RMC-7977 / Revolution Medicines - LARVOL DELTA

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

THE MOLECULAR BACKGROUND DETERMINES THE EXTENT BY WHICH LSD1 INHIBITORS SENSITIZE AML CELLS TO KINASE AND RAS INHIBITORS (EHA 2025) - "These cells present FLT3, NRAS and JAK2 activating mutations, respectively.Independently of FLT3 and RAS mutations, Iadademstat, sensitized 10, 8, 8 and 7 AML cell lines to gilteritinib, trametinib, pictilisib and RMC-7977, respectively...These included the phosphorylations of pNIBAN2(Ser692) and pNFIL3(Ser287)...Remarkably, gilteritinib reduced STAT5A/B phosphorylation, and iadademstat sensitised HEL cells to the JAK inhibitor ruxolitinib. In summary, the heterogeneity by which LSD1 inhibition sensitizes AML cells to FLT3, PI3K, RAS and MEK inhibitors can be rationalised by differences in how LSD1 regulates the wirings of kinase signalling networks irrespective of FLT3 and RAS mutations."

Acute Myelogenous Leukemia • FLT3 • NRAS • STAT5

Pan-RAS inhibitor RMC-7977 is efficacious in treating NF1-related tumors. (PubMed, Neurooncol Adv) - No abstract available

Journal • Oncology • NF1

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

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

Combining RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitors overcomes sotorasib resistance driven byKRASG12C amplification or NRASG13R mutation (AACR 2025) - "Amplification of the KRASG12C mutant allele and acquisition of NRAS mutations have been reported as resistance mechanisms in tumors progressing on sotorasib and adagrasib...We generated five sotorasib-resistant cell lines from relapsed tumors of sotorasib-treated H358 xenografts (MR1-MR5) and two vehicle-treated tumors (MV1 and MV2). We created an additional isogenic cell line model, H358-MX1, by treating H358 cells with sotorasib and a SHP2 inhibitor, RMC-4550...In H358-MX1 mouse xenografts, RMC-7977 + RMC-4998 significantly inhibited tumor growth compared to single-agent treatments or other combination regimens. These preclinical data suggest that combination of RAS(ON) mutant-selective and RAS(ON) multi-selective inhibitors overcome resistance to KRASG12C (OFF) inhibitors driven by KRASG12C amplification and secondary NRASG13R mutation in KRASG12C mutated lung cancer models."

Lung Cancer • Oncology • Solid Tumor • KRAS • MX1 • NRAS

Targeting RAS in angiosarcoma (AACR 2025) - "Our results show that RMC-7977 and MEK1/2 inhibitor mirdametinib exhibit strong potency against angiosarcoma cell lines harboring mutations in RAS and VEGFR/TIE2 pathways. We will also investigate the molecular mechanisms underlying oncogenic signaling to elucidate RAS dependency and strengthen the rationale for using RAS inhibitors to treat angiosarcoma. This approach aims to demonstrate that targeting RAS through RAS(ON) multi-selective inhibitors is effective, highlighting the urgent need for clinical trials to advance treatment options for angiosarcoma patients."

Angiosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • FLT4 • HRAS • KDR • KRAS • NF1 • NRAS • PIK3CA • PLCG1 • PTEN

Mechanisms of resistance to RAS-GTP inhibition in pancreatic cancer (AACR 2025) - "A related compound, RMC-6236, is under clinical investigation for both RAS-mutant solid tumors and metastatic PDAC. Targeting these kinases in combination with RMC-7977 reverted resistance in models of innate and acquired resistance, suggesting a potential approach to investigate preventing or overcoming resistance in patients. Collectively, our pre-clinical data suggest that resistance to RAS inhibition with RMC-7977 may arise via multiple mechanisms, among them secondary RAS mutations, PI3K pathway-activating mutations, or cell-state changes that drive adaptive signaling through ECM-signaling pathways."

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

Direct inhibition of RAS reveals the features of oncogenic signaling in RAS-mutant cancers (AACR 2025) - "Here, we use RMC-7977, a first-in-class RAS·GTP inhibitor (RASMULTI(ON)), to characterize the features and therapeutic vulnerabilities of mutant RAS signaling in various human cancers...These findings provide mechanistic insights into how mutant RAS interacts with upstream and downstream partners to maximize oncogenic signaling. Furthermore, our results shed light on the selective pressure driving the emergence of RASQ61X mutations as a mechanism of resistance against RTK inhibition in colorectal cancer: we show that colorectal cancer cells that acquire RASQ61X mutations to overcome EGFR inhibition become more independent of upstream signaling than those that acquire RASG12X and this may explain the predominance of this mutation in colorectal cancer patients who acquire resistance to EGFR inhibitors."

Colorectal Cancer • Liver Cancer • Oncology • Solid Tumor

Preclinical evaluation of RMC-7977, a multi-selective RAS(ON) inhibitor, as a therapeutic strategy for KRAS-mutant cholangiocarcinoma (AACR 2025) - "In summary, our preclinical findings support the clinical testing of a RAS(ON) multi-selective inhibitor, either alone or in combination with other in-pathway or out-of-pathway partners, as a potential therapeutic strategy for CCA treatment."

IO biomarker • Preclinical • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CD4 • CD8 • FGFR • KRAS

Distinct regulation of Cyclin D mediates heterogenous response to RAS inhibition in colorectal cancer models (AACR 2025) - "In these cells, either RMC-7977 or the MEK inhibitor trametinib are sufficient to fully inhibit Cyclin D1 and cause G1 cell cycle arrest. Thus, we find a potential mechanism of resistance to RAS inhibition in CRC is persistent Cyclin D1 expression, mediated either through ERK-pathway re-activation or a shift in CCND1 mRNA regulation away from the ERK pathway. Depending on the tumor's distinct regulation of Cyclin D1, its full suppression can be achieved through increased inhibition of RAS-MAPK pathway signaling or a parallel inhibition strategy with RAS + PI3K combination inhibition."

Late-breaking abstract • Preclinical • Colorectal Cancer • Oncology • Solid Tumor • CCND1 • HER-2 • KRAS

Determination of the MYC- and TEAD-dependent transcriptome in pancreatic cancer (AACR 2025) - "We recently reported MYC amplification and TEAD-dependent transcriptional activation by YAP as drivers of resistance to the multi-RAS inhibitor RMC-7977 (RASmulti), the preclinical analog of RMC-6236...To determine the TEAD-dependent transcriptome, we treated a panel of three sets of paired naïve and RASmulti-resistant KPC cell lines, derived from an autochthonous mouse model of PDAC, and of six human KRAS-mutant PDAC cell lines with the TEAD inhibitor IAG933, with RMC-7977, or with the combination...Proteomic profiling of PDAC cell lines with acquired resistance to RMC-7977 showed upregulation of TEAD-dependent gene products, supporting TEAD activation as a non-genetic mechanism of acquired resistance. Together, our findings expand the role of MYC and TEAD in supporting PDAC cell growth and resistance to RAS inhibition and provide rationale for further evaluation of combination therapeutic strategies to limit resistance."

Late-breaking abstract • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • KRAS • MYC

T-cell dependency of tumor regressions and complete responses with RAS(ON) multi-selective inhibition in preclinical models of PDAC (AACR 2025) - "Activating mutations in KRAS drive tumorigenesis in more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC), promoting tumor cell proliferation and survival and contributing to an immunosuppressive tumor microenvironment (TME).RAS(ON) multi-selective inhibitors, such as RMC-6236 and RMC-7977, potently block the active state of mutant and wild-type RAS isoforms and show profound anti-tumor activity in PDAC murine models1. Although the RAS-MAPK signaling is essential to T cell function, incubation of pre-activated murine or human CD8+ T cells with RMC-7977 did not impede viability, activation, or proliferation in vitro. In addition, treatment of mice with RMC-7977 did not affect T cell responses to vaccination challenge in vivo.Overall, our preclinical data suggest that an adaptive immune response contributes to the anti-tumor effects of RAS(ON) multi-selective inhibitors in PDAC models, supporting clinical evaluation of the combination of RAS(ON) multi-selective..."

IO biomarker • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BATF3 • CD40 • CD8 • KRAS • PDX1

Pan-RAS inhibitor RMC-7977 overcomes oncogenic RAS signaling and exerts antileukemic effects in CMML/AML cells (AACR 2025) - "We have demonstrated that the pan-RAS inhibitor RMC-7977 is highly effective against RAS mutated AML cell lines arising from chronic myeloid neoplasms including CMML while sparing healthy hematopoietic stem and progenitor cells. This work provides the rationale to continue evaluating RAS inhibitors as a targeted therapy in RAS-mutated myeloid malignancies, which is a significant unmet need in the treatment of these conditions."

Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • HRAS • KRAS • NRAS

Revolution Medicines to Deliver Multiple Presentations at the 2025 American Association for Cancer Research (AACR) Annual Meeting (GlobeNewswire) - "Revolution Medicines...announced 11 oral and poster presentations will be featured at the American Association for Cancer Research (AACR) Annual Meeting....The first clinical data in non-small cell lung cancer from the Phase 1 study of zoldonrasib, a RAS(ON) G12D-selective inhibitor, will be featured in a late breaking oral presentation."

Clinical data • Late-breaking abstract • Preclinical • Cholangiocarcinoma • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

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

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

Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer. (PubMed, bioRxiv) - "Single cell profiling of AC-PC pairs reveals dedifferentiation from mucinous differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. Through hypothesis-driven drug testing, we identify KRAS MULTI -ON inhibitor RMC-7977 and Wnt-targeting tyrosine kinase inhibitor WNTinib as novel, clinically actionable strategies to target AC-PC more effectively."

Journal • Preclinical • Appendix Cancer • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Peritoneal Cancer • Solid Tumor • KRAS

Clinico-genomic landscape and therapeutic vulnerabilities of wild-type KRAS amplification in non-small cell lung cancer (IASLC-TTLC 2025) - "KRAS amplification defines a novel subset of oncogene-driven NSCLCs characterized by distinct clinicopathologic and genomic features, worse survival, but increased sensitivity to RAS inhibition."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • KEAP1 • KRAS • PD-L1 • RBM10 • SMARCA4

Genomic landscape of clinically acquired resistance alterations in patients treated with KRASG12C inhibitors. (PubMed, Ann Oncol) - "Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRASG12Ci detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations."

Journal • Preclinical • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • 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

Pan-RAS Inhibitor RMC-7977 Overcomes Oncogenic RAS Signaling and Exerts Antileukemic Effects in CMML/AML Cells (ASH 2024) - "FDA-approved KRASG12C inhibitors sotorasib and adagrasib demonstrate significant clinical response for non-small cell lung cancer patients harboring KRAS G12C mutation, and early data suggests that pan-RAS inhibitors are safe and effective in PDAC and NSCLC. Experiments evaluating the effects of RMC-7977 in cell line xenografts and additional patients' primary samples are ongoing and will be presented.Collectively, we have demonstrated that the pan-RAS inhibitor RCM-7977 is highly effective against RAS mutated CMML/AML cell lines arising from chronic myeloid neoplasms including CMML while sparing healthy hematopoietic stem and progenitor cells. This work provides the rationale to continue evaluating RAS inhibitors as a targeted therapy in RAS-mutated myeloid malignancies, which is a significant unmet need in the treatment of these conditions."

IO biomarker • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lung Cancer • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • CD34 • FLT3 • HRAS • IDH1 • IDH2 • JAK2 • KIT • KRAS • NRAS

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

RMC-7977, a highly selective inhibitor of the active RAS-GTP to treat pancreatic cancer. (PubMed, Acta Pharm Sin B) - No abstract available

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Advancing RAS inhibition: broad-spectrum targeting and tumor-selective activity of RMC-7977 in cancer therapy. (PubMed, Sci China Life Sci) - No abstract available

Journal • Oncology