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

RASolve 301: A Phase 3 Study of Daraxonrasib (RMC-6236) Versus Docetaxel in Previously Treated Non-small Cell Lung Cancer (NSCLC) Patients with RAS Mutations (clinicaltrials.gov) - P3 | N=420 | Not yet recruiting | Sponsor: Revolution Medicines, Inc.

New P3 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Safety and clinical activity of daraxonrasib (RMC-6236) in RAS mutant non-small cell lung cancer (NSCLC) (ELCC 2025) - P1 | "Funding: Revolution Medicines, Inc. Daraxonrasib (120–220 mg daily) demonstrated encouraging and durable clinical activity in patients with NSCLC with a manageable safety and tolerability profile and favorable dose intensity. These data support the initiation of a randomized phase III study (RASolve 301) of daraxonrasib versus docetaxel in patients with previously treated, locally advanced or metastatic RASmut NSCLC."

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

RRAS and RRAS2 hotspot mutations as novel actionable oncogenic drivers in lung adenocarcinoma (ELCC 2025) - P1 | "Growth of HBEC and Ba/F3 cells expressing RRAS or RRAS2 mutations was sensitive to inhibitors of ERK1/2 (ulixertinib, SCH772984), MEK1/2 (binimetinib), and RAS (RMC-6236). Our findings suggest that patients with RRAS/RRAS2-mutant tumors are likely to derive benefit from RMC-6236 (NCT05379985). Finally, the results are relevant beyond LUAD, as RRAS2 Q72L mutations are also seen in endometrial and ovarian cancers, as well as germ cell tumors."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • MAP2K1 • NRAS • RRAS2

Exploring the Sensitivity of NRAS Mutations in Melanoma towards Pan-RAS Inhibitors (EADO-WCM 2025) - "In contrast, these mutations showed resistance to the G12 inhibitors sotorasib and adagrasib. Conclusions The majority of NRAS mutations in melanoma exhibit sensitivity to the pan-RAS inhibitors RMC-7977 and RMC-6236, both of which are promising candidate for clinical evaluation of NRAS-mutated melanoma."

Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • KRAS • NRAS

Inhibitors of oncogenic Kras specifically prime CTLA4 blockade to transcriptionally reprogram Tregs and overcome resistance to suppress pancreas cancer. (PubMed, bioRxiv) - "We show a specific synergy of anti-CTLA4 immune checkpoint blockade with Kras* targeting primed by Kras G12D allele specific inhibitor, MRTX1133 and multi-selective pan-RAS inhibitor, RMC-6236, both currently in clinical testing phase. Single cell ATAC sequencing analysis revealed that transcriptional reprogramming of Tregs is epigenetically regulated by downregulation of AP-1 family of transcription factors including Fos, Fos-b, Jun-b, Jun-d in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with important clinical implications."

IO biomarker • Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • KRAS

T-cell dependency of tumor regressions and complete responses with RAS(ON) multi-selective inhibition in preclinical models of PDAC. (PubMed, Cancer Discov) - "RAS(ON) multi-selective inhibitors, such as daraxonrasib (RMC-6236) and RMC-7977, target the active state of RAS, with potent anti-tumor activity in PDAC murine models. Moreover, the combination of RAS(ON) multi-selective inhibitors with immunotherapy conferred deeper and more durable tumor regressions, including complete responses not seen with either treatment alone. In summary, concurrent inhibition of mutant and wild-type RAS is active in concert with T cell immunotherapy, revealing RAS(ON) multi-selective inhibitors as a potential therapeutic immuno-sensitizing strategy in PDAC."

IO biomarker • Journal • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers. (PubMed, J Med Chem) - P1, P1/2 | "To achieve broad-spectrum RAS isoform activity, we deployed an SAR campaign that focused on interactions with residues conserved between mutants and WT RAS isoforms. Concurrent optimization of potency and drug-like properties led to the discovery of daraxonrasib (RMC-6236), currently in clinical evaluation in RAS mutant advanced solid tumors (NCT05379985; NCT06040541; NCT06162221; NCT06445062; NCT06128551)."

Journal • Oncology • Solid Tumor

Strategic Priorities and Markers of Progress…Execute pivotal trials with daraxonrasib monotherapy in patients with previously treated metastatic PDAC and NSCLC (GlobeNewswire) - "The company anticipates substantially completing enrollment in RASolute 302, the company’s randomized Phase 3 trial comparing daraxonrasib to standard of care chemotherapy in 2L patients with metastatic PDAC, in 2025 to enable an expected data readout in 2026. Having finalized the study design disclosed on December 2, 2024, the company is now activating investigational sites for RASolve 301, its global randomized Phase 3 trial comparing daraxonrasib to docetaxel in patients with previously treated, locally advanced or metastatic RAS mutant NSCLC."

Enrollment status • New P3 trial • P3 data • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Strategic Priorities and Markers of Progress…Advance daraxonrasib into earlier-line randomized pivotal trials in patients with PDAC (GlobeNewswire) - "The company anticipates initiating two pivotal trials in earlier lines of treatment for PDAC in the second half of 2025: (i) A global, randomized Phase 3 trial in first-line patients with metastatic PDAC. The trial is expected to compare a reference arm of patients treated with chemotherapy to two investigational arms, one with patients treated with daraxonrasib monotherapy and one with patients treated with daraxonrasib plus chemotherapy; (ii) A global, randomized Phase 3 trial of daraxonrasib as adjuvant treatment for patients with resectable PDAC."

New P3 trial • Pancreatic Ductal Adenocarcinoma

RRAS and RRAS2 are actionable oncogenic drivers in NSCLC (IASLC-TTLC 2025) - P1 | "Growth of HBEC and Ba/F3 cells expressing RRAS or RRAS2 mutations showed enhanced sensitivity to inhibitors of ERK1/2 (ulixertinib and SCH772984), MEK1/2 (binimetinib), and RAS (RMC-6236). RRASQ87L and RRAS2Q72L are oncogenic in NSCLC and are mutually exclusive with other known lung cancer drivers. Constitutive activation of RRAS and RRAS2 elevated both the MAPK and PI3K-AKT axes and confers susceptibility to targeted inhibition of the MAPK pathway. Notably, the novel pan-RAS inhibitor RMC-6236 diminished RRAS and RRAS2-driven tumor growth in vivo."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • MAP2K1 • NRAS • RRAS2

Assessing KRAS inhibitors in pancreatic cancer using multiomics and advanced imaging to identify novel treatment co-targets (LCC 2025) - "For example, Mirati's G12D KRAS inhibitor, MRTX1133, can cause a >50% decrease in tumour burden in mouse models of PC4. More broadly, pan-KRAS inhibitors can act on all KRAS mutations, such as RMC-6236 (Revolution Medicines) and BI-2493 (Boehringer Ingelheim)5,6...Future work will also include assessment of our new putative co-targets using intravital (in vivo) imaging and biosensor technology. Overall, we aim to find new targets for combination treatment to improve the efficacy and durability of these first-in-class KRAS inhibitors."

Metastases • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Daraxonrasib Demonstrates Efficacy, Potential to Inhibit Major RAS(ON) Variants in RAS+ PDAC (OncLive) - P1/1b | N=614 | NCT05379985 | Sponsor: Revolution Medicines, Inc. | "Among patients with metastatic PDAC who received daraxonrasib at the recommended phase 2 dose (RP2D) of 300 mg in the second line (n = 59), the median progression-free survival (PFS) was 8.8 months (95% CI, 8.5-not evaluable [NE]) in those with KRAS G12X–mutated disease (n = 22) and 8.5 months (95% CI, 5.9-NE) in those with RAS-mutated disease (n = 37). The overall response rates (ORR) were 36% and 27% in the KRAS G12X– and RAS-mutated subgroups, respectively; disease control rates (DCR) for these respective groups were 91% and 95%. Comparatively, at doses ranging from 160 to 300 mg, the median PFS was 8.5 months (95% CI, 5.3-11.7) in the KRAS G12X–mutated group (n = 42) and 7.6 months (95% CI, 5.9-11.1) in the with RAS-mutated group (n = 57)."

P1 data • Pancreatic Ductal Adenocarcinoma

Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors. (ASCO-GI 2025) - P1 | "Oral RMC-9805 showed encouraging initial antitumor activity with early and deep reductions in KRAS G12D ctDNA in patients with KRAS G12D PDAC. Tolerability was favorable relative to SOC chemotherapy for PDAC and manageable. This overall safety profile and antitumor activity support continued evaluation as monotherapy in patients with KRAS G12D PDAC, and in combination with chemotherapy and targeted therapies, including the RAS(ON) multi-selective inhibitor RMC-6236."

Circulating tumor DNA • Clinical • Metastases • P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC). (ASCO-GI 2025) - P1 | "RMC-6236 showed a manageable safety profile and encouraging efficacy in patients with previously treated RAS mutant PDAC, and early and deep reductions in RAS mutant ctDNA. RASolute 302, a global, randomized, Phase 3 trial evaluating RMC-6236 as 2L treatment vs chemotherapy in patients with metastatic PDAC, is ongoing."

Circulating tumor DNA • Clinical • P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Study of RAS(ON) Inhibitors in Patients with Gastrointestinal Solid Tumors (clinicaltrials.gov) - P1/2 | N=1130 | Recruiting | Sponsor: Revolution Medicines, Inc. | N=406 ➔ 1130

Enrollment change • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

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

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

RMC-6236 with Pembrolizumab (GlobeNewswire) - P1b/2 | N=484 | RMC-LUNG-101B (NCT06162221) | Sponsor: Revolution Medicines, Inc. | "RMC-LUNG-101B is an arm of the Phase 1b study of RMC-6236 in combination with pembrolizumab, with or without chemotherapy, in patients with RAS mutant NSCLC....The combination of RMC-6236 with pembrolizumab was generally well tolerated and the safety profile was consistent with previously reported results for the individual agents. TRAEs of Grade 1 aspartate aminotransferase (AST) elevation were reported in two patients (10%) and a TRAE of Grade 2 AST elevation was reported in one patient (5%). A TRAE of Grade 1 alanine transaminase (ALT) elevation was reported in one patient (5%) and a TRAE of Grade 3 ALT elevation was reported in one patient (5%). The mean dose intensity for RMC-6236 was 97%. Next steps: The company believes the data from this study support continued evaluation of the combination of RMC-6236 with pembrolizumab in 1L NSCLC patients."

P1 data • Non Small Cell Lung Cancer

Revolution Medicines Provides Clinical Updates from its RAS(ON) Inhibitor Portfolio (GlobeNewswire) - P1 | N=614 | NCT05379985 | Sponsor: Revolution Medicines, Inc. | "RMC-6236 at 120 mg to 220 mg QD demonstrated encouraging antitumor activity in the population of 40 efficacy-evaluable 2L or third-line (3L) patients with NSCLC who had received immunotherapy and platinum chemotherapy but had not received docetaxel. These patients achieved a median PFS of 9.8 months (95% CI, 6 – 12.3 months), a median OS of 17.7 months (95% CI, 13.7 months – NE) and an ORR of 38%. Next steps: The company expects to initiate RASolve 301, a randomized Phase 3 study of RMC-6236 versus docetaxel in patients with previously treated, locally advanced or metastatic RAS mutant NSCLC, in the first quarter of 2025."

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

RMC-6291 and RMC-6236 RAS(ON) Inhibitor Doublet (GlobeNewswire) - P1 | N=210 | RMC-6291-101 (NCT06128551) | Sponsor: Revolution Medicines, Inc. | "The combination of RMC-6291 with RMC-6236 was generally well tolerated across all dose levels evaluated. The most common TRAEs were rash and GI-related toxicities that were primarily Grade 1 or 2 in severity....In the combination study, patients with CRC who were previously treated with a KRAS(OFF) G12C inhibitor and who received their first doses of the two study drugs at least 8 weeks prior to data cutoff were included in the analyses (n=12). The ORR was 25%, including one patient with an unconfirmed complete response, and the DCR was 92%. The median treatment duration was 2.3 months."

P1 data • Colorectal Cancer

RMC-LUNG-101: Study of RAS(ON) Inhibitor Combinations in Patients with Advanced RAS-mutated NSCLC (clinicaltrials.gov) - P1/2 | N=484 | Recruiting | Sponsor: Revolution Medicines, Inc. | N=352 ➔ 484

Enrollment change • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Breakthrough in RAS targeting with pan-RAS(ON) inhibitors RMC-7977 and RMC-6236. (PubMed, Drug Discov Today) - "MYC amplification was reported to be a main contributor to the development of resistance. Six trials are currently ongoing, including one randomized trial, and promising results are expected from combination with other agents, such as immune-checkpoint blockers."

Journal • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • MYC

Clinical collaboration with Revolution Medicines (Businesswire) - "In November 2024, the Company entered into a clinical collaboration with Revolution Medicines to evaluate the efficacy and safety of TNG462 in combination with RMC-6236, a RAS(ON) multi-selective inhibitor, and with RMC-9805, a RAS(ON) G12D-selective inhibitor. The agreement provides that Revolution Medicines will supply RMC-6236 and RMC-9805 to Tango and that Tango will be the sponsor of any combination trials. Each company will retain commercial rights to their respective compounds and the agreement is mutually non-exclusive."

Commercial • Oncology

RMC-6236-001: Study of RMC-6236 in Patients With Advanced Solid Tumors Harboring Specific Mutations in RAS (clinicaltrials.gov) - P1 | N=614 | Recruiting | Sponsor: Revolution Medicines, Inc. | Trial completion date: Dec 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2024 ➔ May 2026

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