RMC-9805

Shows activity

Cancer types include:

colon cancer non-small cell lung cancer pancreas cancer rectal cancer small cell lung cancer

HealthScout AI Analysis

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Overview

RMC-9805 (zoldonrasib) is an oral, covalent, mutant-selective inhibitor of KRAS G12D that targets the active, GTP‑bound “RAS(ON)” state. It is being evaluated in a Phase 1/1b, multicenter, open-label study in adults with advanced solid tumors harboring KRAS G12D, as monotherapy and in combination with the RAS(ON) multi-selective inhibitor RMC‑6236 (NCT06040541). (ascopubs.org)

Mechanism of action

Tri-complex KRAS G12D(ON) inhibition: RMC‑9805 forms a high‑affinity tri‑complex with cyclophilin A and KRAS G12D in its GTP‑bound state, enabling selective covalent engagement at Asp12 and sterically blocking effector interactions (for example, RAF), thereby suppressing downstream signaling. Preclinical studies demonstrated durable pathway suppression, apoptosis, and tumor regressions in KRAS G12D models. (aacrjournals.org)

Efficacy

Pancreatic ductal adenocarcinoma (PDAC), 2L+ setting (Phase 1 monotherapy):
Among patients dosed at the candidate RP2D of 1200 mg daily (1200 mg QD or 600 mg BID), efficacy-evaluable PDAC patients enrolled ≥14 weeks before data cutoff (n=40) achieved an objective response rate (ORR) of 30% and a disease control rate (DCR) of 80% (data cutoff September 2, 2024; ASCO GI 2025 abstract). Circulating tumor DNA analyses showed >50% on‑treatment KRAS G12D reductions in 86% (24/28) and 100% clearance in 39% (11/28). (ascopubs.org)
Non–small cell lung cancer (NSCLC), previously treated (Phase 1 monotherapy):
At 1200 mg QD, preliminary results in efficacy‑evaluable patients (n=18) showed ORR 61% (confirmed or pending) and DCR 89%; median time to initial response was 1.4 months (data cutoff December 2, 2024; AACR 2025). (aacrjournals.org)

Note: Results are early-phase and based on small cohorts; follow‑up and confirmation are ongoing in expansion cohorts. (ascopubs.org)

Safety

Across doses up to 1200 mg daily, no dose‑limiting toxicities were observed and the maximum tolerated dose was not reached in the Phase 1 study. At the candidate RP2D (1200 mg daily), the most common treatment‑related adverse events were nausea (~27–39%), diarrhea (~20–24%), vomiting (~15–18%), and rash (~10–12%), predominantly Grade 1–2; isolated Grade 3 ALT elevation was reported. Discontinuations due to TRAEs were not observed, and dose reductions occurred in about 4% of patients. (ascopubs.org)

Study status and design

Phase 1/1b trial (NCT06040541): open‑label, dose exploration and expansion of RMC‑9805 as monotherapy and in combination with RMC‑6236 in KRAS G12D‑mutant solid tumors; primary completion currently estimated for April 2026. (cdek.pharmacy.purdue.edu)

Active trials using RMC-9805

Found 4 active trials using this drug:

A Phase 1/2, Multicenter, Open-Label Study to Evaluate Safety, Tolerability & Antitumor Activity of TNG462 in Combination With Other Agents in Patients With Pancreatic or Non-Small Cell Lung Cancer With MTAP Loss & RAS Mutation

Sponsor: Tango Therapeutics, Inc. (industry) Phase: 1/2 Start date: May 31, 2025

HealthScout AI summary: This trial enrolls adults with metastatic pancreatic or non-small cell lung cancer harboring both MTAP loss and a RAS mutation, previously treated with standard therapies, to receive TNG462 (a selective PRMT5 inhibitor exploiting MTAP-deleted tumor vulnerabilities) combined with either RMC-6236 (a multi-RAS mutant inhibitor) or RMC-9805 (a KRAS G12D-selective inhibitor). Prior treatment with RAS-targeted, PRMT5, or MAT2A inhibitors is not allowed.

ClinicalTrials.gov ID: NCT06922591

A Platform Study of RAS(ON) Inhibitors in Patients With Gastrointestinal Solid Tumors

Sponsor: Revolution Medicines, Inc. (industry) Phase: 1/2 Start date: May 24, 2024

HealthScout AI summary: This trial enrolls adults with metastatic or unresectable, RAS-mutant colorectal or pancreatic cancer (including KRAS G12D subsets), and tests oral RAS(ON) inhibitors—RMC-6236 (a multi-selective tri-complex RAS inhibitor) and RMC-9805 (a KRAS G12D-selective molecular glue)—either as monotherapy or combined with standard therapies such as mFOLFOX6, mFOLFIRINOX, gemcitabine/nab-paclitaxel, bevacizumab, or cetuximab. All patients must have ECOG 0-1 and adequate organ function.

ClinicalTrials.gov ID: NCT06445062

A Platform Study of RAS(ON) Inhibitor Combinations in Patients With RAS-Mutated Non-Small Cell Lung Cancer (NSCLC)

Sponsor: Revolution Medicines, Inc. (industry) Phase: 1/2 Start date: Jan. 18, 2024

HealthScout AI summary: This trial enrolls adults with advanced or metastatic RAS-mutated NSCLC (including KRAS G12C and G12D subtypes) who have progressed on standard therapies, testing investigational RAS(ON) inhibitors—RMC-6291 (KRAS G12C-selective), RMC-6236 (multi-selective RAS), and RMC-9805 (KRAS G12D-selective via cyclophilin A tri-complex)—alone or combined with pembrolizumab or platinum-based chemotherapies. Eligible patients must have ECOG 0–1 and adequate organ function.

ClinicalTrials.gov ID: NCT06162221

Phase 1/1b, Multicenter, Open-Label, Study of RMC 9805 in Participants With Advanced KRASG 12D-Mutant Solid Tumors

Sponsor: Revolution Medicines, Inc. (industry) Phase: 1 Start date: Sept. 7, 2023

HealthScout AI summary: This trial enrolls adults with advanced, previously treated KRAS G12D-mutant solid tumors (excluding those with CNS involvement or prior direct RAS inhibitor use) to receive the selective KRAS G12D inhibitor RMC-9805, either as monotherapy or combined with the RAS(ON) multi-selective inhibitor RMC-6236. RMC-9805 acts as a molecular glue inducing covalent modification of KRAS G12D, while RMC-6236 targets multiple active KRAS G12X mutations.

ClinicalTrials.gov ID: NCT06040541