RMC-8839 / Revolution Medicines - LARVOL DELTA

Selective Inhibition of KRASG13C Reveals an Increased Dependence on Wild-Type RAS Isoforms in Codon 13 RAS-Mutant Cancers. (PubMed, Cancer Discov) - "Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13 mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, combination of RMC-8839 with a RAS(ON) multi-selective inhibitor resulted in deeper inhibition of KRAS G13C-mutant xenograft tumor growth than either inhibitor alone."

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

Targeting KRAS codon 13 mutations using direct combination approaches in non-small cell lung cancer. (PubMed, Cancer Discov) - "To determine combination partners that enhance RAS(ON) mutant-selective inhibition, a drug repurposing screen revealed that KRASG13C models are selectively vulnerable to chemotherapy. Combination of docetaxel with RMC-8839 demonstrated robust anti-proliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • KEAP1 • KRAS • NF1 • STK11

Targeting KRAS codon 13 mutations using combinations with RMC-8839, a novel RAS(ON) G13C-selective, tri-complex inhibitor, in non-small cell lung cancer (ESMO 2025) - "The combination of docetaxel with RMC-8839 demonstrates robust and synergistic anti-tumor activity in vitro and in vivo. Preclinical data demonstrating the potential to combine taxanes with inhibition of G13C RAS(ON) are immediately relevant to patient care and support clinical testing. Legal entity responsible for the study The University of Manchester."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • KEAP1 • KRAS • NF1 • STK11

Targeting KRAS codon 13 mutations using direct combination approaches in non-small cell lung cancer (EORTC-NCI-AACR 2024) - "KRAS G13C confers reduced oncopotency as compared to KRAS G12 mutations and is enhanced by pathogenic co-mutations in genes such as NF1. Preliminary preclinical combination data has identified approaches to address KRASG13X NSCLC, such as RMC-8839 plus docetaxel, that are supportive of potential future clinical evaluation."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • KEAP1 • KRAS • NF1 • STK11

Selective Inhibition of Active KRASG13C with RMC-8839 Reveals an Increased Dependence of Codon-13 KRAS-Mutant Cancers on Wild-Type RAS Isoforms (EORTC-NCI-AACR 2024) - "To pharmacologically inhibit wild-type RAS, RMC-8839 was combined with the RAS(ON) multi-selective inhibitor RMC-7977, resulting in deeper pathway suppression and inhibition of cell proliferation as compared with either single agent.With an anticipated increase in the number of therapeutic options for treatment of RAS-addicted cancers, an enhanced understanding of the underlying biology of different RAS mutations may help inform optimal therapeutic strategies. Our preclinical data highlight that codon-13 mutations make tumors more reliant on wild-type RAS signaling and demonstrate that this can be addressed through the combination of a mutant-selective and multi-selective RAS(ON) inhibitor."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • HRAS • KRAS • NF1 • NRAS

Targeting KRASG12C and beyond (ACS-Fall 2022) - "Our current development-stage portfolio includes four compounds: RMC-6236 (RASMULTI), RMC-6291 (KRASG12C), RMC-9805 (KRASG12D), and RMC-8839 (KRASG13C). These properties contribute to a favorable anti-tumor activity profile for RMC-6291, a KRASG12C(ON) inhibitor, compared to a first generation KRASG12C(OFF) inhibitor across a panel of preclinical NSCLC models. The RAS(ON) inhibitors are also designed to drive rational, mechanism-based combinations with approved drugs and investigational drug candidates, particularly in-pathway agents, to achieve optimal tumor suppression in diverse RAS-addicted cancers."

Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Revolution Medicines Reports Second Quarter 2022 Financial Results and Update on Corporate Progress (GlobeNewswire) - "RMC-8839 (KRASG13C)...For 2022 and 2023 the company currently intends to concentrate its development resources on its three most advanced RAS(ON) Inhibitors (RMC-6236, RMC-6291 and RMC-9805) and two RAS Companion Inhibitors that are in the clinic (RMC-4630 and RMC-5552) and therefore expects to determine the timing for announcement of initiating clinical evaluation of RMC-8839 at a future date....RAS Innovation Engine...The company is conducting multiple pipeline expansion programs focused on RAS mutation hotspots G12 (e.g., G12V and G12R), G13 (e.g., G13D) and Q61; The company expects to nominate a fifth RAS(ON) Inhibitor development candidate in the second half of 2022."

Pipeline update • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Revolution Medicines Announces Seven Oral Presentations at the Upcoming American Association for Cancer Research Annual Meeting 2022 (GlobeNewswire) - "Four of the company’s oral presentations will be featured in the conference mini-symposium session entitled 'Targeting the RAS Oncogene.' These presentations will describe recent research findings regarding Revolution Medicines’ broad pipeline of RAS(ON) Inhibitors currently in development, including RMC-6236 (RASMULTI), RMC-6291 (KRASG12C), RMC-9805 (KRASG12D) and RMC-8839 (KRASG13C)....Three additional oral presentations from Revolution Medicines will provide deeper insights into the tri-complex RAS(ON) inhibitor platform."

Preclinical • Oncology • Solid Tumor

Revolution Medicines Reports Fourth Quarter and Year-End 2021 Financial Results and Update on Corporate Progress (GlobeNewswire) - "The company remains on track to submit an IND for RMC-8839 in the second half of 2023; The company has a goal of nominating a fifth development candidate in the second half of 2022; RMC-4630 - The company expects to complete enrollment of this study in the second half of 2022 and to provide preliminary evidence of clinical benefit in 2022, with additional evidence of clinical benefit as a RAS Companion Inhibitor expected to be provided in 2023."

Enrollment status • IND • Oncology

Revolution Medicines Reports Progress Across Pipeline of Targeted Therapeutics for RAS-Addicted Cancers in Presentation at 40th Annual J.P. Morgan Healthcare Conference (GlobeNewswire) - "The company is on track to file investigational new drug (IND) applications in the first half of 2022 for its two most advanced RAS(ON) Inhibitors, RMC-6236 (RASMULTI) and RMC-6291 (KRASG12C), both of which have shown attractive preclinical profiles including strong anti-tumor activity....Evaluation in preclinical in vivo cancer models has demonstrated best-in-class potential for RMC-9805, and the company aims to file an IND application in the first half of 2023....This first-in-class development candidate...RMC-8839...has demonstrated strong anti-tumor responses in in vivo cancer models and the company aims to file an IND application in the second half of 2023."

IND • Oncology