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

RASolute 302: Phase 3 Study of Daraxonrasib (RMC-6236) in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC) (clinicaltrials.gov) - P3 | N=501 | Active, not recruiting | Sponsor: Revolution Medicines, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

BIRC5 inhibition as a novel approach to target RAS mutant and drug-resistant multiple myeloma (ASH 2025) - "Finally, we compared the efficacy of these BIRC5 inhibitors against severalRAS inhibitors, including cyclorasin B4-27, a bicyclic peptidyl pan-RAS inhibitor, RMC-6236, a multi-selective noncovalent RAS(on) inhibitor, and ADT-007, a novel, highly potent, and selective pan-RASinhibitor that we have synthesized, and observed comparable effects on cell death and apoptosis. Ex vivoanalysis in bone marrow-derived CD138+ cells from myeloma patients using high-throughput MassCytometry (CyTOF or Cytometry by Time-Of-Flight) confirmed the dose-dependent reduction of MCL1, Ki-67, CCND1, c-KIT, and MYC.We will present these results that demonstrate the clinical potential of BIRC5 inhibitors as novelcandidates in curbing progression and drug resistance in RAS-mutant myeloma."

Hematological Malignancies • Multiple Myeloma • BIRC5 • CCND1 • HRAS • KIT • KRAS • MCL1 • NRAS • SDC1

Functional genomics studies identify determinants of response vs. resistance to pharmacological inhibitors of KRAS in multiple myeloma (ASH 2025) - "We evaluated Rasinhibitors in preclinical models of MM, with emphasis on genome-scale CRISPR studies to define themolecular determinants of response and resistance to these agents.We studied selective inhibitors of KRAS G12C (MRTX-1257) or G12D (MRTX-1133) mutants; the broaderspectrum mutant-KRAS inhibitor BI-2865; or the tricomplex pan-Ras inhibitor RMC-6236. Notably, even MM cells with the same KRASmutation can display distinct "resistomes", highlighting the complex functional genomic landscapeunderlying Ras inhibitor responses. We envision that these results will inform personalized uses of Rasinhibitors in future clinical studies in MM."

Genomic study • Hematological Malignancies • Multiple Myeloma • Solid Tumor • ABCB1 • DUSP6 • EGFR • FGFR3 • IL6 • KEAP1 • KRAS • LZTR1 • NRAS • PPIA

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

A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance. (PubMed, Proc Natl Acad Sci U S A) - "Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment...Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • EGFR • KRAS • TP53

RASolute 304: Study of Daraxonrasib (RMC-6236) in Patients With Resected Pancreatic Ductal Adenocarcinoma (PDAC) (clinicaltrials.gov) - P3 | N=500 | Recruiting | Sponsor: Revolution Medicines, Inc.

New P3 trial • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

RRAS and RRAS2 mutations are recurrent oncogenic drivers in lung cancer and are sensitive to the pan-RAS inhibitor RMC-6236. (PubMed, bioRxiv) - "These data support RRAS Q87L and RRAS2 Q72L as bona fide lung cancer drivers and nominate RRAS/RRAS2-mutant tumors as candidates for pan-RAS-targeted therapeutics. Our findings provide a biologic rationale and preclinical evidence to inform molecular testing paradigms and to prioritize enrollment of patients with RRAS/RRAS2-mutant NSCLC into future clinical trials of pan-RAS inhibitors."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • NRAS • NRG1 • NTRK • RRAS2

PAN-RAS INHIBITION AS A NOVEL THERAPEUTIC STRATEGY FOR RAS-DRIVEN RHABDOMYOSARCOMA (CTOS 2025) - P1/2, P3 | "RMC-6236 and its tool compound RMC-7977 are novel state selective pan-RAS inhibitors that inhibit GTP-bound oncogenic and wild-type (WT) RAS, known as RAS(ON)i. Our data demonstrate that RAS(ON)i decreases RAS-MEK-ERK signaling, prevents adaptive PI3K-AKT signaling, and decreases in vitro and in vivo tumor growth in RAS-driven RMS. These findings can rapidly translate into a clinical trial for patients with RAS-pathway-altered RMS using clinically available compounds in late-stage clinical development."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • HRAS • KRAS • Myogenin • NRAS

Preclinical Activity of RAS(ON) Multi-Selective Inhibitor RMC-7977 and Therapeutic Combinations in AML with Signaling Mutations (ASH 2024) - "RMC-7977 is a potent, oral small molecule inhibitor of both wild-type and mutant GTP-bound RAS (RAS(ON) multi-selective) and is a preclinical tool compound representative of the investigational drug RMC-6236...Mice receiving vehicle, venetoclax or gilteritinib had an average residual leukemic burden of 88.9% (SD=±23.3), 98.9% (SD=±0.4), and 79.7% (SD=±5.3) respectively, while those receiving RMC-7977 or RMC-7977 + venetoclax exhibited 46.12% (SD=±23.9) and 44.27% (SD=±15.8), respectively...Our data suggest that RAS(ON) multi-selective inhibition is an effective therapeutic approach to overcome RAS/MAPK-mediated resistance to FLT3i and is active in AML driven by oncogenic RAS mutations, addressing limitations of current standard of care treatments for AML with signaling mutations. These results provide a strong preclinical rationale for the clinical investigation of RAS(ON) multi-selective inhibition in FLT3- and RAS- mutant AML."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3 • IDH1 • IDH2 • KMT2A • KRAS • NRAS • PTPRC

RASMULTI(ON) Inhibitor RMC-7977 Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 Inhibitors in AML Models (ASH 2023) - P1/2 | "RMC-7977 is a potent, oral small molecule inhibitor of both wild-type and mutant GTP-bound RAS oncoproteins (RASMULTI) and is a preclinical tool compound representative of the clinical candidate RMC-6236, currently in clinical evaluation (NCT05379985)...Gilteritinib and the gilteritinib/venetoclax combination selected for survival of cells harboring NRAS mutations, but RMC-7977 inhibited outgrowth of all cell populations...In vivo studies investigating the tolerability and activity of RMC-7977 and RMC-7977 combinations in RAS mutant/FLT3i-resistant patient-derived xenograft models are ongoing and will be presented. Collectively, our data provide preclinical evidence that combination therapies leveraging RASMULTI(ON) inhibition are effective in suppressing RAS-mutant AML clones, a common mechanism of resistance to currently approved targeted therapies in AML and a current area of high unmet clinical need."

IO biomarker • Acute Myelogenous Leukemia • Oncology • CASP3 • CASP7 • FLT3 • IDH1 • IDH2 • KIT • KRAS • NRAS

RMC-6236-001: Study of RMC-6236 in Patients With Advanced Solid Tumors Harboring Specific Mutations in RAS (clinicaltrials.gov) - P1/2 | N=754 | Recruiting | Sponsor: Revolution Medicines, Inc. | Phase classification: P1 ➔ P1/2 | Trial completion date: Jun 2026 ➔ Jul 2027 | Trial primary completion date: May 2026 ➔ May 2027

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

Functional Genomics Studies Decipher the Genetic Perturbations and Unravel Mechanisms of Response/Resistance upon Mutant-Specific KRAS Inhibition in Multiple Myeloma (ASH 2024) - "METHODS : We performed a total of 11 genome-scale CRISPR gene activation or CRISPR gene editing (knockout, KO) studies in 5 MM lines with distinct KRAS point mutations (KHM-1B and XG-7 [G12C]; KARPAS-620 and KP-6 [G12D]; or MM.1S [G12A]) after treatment with specific KRAS inhibitors (MRTX-1133, MRTX-1257, BI-2865, RMC-6236) in clinically achievable concentration ranges (as used in patients with solid tumors). These compounds exhibit potent and specific activity against MM cells with the respective KRAS mutations, but our functional studies point to individual lines, even those harboring the same KRAS mutation, exhibiting their own distinct "resistome" against these inhibitors. These results underscore the complex functional genomics of MM cell sensitivity vs. resistance to KRAS inhibitors and have implications for the choice of potential combination partners of these inhibitors in future preclinical or clinical studies."

Genomic study • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • ANXA5 • DUSP6 • EGFR • ETV4 • ETV5 • KEAP1 • KRAS • LZTR1

Preclinical Development of a Novel Pan-RAS Inhibitor Against Relapsed/Refractory Multiple Myeloma (ASH 2024) - "Furthermore, the in vitro efficacy of ADT-007 was significantly better (nM vs. µM IC50) than cyclorasin B4-27, a bicyclic peptidyl that has been reported as a potent pan-RAS inhibitor against several other cancers, and RMC-6236, a multi-selective noncovalent RAS(on) inhibitor which is in clinical trial for patients with advanced solid tumors harboring G12X, G13X, and Q61X mutations. Next, we plan to evaluate the antitumor activity of ADT-1004 in mouse xenograft models of human myeloma using immunocompromised mice. Our research will lay the groundwork for future development efforts needed to advance ADT-1004 to clinical trials involving patients with RRMM."

Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • Pancreatic Cancer • Solid Tumor • ANXA5 • CASP3 • CASP7 • IKZF1 • IKZF3 • IRF4 • KRAS • MYC • NRAS

Execute pivotal trials with daraxonrasib monotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) (GlobeNewswire) - "RASolute 302, a global Phase 3 trial of daraxonrasib in patients with previously treated PDAC, continues to enroll well. The company is winding down enrollment in the U.S. while continuing to enroll patients outside the U.S. to support global registration. The company expects to complete enrollment in this trial this year to enable an expected data readout in 2026....In RASolve 301, a global Phase 3 trial of daraxonrasib in patients with previously treated NSCLC, the company continues enrolling patients in the U.S. and is now activating trial sites in Europe and Japan."

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

"Preclinical activity of pharmacological KRAS and pan-RAS inhibitors in multiple myeloma" (DGHO 2025) - "Novel and more broadly effective pharmacological RAS inhibitors show promising activity against RAS-mutated MM cell lines. These compounds significantly broaden the spectrum of efficacy and increase the number of MM patients that may be eligible for RAS-targeted inhibitor therapy."

Preclinical • Hematological Malignancies • Lung Cancer • Multiple Myeloma • Non Small Cell Lung Cancer • Solid Tumor • KRAS • NRAS

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 remains on track to initiate a registrational trial in 2026 evaluating daraxonrasib in patients with first line metastatic RAS mutant NSCLC in combination with pembrolizumab and chemotherapy (GlobeNewswire)

New P3 trial • Non Small Cell Lung Cancer

…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

The company has initiated RASolute 304, a Phase 3 trial of daraxonrasib as adjuvant treatment for patients with resectable PDAC, and is currently activating trial sites (GlobeNewswire) - "The trial will evaluate patients who have received surgery and perioperative chemotherapy per standard of care, who will be randomized to either observation or daraxonrasib monotherapy for two years. The primary endpoint is disease-free survival, with secondary endpoints of overall survival and safety."

Trial status • Pancreatic Ductal Adenocarcinoma

…initiation of RASolute 303, a global Phase 3 registrational trial of daraxonrasib in first line metastatic PDAC (GlobeNewswire) - "The company remains on track to initiate the trial this year. The trial will evaluate daraxonrasib as monotherapy and in combination with gemcitabine nab-paclitaxel (GnP), each compared with GnP alone. The company expects to share updated daraxonrasib monotherapy and daraxonrasib plus GnP combination data, each in patients with first line PDAC, including preliminary durability, in the first half of 2026."

New P3 trial • Pancreatic Ductal Adenocarcinoma

RAS(ON) multi-selective inhibition drives antitumor immunity in preclinical models of NRAS-mutant melanoma. (PubMed, Cancer Immunol Res) - "Here, we demonstrate that RMC-7977, a preclinical RAS(ON) multi-selective inhibitor representative of the investigational agent daraxonrasib (RMC-6236), was able to elicit potent antitumor immune responses across multiple NRAS-mutant melanoma models. Consistent with these preclinical data, objective clinical responses were observed in two NRAS-mutant melanoma patients treated with daraxonrasib in an ongoing Phase I/Ib clinical trial. Together, these data support the continued clinical evaluation of RAS(ON) multi-selective inhibitors for the treatment of NRAS-mutant melanoma."

IO biomarker • Journal • Preclinical • Melanoma • Oncology • Solid Tumor • CD4 • CD8 • NRAS • PD-L1

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