elironrasib (RMC-6291) / Revolution Medicines, BeOne Medicines - LARVOL DELTA

Safety and efficacy of elironrasib, a RAS(ON) G12C-selective inhibitor, in previously treated patients with KRAS G12C NSCLC (ESMO Asia 2025) - P1 | "Preliminary data for elironrasib plus pembrolizumab showed a favorable safety profile with minimal liver toxicity. KRAS G12C NSCLC pts who had prior chemo- and/or immunotherapy, but no prior G12Ci, received elironrasib 200 mg twice daily po (BID) (NCT05462717). Elironrasib 200 mg BID as monotherapy for KRAS G12C NSCLC showed a differentiated safety profile and compelling initial antitumor activity. Global development of elironrasib for pts with RAS G12C NSCLC is being actively pursued."

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

Multicenter study of the impact of trial eligibility criteria on enrollment to KRAS G12C inhibitor trials in patients with non-small cell lung cancer. (ASCO 2025) - " We extracted EC for Phase I-III trials of six KRAS G12C inhibitors (sotorasib, adagrasib, olomorasib, divarasib, JDQ443 and RMC-6291) that were published or made available by sponsors. Our data indicate substantial differences between the real-world population of patients treated with KRAS G12C inhibitors and those who were trial eligible. Efforts should focus on improving clinical trial generalizability without compromising safety."

Clinical • Lung Cancer • Nephrology • Non Small Cell Lung Cancer • Oncology • Renal Disease • Solid Tumor • KRAS

Efficacy and safety of Elironrasib, a RAS(ON) G12C-selective inhibitor, in patients with KRAS G12C NSCLC following treatment with a KRAS(OFF) G12C inhibitor (AACR-NCI-EORTC 2025) - P1 | "Elironrasib is the first RAS(ON) G12C-selective inhibitor in clinical development. At 200 mg BID, it has demonstrated compelling initial clinical activity and a differentiated safety profile in heavily pretreated NSCLC pts, nearly all of whom had progressed on a G12Ci. Elironrasib activity was observed in NSCLC pts harboring resistance mechanisms that increased oncogenic flux through KRAS(ON) G12C."

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

Mechanisms of resistance to the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236) in RAS mutant PDAC and potential resolution with RAS(ON) combination therapies (AACR 2025) - "We demonstrate that the combination of daraxonrasib with a mutant-selective RAS(ON) inhibitor (either the RAS(ON) G12C mutant selective inhibitor elironrasib (RMC-6291), or the RAS(ON) G12D mutant selective inhibitor zoldonrasib (RMC-9805)) drove combinatorial benefit and forestalled monotherapy resistance in a series of preclinical models. The RAS(ON) inhibitor doublets of elironrasib or zoldonrasib with daraxonrasib are currently being evaluated in patients with tumors harboring RAS G12C and RAS G12D, respectively."

Combination therapy • Late-breaking abstract • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • MYC

Discovery of RAS(ON) Tri-Complex Inhibitors (ACS-Fall 2026) - "These investigational targeted therapies, including daraxonrasib, zoldonrasib, elironrasib, and RMC-5127, are under clinical evaluation for the treatment of RAS-addicted cancers, an area of important unmet medical need. This brief vignette will focus on the medicinal chemistry journey that led to daraxonrasib."

KRAS G12C-Targeted Therapy in Non-Small Cell Lung Cancer: From Resistant Salvage to Potential First-Line Backbone. (PubMed, Int J Mol Sci) - "The discovery of a cryptic binding pocket accessible in the GDP-bound state enabled covalent inhibitors-sotorasib and adagrasib-that have received regulatory approval for previously treated KRAS G12C-mutant NSCLC, with sotorasib demonstrating PFS and OS superiority over docetaxel in CodeBreaK 200 and adagrasib showing meaningful intracranial activity and a progression-free survival benefit over docetaxel in KRYSTAL-12...Next-generation covalent inhibitors (divarasib, glecirasib, olomorasib), tri-complex RAS(ON) inhibitors (RMC-6291), pan-KRAS agents, and rationally designed combinations with EGFR, SHP2, SOS1, and PD-1 inhibitors are repositioning KRAS-directed therapy toward earlier lines of treatment. This review integrates the structural, signaling, and clinical biology of KRAS G12C with contemporary trial and real-world evidence to examine the emerging case for first-line KRAS G12C inhibition in genomically defined subsets of NSCLC. First-line use nonetheless remains..."

IO biomarker • Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KEAP1 • KRAS • STK11 • TP53

BeOne Medicines and Revolution Medicines Announce Clinical Development and Regional Commercialization Collaboration (Businesswire) - "Potential drug combinations for development as part of the clinical collaboration will include certain BeOne assets and Revolution Medicines’ four clinical RAS(ON) inhibitors: daraxonrasib, a RAS(ON) multi-selective inhibitor; zoldonrasib, a RAS(ON) G12D-selective inhibitor; elironrasib, a RAS(ON) G12C-selective inhibitor; and RMC-5127, a RAS(ON) G12V-selective inhibitor. Planned combination studies include: BeOne’s MTA-cooperative PRMT5 inhibitor, BGB-58067, and an EGFR x MET x MET trispecific antibody, BG-T187, with either daraxonrasib or zoldonrasib....Under the regional rights agreement, Revolution Medicines has granted BeOne exclusive rights in select Asian markets to develop and commercialize or solely commercialize, depending on the market, these four clinical-stage RAS(ON) inhibitors."

Licensing / partnership • Solid Tumor

Elironrasib + daraxonrasib: “Elironrasib + Daraxonrasib: Generally well tolerated in 2L+ NSCLC patients previously treated with G12C(OFF) Inhibitor”; Non-small cell lung cancer (Revolution Medicines) - Corporate Presentation

P1/2 data • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Elironrasib + daraxonrasib: “Elironrasib + Daraxonrasib: “Doublet shows encouraging antitumor activity in patients with CRC previously treated with KRAS(OFF) G12C inhibitor”; Colorectal cancer (Revolution Medicines) - Corporate Presentation

P1/2 data • Colorectal Cancer • Oncology • Solid Tumor

Elironrasib: “Elironrasib + pembrolizumab + chemotherapy encouraging anti tumor activity”; Non-small cell lung cancer (Revolution Medicines) - Q2 2026 Results

P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Today the company is reporting clinical data evaluating elironrasib in combination with standard of care pembrolizumab and platinum doublet chemotherapy in patients with first-line RAS G12C NSCLC. (GlobeNewswire) - "As of a data cutoff of May 11, 2026, the analysis included 39 patients who had at least 14 weeks of follow-up. PD-L1 TPS was <1% in 10% of patients, 1–49% in 67% of patients, and ≥50% in 23% of patients. With a median follow-up of 8.7 months, the elironrasib plus standard of care combination demonstrated encouraging preliminary antitumor activity, including a confirmed ORR of 85% and DCR of 97%. Confirmed ORRs ranged from 50% to 100% across PD-L1 TPS subgroups (<1% to ≥50%)....These findings support the planned global Phase 3 RASolve 307 study evaluating elironrasib in combination with standard of care for patients with first-line metastatic RAS G12C NSCLC, which the company expects to initiate in the fourth quarter of 2026."

New P3 trial • P1/2 data • Non Small Cell Lung Cancer

Evolution of KRAS molecular glues: from allele-selective to Pan-RAS and protein-protein interaction modulators. (PubMed, Acta Pharmacol Sin) - "Molecular glues, such as the RMC macrocyclic series (e.g., RMC-6291 as a G12C-selective MG, RMC-6236 as a pan-MG), function by recruiting endogenous chaperone proteins to form ternary complexes that sterically block KRAS-effector interactions or allosterically restore GTPase activity...Complementarily, PPI inhibitors (e.g., BBO-10203, VVD-699) disrupt critical oncogenic interfaces between KRAS and PI3Kα, offering a strategy to inhibit oncogenic signaling with fewer side effects. Collectively, balancing broad-spectrum versus selective targeting of KRAS, attaining optimal drug-like properties and establishing rational combination therapies with other modalities remain key challenges. The ongoing evolution of MGs and PPI modulators heralds a major expansion of the therapeutic frontier for KRAS-driven cancers and is redrawing the boundaries of precision oncology."

Journal • Review • Oncology • Targeted Protein Degradation • KRAS • LZTR1 • NEDD4 • PIK3CA

Combination RASG12C(ON) and RASMULTI(ON) inhibition overcomes resistance and prolongs durability in preclinical models of mutant KRASG12C-driven cancers (AACR 2024) - "Inhibitors of the GDP-bound state of mutant KRASG12C protein (KRASG12C(OFF)), e.g., adagrasib and sotorasib, have shown clinical activity in patients with KRASG12C-driven NSCLC, CRC and PDAC. The addition of RMC-6236 to RMC-6291 shows combinatorial activity in preclinical models that are relatively less responsive to either inhibitor alone. A clinical trial combining RMC-6291 with RMC-6236 in patients with mutant KRASG12C tumors is currently enrolling."

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

Combination of RAS(ON) mutant-selective and multi-selective inhibitors sensitizes immune-refractory, RAS-driven preclinical models to immunotherapy (AACR 2025) - "Here we evaluated if the RAS(ON) doublet combination of RMC-6291 or RMC-9805, a RAS(ON) G12C-selective inhibitor and a RAS(ON) G12D-selective inhibitor, respectively, with the RAS(ON) multi-selective inhibitor RMC-6236 can sensitize traditionally hard to treat, immune-refractory preclinical models to anti-PD-1. Collectively, these preclinical findings suggest that the RAS(ON) doublet combination of RAS(ON) mutant-selective and multi-selective inhibitors can reverse the immune-evasion mechanisms governed by oncogenic RAS and sensitize immune-refractory tumors to ICB to induce durable CRs. These preclinical data support the clinical evaluation of the RAS(ON) doublets in combination with ICB in patients with RAS driven cancers."

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

Evaluation of combination strategies with RAS-targeted inhibitors in multi-cell type spheroids (AACR 2025) - "As single agents, the KRAS-G12C inhibitors RMC-6291 and divarasib, along with the KRAS-G12D inhibitor MRTX-1133, demonstrated selective activity against the mct tumor spheroids harboring the targeted variants. In contrast, the pan-RAS(ON) inhibitor RMC-6236 demonstrated activity against the mct tumor spheroids harboring a range of KRAS variants or wild-type KRAS...In tumor models harboring different KRAS variants, the pan-RAS(ON) inhibitor showed increased cytotoxicity with the MEK inhibitor cobimetinib, as well as PI3K-AKT-mTOR pathway inhibitors, such as inavolisib (PI3Kα), ipatasertib (AKT), and sapanisertib (mTORC1/2). When the same agents were combined with variant-specific KRAS inhibitors similar effects were observed in mct tumor spheroids carrying the corresponding RAS variant. These preclinical findings might provide guidance for the selection of combination regimens with KRAS inhibitors to improve clinical efficacy."

Oncology • Solid Tumor • KRAS • PIK3CA

RMC-6291-001: Dose Escalation and Dose Expansion Study of RMC-6291 Monotherapy in Subjects With Advanced KRASG12C Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=222 | Active, not recruiting | Sponsor: Revolution Medicines, Inc. | Trial completion date: Dec 2025 ➔ Sep 2027 | Trial primary completion date: Nov 2024 ➔ Mar 2027

Monotherapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

A cellular platform for systematic comparison of RAS inhibitors using PRISM multiplexed screening (AACR 2025) - "For example, all 10 KRAS G12C inhibitors or degraders tested showed significant selectivity for cell lines harboring the G12C mutation, with RMC-6291, adagrasib, divarasib, and sotorasib showing the greatest enrichment. Finally, we also explored orthogonal assay formats, including ultra-low adherent and extended-duration (10-day) screening, to investigate kinetic and environmental factors associated with inhibitor response. Collectively, our work provides a comprehensive profile of the cellular effects of current RAS-targeting therapeutics, and provides a foundation for the characterization of newly-emerging agents."

Oncology • 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

Clinical Collaborations (GlobeNewswire) - "Under a collaboration with Summit Therapeutics, Inc., the APEX-103 trial is evaluating Revolution Medicines’ RAS(ON) inhibitors with ivonescimab, Summit’s PD-1/VEGF bispecific antibody, across multiple solid tumor settings. The first patient was recently dosed in this clinical trial....The company also recently entered into a clinical collaboration with Bristol Myers Squibb to evaluate daraxonrasib in combination with navlimetostat, Bristol Myers Squibb’s MTA-cooperative PRMT5 inhibitor, in patients with pancreatic cancer whose tumors carry both a RAS mutation and MTAP deletion."

Licensing / partnership • Trial status • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer

Elironrasib in NSCLC (GlobeNewswire) - "Elironrasib has demonstrated encouraging results as monotherapy and in combination with either pembrolizumab or as part of a RAS(ON) inhibitor doublet with daraxonrasib. The company plans to share an update on its registrational vision for elironrasib in 2026."

Clinical • Non Small Cell Lung Cancer

Study of RAS(ON) Inhibitors in Combination With Ivonescimab in Patients With Solid Tumors (clinicaltrials.gov) - P1/2 | N=370 | Recruiting | Sponsor: Revolution Medicines, Inc.

New P1/2 trial • Colorectal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • NRAS

RMC-6291-101: Study of Elironrasib and Daraxonrasib as Monotherapies and Combination Therapy in Participants With Advanced KRAS G12C Mutant Solid Tumors (clinicaltrials.gov) - P1/2 | N=534 | Recruiting | Sponsor: Revolution Medicines, Inc. | Phase classification: P1 ➔ P1/2 | N=210 ➔ 534 | Trial completion date: Nov 2026 ➔ Jun 2029 | Trial primary completion date: Nov 2026 ➔ Dec 2028

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-refractory KRAS G12C-mutant NSCLC for Immune Checkpoint Blockade. (PubMed, Cancer Discov) - "To address RAS pathway hyperactivation and targeted therapy resistance in KRAS G12C-mutant NSCLC, we evaluated the potential of the RAS(ON) G12C-selective covalent inhibitor elironrasib and the RAS(ON) multi-selective inhibitor daraxonrasib combination to maximize RAS pathway suppression and forestall pathway reactivation in a series of preclinical models...Additionally, in immune-competent preclinical models, the RAS(ON) inhibitor doublet enhances tumor immune recognition by boosting antigen presentation and remodeling the suppressive tumor microenvironment, thus promoting immune-dependent complete regressions and sensitization of an immuno-refractory model to checkpoint blockade. Collectively these findings provide a preclinical rationale for the evaluation of a targeted RAS(ON) inhibitor doublet therapy regimen in combination with immune checkpoint blockade in patients with KRAS G12C-mutant NSCLC."

Checkpoint inhibition • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Activity of direct KRAS(G12C) inhibitors in preclinical models of pediatric cancer. (PubMed, Mol Cancer Ther) - "Here, we show that sotorasib, adagrasib, and the RAS-ON inhibitor RMC-6291 are effective in a neuroblastoma cell line altered by KRAS(G12C). Importantly, sotorasib also decreased ERK phosphorylation in a NRAS(G12C)-altered cell line xenograft model; however, this treatment did not prolong survival as a single agent. These results suggest that combinations of targeted agents that include sotorasib may be required for clinical benefit in pediatric patients with H- or NRAS(G12C)-altered malignancies in addition to those with KRAS(G12C)-altered malignancies."

Journal • Preclinical • Colorectal Adenocarcinoma • Colorectal Cancer • Hematological Malignancies • Leukemia • Neuroblastoma • Oncology • Pancreatic Cancer • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • KRAS • NRAS

…The company believes this G12D-selective inhibitor has the potential to contribute as a key component of combination regimens in first line PDAC with current standard of care chemotherapy and/or with daraxonrasib as a RAS(ON) inhibitor doublet (GlobeNewswire) - "The company expects to initiate a registrational trial for a zoldonrasib combination in patients with first line metastatic PDAC in the first half of 2026 and one or more additional pivotal combination trials in 2026 that incorporate either zoldonrasib or elironrasib."

New trial • Pancreatic Ductal Adenocarcinoma