daraxonrasib (RMC-6236) / Revolution Medicines, Royalty - LARVOL DELTA

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

Combination therapy with YAP/TEAD and RAS inhibitors overcomes phenotypic cell plasticity-driven resistance in NRAS-mutated melanoma (EACR 2025) - "Material and Loss-of-function approaches using RMC-6236, IAG933 (a YAP-TEAD interaction inhibitor), or siRNAs were employed to evaluate the impact of NRAS inhibition on phenotypic adaptation (RNA-seq, RT-qPCR, western blot analyses) as well as cell proliferation and survival (colony formation assay, flow cytometry) in human and murine NRAS-mutant cell line models. NRAS inhibition in melanoma cells induces a mesenchymal phenotypic transition linked to YAP pathway activation. YAP/TEAD inhibition can overcome resistance to NRAS inhibition by preventing adaptive phenotype switching and inducing tumor cell death. This work provides a scientific rationale for treating NRAS-mutant melanomas with a combination of RAS and YAP-TEAD inhibitors."

Combination therapy • IO biomarker • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • NRAS

Preclinical Evaluation of RAS(ON) Multi-Selective Inhibitors as a Therapeutic Strategy for KRAS mutant Cholangiocarcinoma (EACR 2025) - "Material and Human and murine KRAS mutant cell lines, and immortalized cholangiocytes expressing KRAS wild type and mutant alleles (4B, G12, G13, Q61) were used to study the effect of RAS(ON) multi-selective inhibitors, the investigational agent daraxonrasib (RMC-6236) or the preclinical tool compound RMC-7977, in vitro (2D and 3D) and in vivo (CDX, PDX and CDA)...Consistently, addition of RMC-7977 to the standard of care regimen (Gemcitabine+Cisplatin+antiPD1) exhibited a synergistic antitumor effect, leading to deep regressions in vivo... In summary, our preclinical findings support the clinical testing of RAS(ON) multi-selective inhibitors, either alone or in combination with standard of care regimen or KRAS-pathway inhibitors, as a potential therapeutic strategy for CCA treatment."

Preclinical • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CD4 • CD8 • EGFR • KRAS

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

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

RAS(ON) Therapies on the Horizon to Address KRAS Resistance: Highlight on a Phase III Clinical Candidate Daraxonrasib (RMC-6236). (PubMed, J Med Chem) - No abstract available

Journal • P3 data • KRAS

Revolution Medicines Announces FDA Breakthrough Therapy Designation for Daraxonrasib in Previously Treated Metastatic Pancreatic Cancer with KRAS G12 Mutations (GlobeNewswire) - "Revolution Medicines...announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to daraxonrasib, the company’s RAS(ON) multi-selective inhibitor, for previously treated metastatic PDAC in patients with KRAS G12 mutations. The Breakthrough Therapy Designation is based on encouraging data from the Phase 1 RMC-6236-001 clinical trial evaluating daraxonrasib in patients with previously treated metastatic PDAC."

Breakthrough therapy • Pancreatic Ductal Adenocarcinoma

Revolution Medicines Enters Into $2 Billion Flexible Funding Agreement with Royalty Pharma to Support Global Development and Commercialization of RAS(ON) Inhibitor Portfolio for Patients with RAS-Addicted Cancers (GlobeNewswire) - "Revolution Medicines, Inc...announced that it has partnered with Royalty Pharma on $2 billion in flexible funding to support Revolution Medicines’ independent global development and commercialization strategy and operations. Revolution Medicines retains full strategic and executional control of product development and commercialization for its portfolio of RAS(ON) inhibitors in the US and internationally, enabling the company to leverage its assets, capabilities and momentum toward establishing new global standards of care and creating value for shareholders...The first two $250 million tranches, totaling $500 million, are payable prior to daraxonrasib’s approval by the FDA and royalty obligations begin only after daraxonrasib approval."

Financing • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

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

Molecular landscape and therapeutic vulnerability of RRAS- and RRAS2-mutant solid tumors. (ASCO 2025) - "The sensitivity of cells harboring RRAS and RRAS2-mutations to the clinically active pan-RAS inhibitor RMC6236 was examined in vitro and in vivo... Hotspot RRAS2 mutations are rare but recurrently found in endometrial, ovarian, and germ cell tumors. These mutations are predominantly mutually exclusive with other canonical RAS mutations, although co-mutations with RAS do occur in a subset. RRAS2Q72L-mutant cancer cells are sensitive to inhibition of the MAPK pathway including pan-RAS inhibition both in vitro and in vivo."

Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Germ Cell Tumors • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • HRAS • KRAS • MAP2K1 • NRAS • RRAS2

Trial in progress: RASolute 302—A phase 3, multicenter, global, open-label, randomized study of daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, versus standard of care chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC). (ASCO 2025) - P1, P3 | "Eligibility includes patients ≥18 years old, ECOG performance status 0 or 1, disease progression on 1 prior line of either a 5-fluorouracil or gemcitabine-based regimen in the metastatic setting, and documented RAS mutation status (mutant or wild-type)...A 1:1 randomization of approximately 460 patients will receive daraxonrasib 300 mg daily or investigator's choice of chemotherapy (gemcitabine/nab-paclitaxel, mFOLFIRINOX, nal-IRI/5-FU/LV, or FOLFOX) until unacceptable toxicity or disease progression...Key secondary endpoints include PFS, OS, objective response and quality of life measures in the all-patient population with tumors carrying RAS mutations (G12X, G13X or Q61X) or RAS wild-type. Enrollment for the trial commenced in October 2024."

Clinical • Metastases • P3 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • HRAS • KRAS • NRAS

Combinatorial screen with standard of care and selected anticancer agents identifies multiple combinations with activity against a panel of patient-derived colorectal organoids (AACR 2025) - "Following compound addition, organoid growth was measured by live bright field imaging every 24 h and cell viability was determined by CellTiter-Glo 3D at 48 h and 168 h. Modest responses were observed in most models from the combination of leucovorin with 5-FU; however, >1 log of cytotoxicity was observed in only several models. The panel was more responsive to FOLFOX, which was consistent with the sensitivity of models to oxaliplatin. Responses to TAS-102 varied and >1 log of cytotoxicity was observed in several models...Combination of the BCL-2/BCL-xL inhibitor pelcitoclax plus cobimetinib achieved >1 log of cytotoxicity in most organoid models. Combinations of cobimetinib with the EGFR inhibitors erlotinib, afatinib or cetuximab demonstrated synergy in many organoids according to the Bliss independence model and frequently achieved ≥1 log of cytotoxicity...The combination of cobimetinib and MRTX1133 had synergistic activity by Bliss independence in multiple..."

Clinical • Oncology • BCL2 • BCL2L1 • BRAF • KRAS • PIK3CA

Dr Vonderheide on Responses With RAS(ON) Inhibition in Preclinical Pancreatic Cancer Models (OncLive) - "RAS(ON) multi-selective inhibitors, including agents such as RMC-6236 and RMC-7977, target the active, GTP-bound state of both mutant and wild-type RAS isoforms and have demonstrated potent antitumor activity in PDAC murine models....The findings revealed 3 primary observations, according to Vonderheide. First, treatment with KRAS(ON) multi-selective inhibitors resulted in marked tumor regression, with effects more profound than previously observed in laboratory models. Second, in mice lacking T cells, the antitumor efficacy of KRAS inhibition was significantly diminished, indicating that T cells contribute meaningfully to therapeutic response. Third, the addition of immune-based therapies, including checkpoint blockade, enhanced the depth and durability of tumor regressions. In some cases, mice achieved complete and sustained remissions even after discontinuation of the KRAS inhibitor, suggesting an immunologic memory response."

Preclinical • Pancreatic Ductal Adenocarcinoma

AUM-302, A NOVEL TRIPLE PIM/PI3K/MTOR INHIBITOR, SYNERGIZES WITH KRAS INHIBITION AND IMPEDES THE GROWTH OF PANCREATIC DUCTAL ADENOCARCINOMA SPHEROIDS AND ORGANOIDS (DDW 2025) - "Single- and dual kinase inhibitors TP-3654, GDC-0941, and BEZ-235, and DMSO were used as controls...Finally, combinatorial assays revealed synergy between AUM-302 and the KRAS inhibitor RMC-6236 in reducing the growth of hT1 and hM1A organoids. By blocking kinase activity, AUM-302 demonstrates potent inhibitory activity in PDAC cell lines and organoids in two different 3D culture formats. Treatment with this novel triple PIM/PI3K/mTOR inhibitor may also sensitize PDAC to other therapies, such as KRAS inhibitors."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Revolution Medicines Announces First Patient Dosed in Phase 3 Clinical Trial Evaluating Daraxonrasib in Previously Treated Patients with RAS Mutant Non-Small Cell Lung Cancer (GlobeNewswire) - "Revolution Medicines, Inc...today announced the first patient has been dosed in RASolve 301, a global, randomized, open-label Phase 3 clinical trial. RASolve 301 will evaluate the safety and efficacy of daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, in patients with previously treated, locally advanced or metastatic RAS mutant non-small cell lung cancer (NSCLC) compared to docetaxel chemotherapy....RASolve 301 is anticipated to enroll approximately 420 patients with NSCLC worldwide who have received one to two prior lines of therapy for the treatment of advanced disease including an anti-PD-1/anti-PD(L)-1 agent and platinum-based chemotherapy."

Trial status • Non Small Cell Lung Cancer

Combinations in NSCLC:…Daraxonrasib and pembrolizumab with or without chemotherapy (GlobeNewswire) - P1/2 | N=484 | NCT06162221 | Sponsor: Revolution Medicines, Inc. | "Today, the company shared data for ten patients in the 1L NSCLC setting treated with daraxonrasib and pembrolizumab, as of a February 10, 2025 data cutoff. No new safety signals were seen, and the overall safety profile was consistent with those of daraxonrasib alone and the standard of care agents. Hepatotoxicity did not appear as a safety signal (no Grade 3 or higher events) in the combination of daraxonrasib and pembrolizumab with or without chemotherapy....Daraxonrasib achieved a favorable MDI of 93% in combination with pembrolizumab and 90% with the addition of chemotherapy."

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

Advance daraxonrasib into first-line metastatic and earlier-line randomized pivotal trials in patients with PDAC (GlobeNewswire) - "Planning continues for registrational trials for daraxonrasib as first-line (1L) treatment for patients with metastatic PDAC and as adjuvant treatment for patients with resectable disease, and the company expects to initiate both studies in the second half of this year."

New trial • Pancreatic Ductal Adenocarcinoma

Execute pivotal trials with daraxonrasib monotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) (GlobeNewswire) - "In RASolute 302, a global Phase 3 trial in patients with previously treated PDAC, the company continues its strong pace of enrollment in the U.S. and has begun enrolling patients in the EU and Japan. The company expects to substantially complete enrollment this year to enable an expected data readout in 2026. For RASolve 301, a global Phase 3 trial in patients with previously treated NSCLC, the company is currently activating study sites."

P3 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Evaluating the efficacy of RAS(ON) inhibitor RMC-6236 combined with chemotherapy and other targeted therapies in 3D models involving patients with KRAS-mutated pancreatic cancer (AACR 2025) - "Synergy studies explored combinations of RMC-6236 with gemcitabine and abraxane chemotherapies, along with other targeted therapies, including CDK7, WNT, and mTOR pathway inhibitors. The combination of RMC-6236 with standard chemotherapy and targeted therapies enhances its antitumor activity, suggesting a promising strategy for improving therapeutic outcomes in pancreatic cancer. The observed synergistic interactions, especially with WNTi, warrant further investigation in clinical trials to evaluate the potential of this combination approach in improving treatment responses."

Clinical • Oncology • Pancreatic Cancer • Solid Tumor • CAFs • KRAS

The efficacy of NST-628, a non-degrading pan-RAF/MEK molecular glue, and MEK inhibitors for overcoming acquired osimertinib resistance mediated by TRIM24-BRAF fusions in EGFR mutant NSCLC (AACR 2025) - "Next, we utilized a panel of compounds targeting the RAS/RAF/MAPK pathway including agents targeting pan-RAS (RMC-6236 and RMC-7977), SHP2 (RMC-4550), BRAF (dabrafenib, encorafenib, tovorafenib and vemurafenib), pan-RAF (TAK-632), MEK (binimetinib, cobimetinib, selumetinib and trametinib), pan-RAF/MEK (NST-628) and assessed whether targeting signal transduction molecule downstream of EGFR could overcome this adaptative resistance mechanism. TRIM24-BRAF expressing cells showed minimal sensitivity to BRAF, SHP2 or RAS targeting single agents. Taken together, our findings indicate that expression of TRIM24-BRAF fusion induce osimertinib resistance in EGFR mutant NSCLC and targeting the MEK pathway using trametinib or NST-628 can overcome osimertinib resistance in this setting."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • TRIM24

Drug combination inhibits genes that drive aggressive pancreatic cancer, study finds (Medical Xpress) - "Study findings indicate that a newly discovered drug, RMC-6236, also known as Daraxonrasib, is a powerful inhibitor of RAS (including KRAS, NRAS and HRAS). These are commonly mutated cancer-causing genes that drive the formation of many types of tumors, including pancreatic cancer. This study evaluated the effectiveness of RMC-6236 in patient-derived pancreatic tumors harboring KRAS mutations....According to this initial study to emerge from the Research Institute's new Center for Translational Science laboratory, RMC-6236, when combined with other proven pancreatic cancer drugs, is a promising new agent against RAS, particularly KRASG12X."

Preclinical • Pancreatic Cancer

Oral and selective ribonucleotide reductase (RNR) inhibitor, BBI-825, suppresses acquired resistance to mutant-specific, pan, and multi-RAS targeting inhibitors (AACR 2025) - P1 | "In this preclinical study, we sought to understand whether BBI-825 broadly antagonizes acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of tumor models.We tested the ability of BBI-825 to prevent or delay development of acquired resistance to RAS targeting in a panel of KRASG12D/C/V driven tumor cell lines when used in combination with mutant specific KRASG12D (MRTX-1133, RMC-9805), KRASG12C (adagrasib, sotorasib), pan-KRAS (BI-2493), and multi-RAS (RMC-6236) inhibitors. Overall, we found that BBI-825 successfully antagonizes the development of acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of preclinical models. These findings support clinical investigation of BBI-825 in combination with mutant-specific, pan, and multi-RAS inhibitors to prevent or delay resistance and prolong duration of response."

Preclinical • Oncology • Solid Tumor • KRAS

Integrative analysis of acquired drug resistance to KRAS(G12D) inhibitors (AACR 2025) - "Novel therapeutic approaches such as RAS(ON) inhibitors like RMC-6236 or specific KRAS(G12D) PROTAC degraders can significantly inhibit cell proliferation in vitro not only in MRTX1133 acquired resistance but also in adagrasib resistance models. Complex transcriptomic reorganization shows the upregulation of CD24 -a potential cancer stem cell related gene- and the epithelial to mesenchymal signature highlight the difficulty to target drug resistant cells. These findings emphasize the necessity to design combinatorial treatments to prevent and delay the acquisition of drug resistance in KRAS-driven cancers."

Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AVEN • CD24 • HRAS • KRAS • NRAS

RCZY-690 and RCZY-680: Novel, highly potent, and orally bioavailable, tri-complex pan RAS-MULTI(ON) inhibitors with distinctive oral pharmacokinetic profiles, exhibiting broad anti-tumor activities in CDX models (AACR 2025) - "Although KRAS G12C inhibitors like sotorasib and adagrasib show promise for NSCLC, resistance develops rapidly, and effective therapies are still lacking for over 85% of RAS-driven or RAS-amplified cancers.Herein, we report RCZY-690 and RCZY-680 as novel and potent tri-complex RAS-MULTI(ON) inhibitors...This approach, exemplified by the lead compound RMC-6236, has shown promise in KRAS-mutant PDAC and NSCLC patients in phase 1 study...The superior anti-tumor efficacy may be attributed to their highly potent cellular cytotoxicity, long mouse half-lives (10.1 h and 4.8 h, respectively), and high oral exposure levels. In conclusion, RCZY-690 and RCZY-680 are tri-complex pan RAS-MULTI(ON) inhibitors with best-in-class clinical potential for treating RAS-driven solid tumors."

PK/PD data • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRAF • DUSP6 • HRAS • KRAS • NRAS