elironrasib (RMC-6291) / Revolution 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

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

RAS(ON) inhibitors induce immunogenic cell death, promote antitumor immunity, and synergize with anti-PD-1 immunotherapy in a RAS Mutant NSCLC model (SITC 2025) - P1/2 | "Collectively, our preclinical findings demonstrate that both RAS(ON) mutant-selective and RAS(ON) multi-selective inhibitors can induce ICD and their antitumor activity is enhanced by combination with T cell-directed immunotherapies. The clinical evaluation of daraxonrasib and elironrasib in combination with pembrolizumab is ongoing in RAS mutant advanced NSCLC (NCT06162221)."

Immunogenic cell death • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CALR

In June 2025, we announced a clinical collaboration with Revolution Medicines to evaluate ivonescimab in combination with three RAS(ON) inhibitors, including the multi-selective inhibitor daraxonrasib (RMC6236), G12D-selective inhibitor zoldonrasib (RMC-9805), and G12C-selective inhibitor elironrasib (RMC6291), in solid tumor settings with RAS mutations. (Summit Therapeutics) - "We expect that clinical trials associated with this collaboration will begin in early 2026."

New trial • Solid Tumor

RAS(ON) inhibitor in-pathway combinations maximize RAS pathway suppression, and drive deep and durable antitumor activity in KRAS mutant CRC models (AACR-NCI-EORTC 2025) - "This includes daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor that noncovalently inhibits the GTP-bound state of mutant and wild-type variants of the canonical RAS isoforms (KRAS, NRAS, and HRAS) and the mutant-selective inhibitors elironrasib (RMC-6291) and zoldonrasib (RMC-9805) that covalently engage RAS(ON) G12C and RAS(ON) G12D, respectively...Here we demonstrate that the addition of RAS(ON) multi-selective inhibitors, or the anti-EGFR antibody cetuximab, to RAS(ON) mutant-selective inhibitors leads to sustained RAS/MAPK pathway suppression in KRAS mutant CRC tumors with a corresponding increase in the objective response rates and durability of response in preclinical models compared to monotherapies...This favorable transformation of the TME translated into a combinatorial benefit with anti-PD-1, resulting in durable complete regressions in all animals (10/10) in comparison to 2/10 for the RAS(ON) doublet alone. Together, these preclinical findings of..."

IO biomarker • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • NRAS

Revolution Medicines to Present Updated Elironrasib Safety and Efficacy Data in Patients with KRAS G12C Non-Small Cell Lung Cancer… (GlobeNewswire) - "These results will be highlighted in an oral presentation at the AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics....Elironrasib demonstrated compelling antitumor activity, with a confirmed objective response rate of 42% (95% CI: 22-63) and a disease control rate of 79% (95% CI: 58-93). The median duration of response was 11.2 months (95% CI: 5.9-not estimable), and the median progression-free survival was 6.2 months (95% CI: 4.0-10.3). The median overall survival (OS) was not yet reached and 12-month OS rate was 62% (95% CI: 40-78)."

P1 data • Non Small Cell Lung Cancer

RAS-GTP Inhibition Overcomes Acquired Resistance to KRASG12C Inhibitors Mediated by Oncogenic and Wildtype RAS Activation in Non-Small Cell Lung Cancer. (PubMed, Cancer Res) - "Recently, RAS(ON) G12C-selective inhibitors, which bind to the active GTP-bound state of RAS, were described, and elironrasib is undergoing evaluation in multiple clinical trials...Two models reactivated RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and were vulnerable to dual inhibition by RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitors, RMC-4998 and RMC-7977...Finally, one model displayed epithelial-mesenchymal transition, loss of RAS dependance, and acquired reliance on cell cycle kinases and proteins associated with DNA damage response. This work highlights KRASG12C-selective inhibitor resistant states that parallel and complement clinical findings and demonstrate that a large subset could be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in combination with other therapies."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • 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 • Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • 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

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

Revolution Medicines Announces FDA Breakthrough Therapy Designation for Elironrasib (Yahoo Finance) - "Revolution Medicines, Inc...announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to elironrasib, the company’s RAS(ON) G12C-selective inhibitor, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received prior chemotherapy and immunotherapy but have not been previously treated with a KRAS G12C inhibitor. The Breakthrough Therapy Designation is based on data from the Phase 1 RMC-6291-001 clinical trial evaluating elironrasib monotherapy in patients with advanced KRAS G12C solid tumors."

Breakthrough therapy • Evidence highlight • Non Small Cell Lung Cancer • KRAS

Revolution Medicines and Summit Therapeutics Enter into Clinical Collaboration to Evaluate Combinations of Three RAS(ON) Inhibitors with Ivonescimab in RAS Mutant Tumors (GlobeNewswire) - "Revolution Medicines...and Summit Therapeutics...announced the companies have entered into a clinical collaboration in multiple solid tumor settings to evaluate the safety and efficacy of each of Revolution Medicines’ clinical-stage RAS(ON) inhibitors, including the multi-selective inhibitor daraxonrasib (RMC-6236), G12D-selective inhibitor zoldonrasib (RMC-9805) and G12C-selective inhibitor elironrasib (RMC-6291), in combination with Summit Therapeutics’ ivonescimab, a PD-1 / VEGF bispecific antibody....The clinical collaboration aims to evaluate these combinations across three priority tumor types including RAS mutant...NSCLC, pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). Under the terms of the agreement, Summit Therapeutics will supply ivonescimab for clinical research and Revolution Medicines will be the study sponsor. Each company will retain commercial rights to their respective compounds, and the agreement is mutually non-exclusive."

Licensing / partnership • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

RAS(ON) G12C-selective and multi-selective doublet combination overcomes clinical resistance mechanisms to KRAS G12C(OFF) inhibitors and sensitizes to immune checkpoint blockade in preclinical models (EACR 2025) - "Elironrasib (RMC-6291), a RAS(ON) G12C mutant-selective, covalent inhibitor and daraxonrasib (RMC-6236), a RAS(ON) multi-selective, noncovalent inhibitor have shown profound antitumor activity as monotherapies in preclinical models and, more recently, showed promising clinical activity in patients with RAS-driven tumors at doses that were well tolerated.Material and Here we tested the RAS(ON) doublet combination of elironrasib with daraxonrasib in a panel of KRAS G12C NSCLC xenograft models, including those harboring alterations associated with clinical resistance to KRAS G12C(OFF) inhibitors such as increased RTK signaling, KEAP1 co-mutations and KRAS amplification. These preclinical findings suggest that the RAS(ON) doublet combination can improve the depth and durability of response compared to the respective monotherapies and overcome mechanisms of clinical resistance to KRAS G12C(OFF) inhibitors. Furthermore, in an immune-refractory model the RAS(ON) doublet..."

Checkpoint block • Checkpoint inhibition • IO biomarker • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KEAP1 • 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

Elironrasib with pembrolizumab in 1L RAS G12C mutant NSCLC (GlobeNewswire) - P1/2 | N=484 | NCT06162221 | Sponsor: Revolution Medicines, Inc. |"Today, the company shared data for eight patients with 1L KRAS G12C NSCLC from the combination of elironrasib with pembrolizumab, which showed acceptable tolerability and encouraging preliminary antitumor activity. As of a February 10, 2025 data cutoff, Grade 3 or higher TRAEs were reported in 25% of patients, and no new safety signals were observed. The MDI was favorable at 85%. Among five efficacy-evaluable patients with 1L NSCLC with a TPS score of greater than or equal to 50% (where pembrolizumab monotherapy is the preferred standard of care), the ORR and DCR were both 100%."

P1/2 data • Non Small Cell Lung Cancer

RAS(ON) inhibitor doublet of elironrasib with daraxonrasib in NSCLC (GlobeNewswire) - P1b | N=210 | NCT06128551 | Sponsor: Revolution Medicines, Inc. | "As of a February 10, 2025 data cutoff, in 33 patients treated with elironrasib at 200 mg BID and daraxonrasib at doses ranging from 100 mg to 200 mg daily, Grade 3 TRAEs were reported in 46% of patients. There were no Grade 4 or 5 TRAEs. Hepatotoxicity was not observed as a safety signal (no Grade 3 or higher events) and QT prolongation was limited with one asymptomatic Grade 3 event (3%). The MDIs were favorable at 95% for elironrasib and 85% for daraxonrasib. The combination of elironrasib with daraxonrasib showed encouraging preliminary antitumor activity in patients with NSCLC who have been previously treated with a KRAS G12C(OFF) inhibitor. The ORR was 62% and the DCR was 92%."

P1 data • Non Small Cell Lung Cancer

Elironrasib monotherapy in previously treated G12C NSCLC patients (GlobeNewswire) - P1/1b | N=222 | NCT05462717 | Sponsor: Revolution Medicines, Inc. | "Today, the company shared data for 36 patients who were treated with elironrasib monotherapy at the candidate monotherapy recommended dose of 200 mg twice daily (BID) as of an April 7, 2025 data cutoff. Elironrasib was generally well tolerated with predominantly low-grade TRAEs. Grade 3 TRAEs were reported in 19% of patients and there were no Grade 4 or 5 TRAEs. The MDI was favorable at 94%. At the 200 mg BID dose, the ORR in NSCLC patients was 56%, and the DCR was 94%. The estimated median progression-free survival (PFS) in these patients was 9.9 months."

P1 data • Non Small Cell Lung Cancer

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

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

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) - "Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is driven by oncogenic RAS mutations in >90% of cases. 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

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

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

Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers. (PubMed, J Med Chem) - P1, P1/2 | "Here we report structure-guided medicinal chemistry efforts that led to the discovery of elironrasib, a potent, orally bioavailable, RAS(ON) G12C-selective, covalent, tri-complex inhibitor. The investigational agent elironrasib is currently undergoing phase 1 clinical trials (NCT05462717, NCT06128551, NCT06162221), with preliminary data indicating clinical activity in patients who had progressed on first-generation inactive state-selective KRASG12C inhibitors."

Journal • Oncology • KRAS