zoldonrasib (RMC-9805) / Revolution Medicines - LARVOL DELTA

Study to Evaluate the Safety, Tolerability & Efficacy of TNG462 in Combination in PDAC & NSCLC Patients (clinicaltrials.gov) - P1/2 | N=183 | Recruiting | Sponsor: Tango Therapeutics, Inc. | N=133 ➔ 183

Enrollment change • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

Tango Therapeutics…Provides Business Highlights (GlobeNewswire) - "Upcoming Milestones: (i) Combination trial with vopimetostat + daraxonrasib, and vopimetostat + zoldonrasib (Revolution Medicines), phase 1/2 initial safety and efficacy data 2026; (ii) Vopimetostat monotherapy Phase 1/2 clinical data lung cancer update in 2026; (iii) Vopimetostat monotherapy 2L pancreatic cancer pivotal study start 2026; (iv) TNG456 monotherapy phase 1/2 trial initial safety and efficacy data 2026."

New trial • P1/2 data • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

…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

…At the Triple Meeting the company presented encouraging preclinical data supporting the RAS(ON) inhibitor doublet of zoldonrasib, the company’s G12D-selective inhibitor, and daraxonrasib in models of KRAS G12D PDAC, furthering the rationale for this RAS(ON) inhibitor doublet as a therapeutic strategy (GlobeNewswire)

Preclinical • Pancreatic Ductal Adenocarcinoma

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

VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with superior anti-tumor efficacy relative to ON-only KRAS inhibitors (AACR-NCI-EORTC 2025) - P1/2 | "In 3D proliferation assays among a panel of human tumor cell lines, VS-7375 showed improved KRAS G12D potency and selectivity relative to the G12Di RMC-9805 and MRTX1133...To assess potential benefits of dual ON/OFF inhibition in KRAS G12D in vivo models, we compared efficacy relative to the ON-only inhibitors RMC-9805 (G12Di) and RMC-6236 (pan-RAS inhibitor)...Combination of VS-7375 with the anti-EGFR antibody cetuximab induced complete responses in all mice in a colorectal cancer xenograft model, and cetuximab also augmented the antitumor efficacy of VS-7375 in pancreatic and lung cancer models...VS-7375 is now being evaluated as monotherapy and in combinations in the US (NCT07020221). Altogether, these results demonstrate that the dual ON/OFF profile of VS-7375 corresponds with strong preclinical anti-tumor efficacy in KRAS G12D mutant cell lines and animal models, along with promising initial response rates for patients with KRAS G12D mutant solid tumors."

Clinical • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

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

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

Dual targeting of BET and EP300 with XP-524 in pancreatic cancer lines resistant to KRAS inhibitors (AACR-NCI-EORTC 2025) - " We treated PDAC cell lines, Panc1 and AsPC1, with KRAS-G12D inhibitor (MRTX1133), selecting surviving cells after each passage...The concentration-response of both parent and resistant cell cultures was assayed after treatment with XP-524, pan-KRAS inhibitor (BI-2865), RAS-ON inhibitor (RMC-6236), or KRAS G12D inhibitor (RMC-9805), measuring antiproliferative potency and both mRNA and protein expression... Panc1-MR cells were resistant to all evaluated KRAS inhibitors in clinical development, showing no response to KRAS inhibitors below 1 µM concentration. Small right shifts in concentration-response were seen for all inhibitors in AsPC1-MR cells. XP-524 retained efficacy as an antiproliferative agent in kinase-resistant PDAC cells, with a small right-shift in antiproliferative potency in Panc1-MR cell cultures relative to parental cell lines."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • EP300 • KRAS

The phase 1/2 combination study of vopimetostat with RAS(ON) multi-selective inhibitor daraxonrasib, and RAS(ON) G12D-selective inhibitor zoldonrasib (both from Revolution Medicines, RVMD), is ongoing with robust enrollment in previously treated MTAP-del/RAS mut pancreatic and lung cancer. (The Manila Times) - "The first dose escalation cohort of this study has been fully enrolled (n=7) and backfill is ongoing. Vopimetostat in combination with both daraxonrasib and zoldonrasib have been well-tolerated to date with exposures in the active range for each compound. The second cohort was initiated in early October. A cohort of 1L patients is expected to begin enrolling after go-forward doses have been selected. The data from this study have the potential to support a pivotal study in 1L MTAP-del/RAS mut pancreatic cancer. Initial data from the Phase 1/2 study are anticipated in 2026."

P1/2 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Cancer

Characterization of PSTA-5204, an oral KRAS G12D (ON) inhibitor with potent in vitro and in vivo efficacy (AACR-NCI-EORTC 2025) - "At ASCO, KRAS G12D (ON) inhibitor RMC-9805 and (ON/OFF) inhibitor VS-7375 showed promising clinical antitumor activity in NSCLC and PDAC. Notably, tumors in the PSTA-5204 15 mg/kg group showed near-complete regression by day 21 post-treatment. PSTA-5024 was well tolerated throughout the study and showed no evidence of hERG inhibition, supporting its safety profile.Conclusions PSTA-5204, an oral KRAS G12D (ON) inhibitor, demonstrates enhanced in vitro potency, near-complete tumor growth inhibition at a low dose of 7.5 mg/kg, along with a favorable pharmacokinetic and safety profile—highlighting its potential as a preclinical candidate."

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

Targeting the Oncogenic State of RAS in Pancreatic Cancer with Tri-Complex Inhibitors Free (AACRPanCa 2025) - "These include 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 inhibitor zoldonrasib (RMC-9805) that covalently engages RAS(ON) G12D. We will describe the mechanism of action of these investigational agents and their activity in a variety of RAS-driven preclinical models supporting their clinical evaluation in RAS-addicted cancers. Moreover, we will describe our emerging understanding of acquired resistance to RAS(ON) inhibitor monotherapy that is informing potential combination regimens, including with RAS(ON) inhibitor doublets."

Colon Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRAS • KRAS • NRAS

Treatment of KRAS-Mutated Pancreatic Cancer: New Hope for the Patients? (PubMed, Cancers (Basel)) - "Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations...RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC."

IO biomarker • Journal • Review • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • 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

Portoghese lecture: Advancing bRo5 chemical matter to the clinic (ACS-Fall 2025) - P1, P3 | "Using this approach, we developed the investigational agent, RMC-5552, a bi-steric inhibitor that is mTORC1-selective via its FKBP12-binding moiety and potently inhibits phosphorylation of the 4EBP1 tumor suppressor via a linked ATP-competitive moiety. The RASG12D mutation increases the abundance of RASG12D(ON) and occurs commonly in multiple tumor histotypes, including RAS mutant pancreatic, colorectal, and non-small cell lung cancers. We are exploring two approaches for the treatment of RASG12D-addicted cancers, including the investigational agents daraxonrasib (RMC-6236), an oral, RAS(ON) multi-selective inhibitor currently in Phase III (NCT06625320), and zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, covalent inhibitor currently in Phase I/Ib (NCT06040541) as a monotherapy and in combination with daraxonrasib."

Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EIF4EBP1

RMC-9805-001: Study of RMC-9805 in Participants With KRAS G12D-Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=604 | Recruiting | Sponsor: Revolution Medicines, Inc. | N=444 ➔ 604

Enrollment change • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • 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 Publication of a Peer-Reviewed Research Paper in Science on the Discovery and Development of Zoldonrasib, a RAS(ON) G12D-Selective Inhibitor (GlobeNewswire) - "Revolution Medicines...announced the publication of a peer-reviewed research paper in Science. The scientific paper details the discovery and development of zoldonrasib (RMC-9805)....This publication details the novel mechanism of zoldonrasib, a member of the differentiated class of targeted protein binders called tri-complex inhibitors. This natural product-like compound successfully overcomes the challenge of engaging aspartic acid residues by leveraging a neomorphic protein-protein interface between the cellular chaperone cyclophilin A and activated RAS, or RAS(ON), to selectively catalyze covalent bond formation with RAS(ON) G12D proteins. Data reported in this paper demonstrate that this activity drives deep and durable tumor regressions in preclinical models of multiple tumor types with KRAS G12D mutations."

Preclinical • Solid Tumor

A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors. (PubMed, Science) - P1 | "We overcame these challenges with compounds that bind cyclophilin A (CYPA) to create a neomorphic protein-protein interface between CYPA and active RAS that enables selective, enzyme-like rate enhancement of the covalent reaction between D12 and electrophilic warheads with exceptionally low intrinsic reactivity. This approach yielded orally bioavailable compounds with marked antitumor activity in multiple preclinical models of KRASG12D cancers, including the investigational agent zoldonrasib (RMC-9805) currently undergoing clinical evaluation (NCT06040541)."

Journal • Oncology • KRAS

Drugging the 'undruggable' KRAS: breakthroughs, challenges, and opportunities in pancreatic cancer. (PubMed, Cancer Biol Med) - "While FDA-approved mutation-specific and pan-KRAS inhibitors show limited efficacy in PDAC, emerging agents (MRTX1133 and RMC-9805) have demonstrated preclinical promise. The molecular basis of KRAS-driven PDAC, current inhibitors, resistance mechanisms, and innovative strategies are discussed herein to address treatment barriers. Opportunities to improve clinical outcomes are underscored in this challenging malignancy by integrating insights from preclinical and clinical research."

IO biomarker • Journal • Review • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • 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

Tango Therapeutics Announces First Patient Dosed in Phase 1/2 Trial of TNG462 plus Revolution Medicines’ Daraxonrasib or Zoldonrasib in Patients with RAS-Mutant MTAP-deleted Pancreatic or Lung Cancer (GlobeNewswire) - "Tango Therapeutics...announced that the first patient has been dosed in the Phase 1/2 trial of TNG462 and Revolution Medicines’ daraxonrasib (RAS(ON) multi-selective inhibitor) or zoldonrasib (RAS(ON) G12D-selective inhibitor) in patients with MTAP-deleted and RAS mutant metastatic pancreatic or lung cancer....The Phase 1/2 combination trial (NCT06922591) is evaluating safety, pharmacokinetics, pharmacodynamics and antitumor activity in TNG462 in combination with daraxonrasib and TNG462 in combination with zoldonrasib in pancreatic and lung cancer patients with an MTAP deletion and a co-occurring RAS mutation. TNG462...is currently being evaluated as monotherapy in a Phase 1/2 trial, with data expected in the second half of 2025. This upcoming monotherapy data update is anticipated to provide sufficient information to inform a registrational trial in pancreatic cancer next year and advance the development plan for lung cancer."

P1/2 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Cancer

Study to Evaluate the Safety, Tolerability & Efficacy of TNG462 in Combination in PDAC & NSCLC Patients (clinicaltrials.gov) - P1/2 | N=133 | Recruiting | Sponsor: Tango Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy as single agent and in combination with other anticancer therapies in preclinical models (AACR 2025) - P1/2 | "Furthermore, GFH375 was more potent than other KRAS G12D inhibitors (e.g. RMC-9805, MRTX1133) in reducing the level of RAF1-bound active KRAS G12D-GTP (ON) and inhibiting cell proliferation in MEFs expressing human KRAS G12D...Combination with the RAF/MEK clamp avutometinib also enhanced the anti-tumor efficacy of GFH375...Altogether, GFH375 is a potent and selective orally active inhibitor of KRAS G12D (ON/OFF) and demonstrated promising anti-tumor activity in multiple KRAS G12D tumor models in vivo as single agent and in combination with other anticancer therapies including cetuximab. These results support the ongoing clinical evaluation of GFH375 for treatment of patients with KRAS G12D mutant cancers (NCT06500676)."

Combination therapy • Preclinical • Colorectal Cancer • Endometrial Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Revolution Medicines Presents Initial Data from Zoldonrasib (RMC-9805) Study in Patients with KRAS G12D Mutant Non-Small Cell Lung Cancer at the 2025 AACR Annual Meeting (GlobeNewswire) - P1 | N=444 | NCT06040541 | Sponsor: Revolution Medicines, Inc. | "Revolution Medicines, Inc.,,announced new clinical data for zoldonrasib (RMC-9805), a RAS(ON) G12D-selective inhibitor, as monotherapy in patients with KRAS G12D mutant non-small cell lung cancer (NSCLC)....As of a December 2, 2024 data cutoff date, 90 solid tumor patients were treated with 1200 mg once daily (QD), the candidate recommended Phase 2 dose. In these patients, zoldonrasib demonstrated an acceptable safety profile, that was generally consistent with previously reported data for this compound in pancreatic cancer, and was generally well tolerated....Preliminary antitumor activity was assessed in 18 efficacy-evaluable patients with NSCLC at the 1200 mg QD dose. The objective response rate (confirmed or pending confirmation) was 61% (n=11) and the disease control rate was 89% (n=16)."

P1 data • Non Small Cell Lung Cancer