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

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

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

Combination of RAS(ON) mutant-selective and multi-selective inhibitors sensitizes immune-refractory, RAS-driven preclinical models to immunotherapy (AACR 2025) - "Here we evaluated if the RAS(ON) doublet combination of RMC-6291 or RMC-9805, a RAS(ON) G12C-selective inhibitor and a RAS(ON) G12D-selective inhibitor, respectively, with the RAS(ON) multi-selective inhibitor RMC-6236 can sensitize traditionally hard to treat, immune-refractory preclinical models to anti-PD-1. Collectively, these preclinical findings suggest that the RAS(ON) doublet combination of RAS(ON) mutant-selective and multi-selective inhibitors can reverse the immune-evasion mechanisms governed by oncogenic RAS and sensitize immune-refractory tumors to ICB to induce durable CRs. These preclinical data support the clinical evaluation of the RAS(ON) doublets in combination with ICB in patients with RAS driven cancers."

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

Mechanisms of resistance to the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236) in RAS mutant PDAC and potential resolution with RAS(ON) combination therapies (AACR 2025) - "Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is driven by oncogenic RAS mutations in >90% of cases. We demonstrate that the combination of daraxonrasib with a mutant-selective RAS(ON) inhibitor (either the RAS(ON) G12C mutant selective inhibitor elironrasib (RMC-6291), or the RAS(ON) G12D mutant selective inhibitor zoldonrasib (RMC-9805)) drove combinatorial benefit and forestalled monotherapy resistance in a series of preclinical models. The RAS(ON) inhibitor doublets of elironrasib or zoldonrasib with daraxonrasib are currently being evaluated in patients with tumors harboring RAS G12C and RAS G12D, respectively."

Combination therapy • Late-breaking abstract • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • MYC

TNG462, an MTA-cooperative PRMT5 inhibitor, demonstrates strong efficacy in combination with clinically relevant targeted therapies in MTAP-null preclinical models (AACR 2025) - "This supports our clinical development plans for TNG462, which include targeted combinations with two RAS(ON) inhibitors, RMC-6236 and RMC-9805 from Revolution Medicines, as well as the EGFR inhibitor osimertinib from AstraZeneca...Significant efficacy was observed in preclinical models with the combination of TNG462 and CDK4/6 inhibitors, supporting a potential development path in GBM for our next generation CNS penetrant PRMT5 inhibitor, TNG456, with abemaciclib...However, TNG462 monotherapy at a clinically relevant dose achieved comparable benefits to the combination. Collectively, these findings strongly support evaluating TNG462 in combination with other targeted therapies in clinical trials for patients with cancers that exhibit MTAP loss."

Combination therapy • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • KRAS • MAT2A • MTAP

Co-targeting the HER family and mutant KRAS is efficacious in colorectal cancer (AACR 2025) - "We have found that there is a striking increase in total HER3 levels in SNU-407, LS180, LS513 cells and 572918-348-R and 172845-121-B patient derived organoids (PDOs) when treated with the KRASG12D inhibitorsMRTX1133 and RMC9805, creating an adaptive response that could limit the efficacy of a KRAS inhibitor as a single agent...Co-targeting EGFR and mutant KRAS resulted in a slight synergistic effect in KRASG12D mutant cell lines usingMRTX1133 in combination with sapitinib, afatinib or peltinib. Currently, we are assessing if there is a synergistic effect directly targeting HER3 with a HER3 antibody-drug-conjugate in combination with a KRAS inhibitor in CRC cells. Our findings may present a new paradigm for targeted combination therapies in colorectal cancer with the eventual goal of increased overall patient survival."

Colorectal Cancer • Oncology • Solid Tumor • EGFR • ERBB4 • HER-2 • KRAS

Preliminary safety and antitumor activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D non-small cell lung cancer (NSCLC) from a phase 1 study in advanced solid tumors (AACR 2025) - "Abstract is embargoed at this time."

Clinical • Metastases • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

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

New P1/2 trial • Hepatology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

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

Revolution Medicines Reports Fourth Quarter and Full Year 2024 Financial Results and Update on Corporate Progress (GlobeNewswire) - "Strategic Priorities and Markers of Progress:...(i) The company expects to share additional clinical safety and antitumor activity on zoldonrasib in the second quarter of 2025. The company currently expects to initiate one or more pivotal combination trials in 2026 that incorporate either elironrasib or zoldonrasib and expects to share clinical data supporting these plans in the second or third quarter of 2025; (ii) The company expects to advance RMC-5127, a RAS(ON) G12V-selective inhibitor, to a clinic-ready stage in 2025 to enable the expected initiation of a first-in-human dose escalation Phase 1 clinical trial in 2026."

Clinical data • New trial • Solid Tumor

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

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

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

Preliminary safety, pharmacokinetics, and antitumor activity of 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 (EORTC-NCI-AACR 2024) - P1 | "Oral RMC-9805 showed encouraging initial antitumor activity in patients with KRAS G12D PDAC. Tolerability was favorable relative to SOC chemotherapy for PDAC and manageable across all dose levels and tumor types evaluated. 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."

Clinical • Late-breaking abstract • Metastases • P1 data • PK/PD data • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Revolution Medicines Presents Initial Data from RMC-9805 Monotherapy Study in Patients with Advanced Pancreatic Ductal Adenocarcinoma (GlobeNewswire) - P1 | N=444 | NCT06040541 | Sponsor: Revolution Medicines, Inc. | "Revolution Medicines...today announced preliminary safety and antitumor data for RMC-9805, its RAS(ON) G12D-selective inhibitor, in patients with previously treated pancreatic ductal adenocarcinoma (PDAC)....As of the September 2, 2024 data cutoff date, 179 patients were treated with escalating doses of RMC-9805 (ranging from 150-1200 mg once daily (QD) and 300-600 mg twice daily (BID)). Study patients had received a median of two prior therapies (range 0-9) and all had previously been treated with standard of care....Preliminary efficacy was assessed in PDAC patients. At a candidate recommended Phase 2 dose of 1200 mg daily (20 patients at 1200 mg QD and 20 patients at 600 mg BID), patients who received a first dose of RMC-9805 at least 14 weeks prior to the data cutoff date achieved a 30% (n = 12) objective response rate (confirmed or pending), with a disease control rate of 80% (n = 32)."

P1 data • Pancreatic Ductal Adenocarcinoma

The novel pan-RAF-MEK glue NST-628 is highly efficacious as monotherapy and as an anchor for vertical inhibition of the RAS-MAPK pathway in KRAS-mutant cancers (EORTC-NCI-AACR 2024) - P1 | " We designed in vitro potency assays (proliferation) to address the efficacy of NST-628 alone and in combination with KRAS G12D-inhibitors RMC-9805 (RAS "ON"), MRTX1133 (RAS "OFF"), and the pan-RAS inhibitor RMC-6236 (RAS "ON"). Collectively, this study warrants further investigation of NST-628 as a vertical combination partner with both RAS "ON" and RAS "OFF" inhibitors targeting KRAS G12D and other RAS mutations. NST-628 is positioned to make an impact clinically in areas of high unmet patient need in KRAS-mutant solid tumors. First-in-human trials of NST-628 in RAS- and RAF-mutant solid tumors are underway in 2024 (NCT06326411)."

Late-breaking abstract • Monotherapy • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Combination of RAS(ON) Multi-Selective and G12D-Selective Inhibitors Improves Antitumor Activity and Enhances Antitumor Immunity in Preclinical Models of KRASG12D-Driven Cancers (EORTC-NCI-AACR 2024) - "In addition, tumors treated with RMC-6236 plus RMC-9805 showed a more profound transformation of the tumor microenvironment (TME) in favor of antitumor immunity, with an increase in T cell infiltration and decrease in immunosuppressive myeloid cells, including M2-like macrophages and MDSCs. Transcriptomic analyses revealed a significant upregulation of antigen processing and presentation genes consistent with promotion of cancer cell recognition by immune cells.Collectively these preclinical findings support the clinical evaluation of the combination of RMC-6236 and RMC-9805 in patients with KRASG12D-mutant cancers."

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

Revolution Medicines to Deliver Multiple Presentations at the 2024 AACR-NCI-EORTC Symposium and Host Investor Webcast (GlobeNewswire) - "Revolution Medicines...announced seven oral and poster presentations will be featured at the 2024 AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics ('Triple Meeting'). The conference is being held October 23-25, 2024 in Barcelona, Spain. Two late-breaking presentations will feature new clinical data from patients treated for PDAC, including updated safety and efficacy data from the ongoing RMC-6236 monotherapy study and initial safety and antitumor activity data from the first-in-human monotherapy study of RMC-9805....Revolution Medicines will host an investor webcast focused on PDAC data from the RMC-6236 and RMC-9805 monotherapy studies on Friday, October 25, 2024, following the AACR-NCI-EORTC Symposium’s Late-Breaking Session."

Late-breaking abstract • P1 data • Pancreatic Ductal Adenocarcinoma

Targeting the oncogenic state of RAS with tri-complex inhibitors (AACRPanCa 2024) - "We have generated mutant-selective inhibitors that covalently engage RAS(ON) G12C (RMC-6291) or RAS(ON) G12D (RMC-9805). In addition, RMC-6236 is a RAS(ON) multi-selective inhibitor that non-covalently inhibits the active, GTP-bound state of mutant and wild-type variants of the canonical RAS isoforms (KRAS, NRAS, and HRAS). Here we will describe the mechanism of action of these investigational agents and the preclinical profiles that support their clinical evaluation in patients with PDAC as monotherapies and in combination therapy regimens with standard-of-care agents or as novel RAS(ON) inhibitor doublets."

Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HRAS • KRAS • NRAS

Revolution Medicines Reports Second Quarter 2024 Financial Results and Update on Corporate Progress (GlobeNewswire) - "Clinical Development Highlights:...(i) Qualifying RMC-6291 for Late-Stage Development:...The company expects to disclose initial clinical PK, safety, tolerability and antitumor activity data for the combination of RMC-6291 with RMC-6236 in the fourth quarter of 2024 and for the combination RMC-6291 with pembrolizumab in the first half of 2025; (ii) Qualifying RMC-9805 for Late-Stage Development: Monotherapy Development. The company expects to disclose initial clinical PK, safety, tolerability and antitumor activity data for RMC-9805 in the fourth quarter of 2024."

P1 data • P1/2 data • Non Small Cell Lung Cancer

Study of RMC-9805 in Participants With KRAS G12D-Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=444 | Recruiting | Sponsor: Revolution Medicines, Inc. | N=290 ➔ 444 | Trial completion date: Jul 2026 ➔ Apr 2027 | Trial primary completion date: Aug 2025 ➔ Apr 2026

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

Discovery of RMC-9805, an oral, covalent tri-complex KRASG12D(ON) inhibitor (AACR 2024) - P1 | "RMC-6236, an investigational RASMULTI(ON) inhibitor currently in clinical testing, selectively targets the active, GTP-bound state of both mutant and wild-type RAS variants, including RASG12D(ON) and has shown clinical anti-tumor activity against tumors harboring KRASG12D. RMC-9805 is also CNS penetrant and drove regressions in intracranial xenograft models of human KRASG12D PDAC. RMC-9805 is a first-in-class orally bioavailable, mutant selective and covalent RASG12D inhibitor currently in Phase 1 clinical trial (NCT06040541)."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Revolution Medicines Reports First Quarter 2023 Financial Results and Update on Corporate Progress (GlobeNewswire) - "The company presented early findings from its Phase 1/1b monotherapy trial (NCT05379985) during its Q4 earnings call....The company currently plans to provide further evidence of first-in-class single agent activity from the ongoing study in mid-2023, with multiple updates this year through a combination of corporate and scientific meeting presentations beginning in Q3....The company currently plans to provide a preliminary report of the clinical profile for RMC-6291 in the second half of 2023....The company currently expects to announce dosing of the first patient in a monotherapy dose-escalation study of RMC-9805 in mid-2023."

Clinical data • P1 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Revolution Medicines to Deliver Multiple Presentations at the Upcoming American Association for Cancer Research Annual Meeting 2024 (GlobeNewswire) - "Revolution Medicines...announced the company will deliver multiple presentations at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2024 being held April 5-10, 2024, in San Diego, California."

Preclinical • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Novel non-KRAS G12C inhibitors in solid tumors (YouTube) - "Alexander Spira, MD...provides an overview of non-KRAS G12C inhibitors for lung cancer and solid tumors, such as RMC-6236, which was assessed in the RMC-6236-001 trial (NCT05379985). In addition to lung cancer, the investigational pan-KRAS inhibitor was promising in pancreatic cancer, which has limited treatment options. KRAS G12D inhibitors under investigation include ASP3082 and RMC-9805. This interview took place at 2024 Targeted Therapies of Lung Cancer Meeting (TTLC 2024) in Santa Monica, CA."

Interview • Video