemented to complete the preclinical candidate (PCC) data package for RCZY-698."

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

RMC-5127, a RAS(ON) G12V-selective inhibitor, drives durable tumor regressions and increases T cell infiltration in KRAS G12V-driven syngeneic models (AACR-IO 2026) - "Oncogenic RAS signaling, drives tumorigenesis through MAPK and PI3K pathway activation and promotes immune evasion via tumor cell–intrinsic suppression of interferon signaling, modulation of immunosuppressive cytokines, and downregulation of MHC class I. We previously demonstrated that the RAS(ON) mutant-selective inhibitors elironrasib (RMC-6291) and zoldonrasib (RMC-9805) favorably remodel the tumor immune microenvironment (TME) and induce immune cell-dependent complete regressions in KRAS G12C and G12D models, respectively. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C019."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Early-Stage Programs: RMC-5127 (GlobeNewswire) - "The company recently advanced its fourth RAS(ON) inhibitor, the RAS(ON) G12V-selective inhibitor RMC-5127, into the clinic....The company expects to identify a recommended monotherapy Phase 2 dose for this compound in the second half of 2026."

Trial status • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Revolution Medicines Doses First Patient in Clinical Trial Evaluating RMC-5127, a RAS(ON) G12V-Selective Inhibitor (GlobeNewswire) - "The first-in-human trial, RMC-5127-001 [NCT07349537], is an open-label trial evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of RMC-5127 as both a monotherapy and in combination settings. The trial will enroll patients with RAS G12V–mutated solid tumors, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non–small cell lung cancer (NSCLC)..."

First-in-human • Trial status • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Study of RMC-5127 in Patients With Advanced KRAS G12V-Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=574 | Recruiting | Sponsor: Revolution Medicines, Inc.

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

Progress earlier stage pipeline… (GlobeNewswire) - "RMC-5127, a RAS(ON) G12V-selective inhibitor, is on track toward planned initiation of a Phase 1 trial in Q1 2026."

New P1 trial • Solid Tumor

Molecule Glue Profiling Unveils the Dynamics of KRAS-Induced Proximity (AACR-NCI-EORTC 2025) - "For example, RMC6236, a pan-KRAS molecular glue, was recently found to exhibit resistance to the KRAS G12C/Y64H mutation in testing; RMC-9805, a bifunctional 'molecular glue-covalent inhibitor,' enhances CYPA-KRAS G12D binding and stabilizes the ternary complex; and RMC5127, a non-covalent selective molecular glue targeting KRAS G12V, all inhibit the activity of KRAS or KRAS mutations by forming CYPA/MG/KRAS ternary complexes. It also including p-ERK panel and 2D/3D cell panel. Overall, we provide a comprehensive platform for the screening and evaluation of KRAS molecular glue, offering a scientific basis for the clinical application of KRAS molecular glue."

Oncology • KRAS

Targeting the oncogenic state of RAS with Tri-complex inhibitors (ACS-Fall 2025) - "We have generated multiple potent, orally bioavailable, covalent and noncovalent inhibitors including the investigational agents, daraxonrasib (RMC-6236) a RAS(ON) multi-selective inhibitor, elironrasib (RMC-6291) a RAS(ON) G12C-selective inhibitor, zoldonrasib (RMC-9805) a RAS(ON) G12D-selective inhibitor, and RMC-5127 a RAS (ON) G12V-selective inhibitor. Upon oral administration, they potently inhibit tumor DUSP6 expression and induce significant tumor regressions in relevant KRAS mutant human xenograft models in mice. Collectively these preclinical data support the ongoing clinical evaluation of investigational tri-complex RAS(ON) inhibitors and leveraging of this platform to advance next-generation RAS-targeted inhibitors."

Pancreatic Cancer • Solid Tumor • DUSP6 • KRAS

Revolution Medicines Reports Second Quarter 2025 Financial Results and Update on Corporate Progress (GlobeNewswire) - "The company expects to initiate one or more pivotal combination trials in 2026 that incorporate either zoldonrasib or elironrasib....Clinical development of RMC-5127, a RAS(ON) G12V-selective inhibitor, remains on track to reach a clinic-ready stage in 2025 to enable an expected Phase 1 initiation in 2026."

New trial • Solid Tumor

Discovery of RMC-5127, an oral, RAS (ON) G12V-selective, noncovalent, tri-complex inhibitor (AACR 2025) - "Across a panel of preclinical PDAC and NSCLC models harboring KRAS G12V, RMC-5127 monotherapy induced tumor regressions in the majority of models and was well-tolerated. In addition, dose-dependent exposure of RMC-5127 was observed in the whole brain of naïve mice, indicating the compound is brain penetrant, and RMC-5127 exhibited profound antitumor activity in relevant intracranial KRAS G12V mutant tumor xenograft models, with regressions observed at well-tolerated doses."

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

Revolution Medicines to Deliver Multiple Presentations at the 2025 American Association for Cancer Research (AACR) Annual Meeting (GlobeNewswire) - "Revolution Medicines...announced 11 oral and poster presentations will be featured at the American Association for Cancer Research (AACR) Annual Meeting....The first clinical data in non-small cell lung cancer from the Phase 1 study of zoldonrasib, a RAS(ON) G12D-selective inhibitor, will be featured in a late breaking oral presentation."

Clinical data • Late-breaking abstract • Preclinical • Cholangiocarcinoma • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Revolution Medicines Reports Fourth Quarter and Full Year 2024 Financial Results and Update on Corporate Progress (GlobeNewswire) - "Strategic Priorities and Markers of Progress:...(i) The company expects to share additional clinical safety and antitumor activity on zoldonrasib in the second quarter of 2025. The company currently expects to initiate one or more pivotal combination trials in 2026 that incorporate either elironrasib or zoldonrasib and expects to share clinical data supporting these plans in the second or third quarter of 2025; (ii) The company expects to advance RMC-5127, a RAS(ON) G12V-selective inhibitor, to a clinic-ready stage in 2025 to enable the expected initiation of a first-in-human dose escalation Phase 1 clinical trial in 2026."

Clinical data • New trial • Solid Tumor

RMC-5127, a first-in-class, orally bioavailable mutant-selective RASG12V(ON) inhibitor is central nervous system (CNS)-penetrant and demonstrates anti-tumor activity in a preclinical intracranial xenograft model (AACR 2024) - "The anti-tumor activity of RMC-5127 in intracranial tumors was consistent with that in subcutaneous tumors at equivalent tumor exposures. In conclusion, these preclinical data demonstrate that RMC-5127 is a CNS-penetrant RASG12V(ON) inhibitor and support further study to determine the potential to benefit patients with advanced RASG12V-mutated cancers, including those that have developed or are at risk of developing brain metastases."

Preclinical • Brain Cancer • CNS Tumor • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRAS • KRAS

Revolution Medicines to Deliver Multiple Presentations at the Upcoming American Association for Cancer Research Annual Meeting 2024 (GlobeNewswire) - "Revolution Medicines...announced the company will deliver multiple presentations at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2024 being held April 5-10, 2024, in San Diego, California."

Preclinical • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma