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The Clinical Landscape of KRAS G12D-Targeted Therapies

Linda
Linda ·

Based on the comprehensive analysis of the provided tool results, here is a detailed summary of KRAS G12D inhibitors in clinical trials as of December 31, 2025.

Executive Summary

As of late 2025, the clinical development landscape for KRAS G12D inhibitors is rapidly advancing, with at least six distinct therapeutic agents in Phase I to Phase III trials. These inhibitors, primarily oral small molecules with one RNAi-based approach, are showing varied but promising results across difficult-to-treat solid tumors like pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC).

Daraxonrasib (RMC-6236) from Revolution Medicines is the most advanced, having entered a Phase III trial for NSCLC 4. However, VS-7375 (GFH375) from Verastem/GenFleet and Zoldonrasib (RMC-9805) from Revolution Medicines have demonstrated the most striking early efficacy signals, with Objective Response Rates (ORR) exceeding 50% in specific patient cohorts 19, 26. Safety profiles are generally manageable, with gastrointestinal and dermatologic toxicities being the most common class effects. Notably, TSN1611 has shown an exceptionally clean safety profile with no severe treatment-related adverse events reported to date 24. In contrast, the development of MRTX-1133 by Mirati/BMS has been halted for strategic review after showing limited activity in Phase I 8, 9.

Key data on long-term efficacy, such as median Progression-Free Survival (PFS), Duration of Response (DoR), and Overall Survival (OS), remain immature for most agents, representing a critical gap that will be addressed as trials mature.

Comprehensive Comparison of KRAS G12D Inhibitors in Clinical Trials

The following table provides a comparative overview of the key KRAS G12D inhibitors based on available clinical trial data up to December 2025.

ParameterDaraxonrasib (RMC-6236)Zoldonrasib (RMC-9805)VS-7375 (GFH375)TSN1611MRTX-1133siG12D-LODER
CompanyRevolution MedicinesRevolution MedicinesVerastem / GenFleetTyligand BioscienceMirati / BMSSilenseed / Silexion
MechanismOral, pan-RAS(ON) inhibitorOral, covalent KRAS G12D(ON) "tri-complex" inhibitor 30Oral, dual KRAS G12D(ON/OFF) inhibitor 25Oral, KRAS G12D inhibitorOral, reversible non-covalent KRAS G12D inhibitor 29Intratumoral siRNA implant 13
Highest PhasePhase III (NSCLC) 4Phase I/II 14, 28Phase I/II 26Phase I/II 24Phase I (Halted) 8Phase II 10
DLTsNone reported up to 300 mg QD 4None DLT reported up to 1200 mg QD 14, 19, 28.None reported up to 900 mg QD or 300 mg BID 26None reported up to 600 mg BID 24Reversible G3 ALT/AST increase at ≥100 mg BID 8None reported; AEs mainly from chemo 12
MTD / RP2DMTD not reached. Prelim RP2D: 160 mg QD 4MTD not reached. RP2D: 1200 mg QD 28MTD not reached. US Phase I starting at 400 mg QD 2MTD not reached. RP2D not established 2MTD not reached before halt. No RP2D declared 8MTD not reached. RP2D: 2.8 mg implant 11
Efficacy (ORR)Overall: 23% (all RAS) 5PDAC (2L): 29% 18NSCLC: 61% (n=18) 19, 31PDAC: 30% (n=40) 28PDAC: 52% (n=23) 26NSCLC: 42% (n=12) 26Overall: Tumor shrinkage in 23% (3/13) 24Overall: 3% (1 PR in 32 pts) 9PDAC (w/ chemo): 20-56% 12, 22
Efficacy (DCR)Overall: 82% 5NSCLC: >80% 31PDAC: 80% 28PDAC: 100% 26NSCLC: 83% 2Overall: 31% (SD) 24Overall: 34% 9PDAC (w/ chemo): 80% 12
Efficacy (PFS/DoR/OS)mPFS: 5.9 mo (all RAS) 5PDAC mPFS: 8.5 mo 18PDAC mOS: 14.5 mo 18Immature data 28Immature dataImmature dataImmature dataPDAC mPFS: 5.7 mo 12PDAC mDoR: 4.5 mo 12
Grade ≥3 TRAEs7% fatigue, 6% diarrhea, 8% rash 6, 18<5% overall. G3 ALT increase 1% 28, 3229% overall. 8% neutropenia, 5% diarrhea 2, 260% 2419% overall (transaminase increase, diarrhea) 9None implant-related 12, 22
SAEs9% treatment-related 60% treatment-related 28Not separately reported0% treatment-related 242 drug-related (ALT increase, pneumonitis) 9None implant-related 12
Discontinuations (due to TRAE)6% 60% 283-6.3% 2, 26Not reported1 patient (hepatic AE) 9None implant-related 12
Regulatory StatusIND active. Phase 3 initiated 7.IND active 28.FDA Fast Track for PDAC 26.FDA IND cleared Feb 2024 24.IND cleared, but program under "strategic review" 9, 20.Investigational device/drug combo 22.

Detailed Drug Profiles

1. Zoldonrasib (RMC-9805) - Revolution Medicines

Zoldonrasib is an oral, covalent inhibitor of the active KRAS G12D(ON) state that works via a "tri-complex" mechanism 30. It has emerged as a highly promising agent with impressive early efficacy and a favorable safety profile.

  • Dosing and Safety: In its Phase 1 trial (NCT06040541), Zoldonrasib has been tested up to 1200 mg once daily (QD), which was established as the Recommended Phase 2 Dose (RP2D) 28. No DLTs were observed in Part 1; MTD was not reached 14, 28. The safety profile is remarkably clean, with zero treatment-related Serious Adverse Events (SAEs) and zero discontinuations due to adverse events across 179 patients treated as of September 2024 28. The most common treatment-related adverse events (TRAEs) were low-grade nausea (30%), diarrhea (16-20%), and vomiting (15%) 28. Grade ≥3 TRAEs are rare (<5%), with Grade 3 ALT elevation noted in only 1% of patients 28, 32.

  • Efficacy: Zoldonrasib has shown significant clinical activity, particularly in NSCLC.

    • NSCLC: In an 18-patient cohort, it achieved an ORR of 61% and a Disease Control Rate (DCR) over 80% 19, 31.
    • PDAC: In a larger cohort of 40 evaluable patients, the ORR was 30% with a DCR of 80% 28. On-target activity was confirmed by ctDNA reductions of >50% in 86% of patients 28.
    • Data on PFS, DoR, and OS are still immature due to short follow-up 28.

2. VS-7375 (GFH375) - Verastem / GenFleet

VS-7375 is an oral inhibitor that uniquely targets both the active (ON) and inactive (OFF) states of KRAS G12D, which may lead to deeper and more durable responses 25. It has demonstrated best-in-class potential, especially in PDAC.

  • Dosing and Safety: The Phase I/II study in China evaluated doses from 100-900 mg QD without reaching an MTD or observing any DLTs 26. The safety profile is manageable, though more active than Zoldonrasib or TSN1611. Grade ≥3 TRAEs occurred in 25-29% of patients, most commonly decreased neutrophil count (8%) and diarrhea (5%) 2, 26. Importantly, dose reductions were required in only 5% of patients, and the discontinuation rate due to AEs was low at 3-6.3% 2, 26. The long half-life of 18.5-21.6 hours supports a convenient once-daily dosing schedule 2.

  • Efficacy: VS-7375 has produced outstanding response rates in heavily pretreated populations.

    • PDAC: In a cohort of 23 patients, it achieved a remarkable ORR of 52% and a DCR of 100%, with all patients showing some degree of tumor shrinkage 26. This strong signal led to an FDA Fast Track designation for PDAC in July 2025 26.
    • NSCLC: In 12 patients, the ORR was 42% and the DCR was 83% 2, 26.
    • Durability data (PFS, DoR, OS) are not yet mature but are eagerly awaited.

3. Daraxonrasib (RMC-6236) - Revolution Medicines

Daraxonrasib is a first-in-class, oral, pan-RAS inhibitor with activity against multiple RAS mutations, including G12D. It is the most clinically advanced agent in this group.

  • Dosing and Safety: The MTD was not reached in Phase 1 dose escalation up to 300 mg QD, with a preliminary RP2D of 160 mg QD selected 4. The safety profile is considered manageable. The most common Grade ≥3 TRAEs include fatigue (7%), diarrhea (6%), nausea (5%), and rash (8%) 6, 18. Treatment-related SAEs were reported in 9% of patients, and 6% of patients discontinued treatment due to drug-related AEs 6.

  • Efficacy: As a pan-RAS inhibitor, efficacy has been demonstrated across various RAS-mutant tumors.

    • Overall (RAS-mutant): Across 133 evaluable patients, the ORR was 23% and DCR was 82% 5.
    • PDAC (2nd Line): The ORR was 29% 18.
    • Durability: The median PFS was 5.9 months across all RAS mutants and 8.5 months in 2L PDAC. Median OS in the PDAC cohort was 14.5 months, the most mature survival data reported for any of these agents 5, 18.

4. TSN1611 - Tyligand Bioscience

TSN1611 is an oral KRAS G12D inhibitor distinguished by its exceptionally favorable safety profile in early trials.

  • Dosing and Safety: In a Phase I/II study (NCT06385925), doses up to 600 mg twice daily (BID) were evaluated with no DLTs, no Grade ≥3 TRAEs, and no treatment-related SAEs reported in the initial 18-patient cohort 24. All AEs were Grade 1-2, with the most common being gastrointestinal (vomiting 44%, nausea/diarrhea 39%) 24. This clean profile suggests a wide therapeutic window and high potential for combination therapies.

  • Efficacy: Efficacy data are still very early.

    • Overall: Among 13 evaluable patients, no confirmed responses were reported, but tumor shrinkage was observed in 3 patients (23%) with CRC, PDAC, and NSCLC. The DCR (stable disease) was 31% 24.
    • Pharmacodynamic data confirmed on-target activity, with decreases in KRAS G12D ctDNA at doses ≥200 mg BID 2.

5. MRTX-1133 - Mirati Therapeutics / BMS

MRTX-1133 is an oral, non-covalent KRAS G12D inhibitor. Its clinical development has been paused.

  • Dosing, Safety, and Efficacy: The first-in-human trial (NCT05737706) was halted in 2024 for corporate reprioritization after the BMS acquisition of Mirati 8.
    • DLTs included reversible Grade 3 elevations in liver enzymes (ALT/AST) at doses of 100 mg BID or higher 8.
    • Efficacy was limited, with only one confirmed partial response (PR) in 32 evaluable patients (ORR 3%) and a DCR of 34% 9.
    • The safety profile included Grade ≥3 TRAEs in 19% of patients (transaminase increases, diarrhea) and two drug-related SAEs (ALT increase, pneumonitis) 9. The program's future is under "strategic review" 9.

6. siG12D-LODER - Silenseed / Silexion

This agent represents a unique modality, using a biodegradable intratumoral implant (LODER) to provide sustained local release of siRNA targeting KRAS G12D.

  • Dosing and Safety: The Phase 2 trial (NCT 2018-00398) evaluates a 2.8 mg implant in combination with chemotherapy for unresectable PDAC 10, 11. The safety profile is favorable, with no DLTs or implant-related SAEs reported. Most Grade ≥3 AEs, such as neutropenia (27%) and diarrhea (13%), were attributed to the background chemotherapy 12.

  • Efficacy: In combination with FOLFIRINOX, siG12D-LODER has shown promising results.

    • PDAC: Interim reviews reported an ORR of 20% to 56%, significantly higher than chemotherapy alone 12, 22.
    • A key finding was a 67% conversion rate to resectability in patients with locally advanced PDAC, and a reported OS benefit of over 9 months versus chemo-alone 22.

Disclosure: All analysis is conducted by Noah. This content is for informational purposes only and does not constitute investment or medical advice.

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