KRAS Inhibitors for Cancer
Incyte's KRAS G12D inhibitor, INCB161734, was placed on clinical hold in four European countries on March 5, 2026, following a Grade 5 pneumonitis death and three additional pneumonitis cases associated with the 1.2g dose. As of March 14, 2026: Revolution Medicines' Daraxonrasib (RMC-6236) received FDA breakthrough therapy designation for metastatic PDAC with KRAS G12X mutations, and Verastem Oncology's VS-7375 showed preliminary antitumor activity in advanced solid tumors with 80% of efficacy-evaluable patients experiencing tumor reduction. MRTX1133, a selective KRAS G12D inhibitor, is in a phase I/II clinical trial, demonstrating potent preclinical antitumor efficacy. Erasca and Tango Therapeutics are collaborating on combination therapy for RAS-mutant cancers, while a PNAS study on December 2, 2025, detailed a triple combination therapy involving daraxonrasib that induced complete regression of pancreatic cancer tumors in mice.
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20 updates
2026
20 updatesMRTX1133, a selective KRAS G12D inhibitor, has demonstrated potent preclinical antitumor efficacy, particularly in pancreatic ductal adenocarcinoma. Research is focused on combining MRTX1133 with chemotherapy to reduce tumor growth and overcome resistance, with a phase I/II clinical trial underway.
Revolution Medicines' investigational pan-RAS inhibitor, Daraxonrasib (RMC-6236), has demonstrated early activity and a manageable safety profile in patients with RAS-mutant pancreatic adenocarcinoma. The drug has received FDA breakthrough therapy designation for previously treated metastatic PDAC with KRAS G12X mutations, and a Phase 3 trial is underway.
Verastem Oncology's investigational oral KRAS G12D inhibitor VS-7375 demonstrated a promising early safety profile and preliminary antitumor activity in patients with advanced solid tumors harboring a KRAS G12D mutation. In the Phase 1/2a VS-7375-101 trial, no dose-limiting toxicities were observed at daily doses of 400 mg and 600 mg, and 80% of efficacy-evaluable patients experienced tumor reduction. The FDA granted VS-7375 Fast Track Designation in July 2025 for KRAS G12D-mutated pancreatic cancer.
Verastem Oncology has outlined a new development pathway for its KRAS G12D inhibitor, VS-7375, for pancreatic, colorectal, and non-small cell lung cancer, following discussions with the US Food and Drug Administration. The investigational oral inhibitor has demonstrated a promising early safety profile and preliminary antitumor activity in pretreated patients with advanced solid tumors harboring a KRAS G12D mutation.
Incyte's KRAS G12D inhibitor, INCB161734, has been placed on clinical hold in four European countries following a Grade 5 pneumonitis death in a participant. Three additional cases of pneumonitis were also reported, all associated with the 1.2g dose.
The KRAS G12D inhibitor INCB161734 demonstrated disease control in nearly 80% of heavily pretreated advanced pancreatic cancer patients, with 37% achieving objective responses. Verastem Oncology's inhibitor VS-7375 has cleared multiple dose levels in early studies without dose-limiting toxicities, allowing for continued dose escalation. Additionally, Erasca and Tango Therapeutics are collaborating to evaluate a combination therapy for RAS-mutant cancers.
A PNAS study published on December 2, 2025, details a triple combination therapy involving daraxonrasib that induced complete regression of pancreatic cancer tumors in mice with no evidence of resistance. Verastem Oncology reported on March 4, 2026, that their oral KRAS G12D inhibitor VS-7375 cleared multiple dose levels in early studies without dose-limiting toxicities, allowing dose escalation to continue.
Erasca presented updates on its pan-RAS inhibitor ERAS-0015 and pan-KRAS inhibitor ERAS-4001, with ERAS-0015 showing a potency advantage over RMC-6236. Separately, a PNAS study details a triple combination therapy including daraxonrasib that induced complete regression of pancreatic cancer tumors in mice with no evidence of resistance.
Preliminary Phase 1 data for INCB161734 presented at ASCO GI 2026 showed a disease control rate of 73% at 600 mg once daily and 86% at 1200 mg once daily in patients with advanced pancreatic cancer. New research also suggests combining chemotherapy with KRAS inhibitors may enhance treatment effectiveness, and that resistance to KRAS G12D inhibitors can be overcome by BET inhibition.
Incyte has announced that based on positive clinical data from a Phase 1 trial of INCB161734 in patients with advanced pancreatic ductal adenocarcinoma, a Phase 3 study is expected to commence in the first quarter of 2026. This marks a significant step forward in the development of this KRAS G12D inhibitor.
via businesswire.com
Verastem Oncology is advancing its clinical development program for VS-7375, a selective oral KRAS G12D inhibitor, and expects to report an interim update on its Phase 1/2 trial in the first half of 2026. Early data for INCB161734 show a manageable safety profile and evidence of antitumor activity in heavily pretreated patients with KRAS G12D-mutated PDAC. Additionally, the investigational oral KRAS G12D inhibitor VS-7375 has demonstrated a promising early safety profile and preliminary antitumor activity in pretreated patients with advanced solid tumors harboring a KRAS G12D mutation.
via targetedoncology.com·oncodaily.com·ascopubs.org·prnewswire.com·businesswire.com
Revolution Medicines has expanded its KRAS inhibitor research with a new molecule, RMC-5127, targeting KRAS G12V, which has just entered its first-in-human trial.
Verastem Oncology discontinued its RAMP 203 Phase 1/2 trial for KRAS G12C-mutated non-small cell lung cancer to prioritize resources for the clinical development of the oral KRAS G12D inhibitor VS-7375.
via prnewswire.com
A new study reported that a triple-targeted drug combination, including the KRAS inhibitor daraxonrasib, achieved complete and lasting regression of pancreatic tumors in preclinical models, demonstrating potential to overcome treatment resistance.
Research indicates that resistance to the KRAS G12D inhibitor MRTX1133 is associated with increased sensitivity to BET inhibition, with murine models showing that BET inhibition cooperated with MRTX1133 to significantly extend overall survival.
via sigma.larvol.com
Preliminary Phase 1 results for Incyte's oral KRAS G12D inhibitor INCB161734 showed promising early clinical efficacy and molecular response in advanced pancreatic cancer patients, with common side effects being nausea and diarrhea. Revolution Medicines' daraxonrasib (RMC-6236) received Orphan Drug Designation from the FDA for pancreatic cancer treatment, building on promising safety and efficacy data from its Phase 1/1b trial.
Preliminary Phase 1 results for INCB161734, an oral KRAS G12D inhibitor, show a manageable safety profile with mostly grade 1/2 adverse events in patients with advanced pancreatic ductal adenocarcinoma. Updated data from a Phase 1 study presented at ASCO GI indicated a 78% disease control rate and a 37% objective response rate among evaluable patients. Additionally, VS-7375 has received Fast Track Designation from the FDA for KRAS G12D-mutated advanced pancreatic cancer.
Daraxonrasib received FDA breakthrough therapy designation for treating metastatic pancreatic cancer with KRAS G12X mutations. Separately, preliminary clinical data for INCB161734 showed nearly 80% disease control in heavily pretreated advanced pancreatic cancer patients.
Incyte's oral KRAS G12D inhibitor, INCB161734, has shown a manageable safety profile and promising early efficacy in patients with advanced solid tumors, including KRAS G12D-mutated pancreatic ductal adenocarcinoma. A Phase 1 study reported a disease control rate of 78% for the investigational drug.
via oncodaily.com
Early clinical data for INCB161734, a novel oral KRAS G12D inhibitor, presented at ASCO GI 2026, shows a manageable safety profile as monotherapy and in combination with chemotherapy for patients with advanced pancreatic ductal adenocarcinoma.
via oncodaily.com
2025
9 updates
2025
9 updatesMRTX1133, a KRAS G12D inhibitor, has advanced to Phase 1 clinical trials, showing tumor shrinkage in four out of five patients with advanced KRAS G12D-mutant cancers. Revolution Medicines reported that its KRAS G12D-selective inhibitor, zoldonrasib (RMC-9805), has demonstrated encouraging safety and antitumor activity in patients with previously treated non-small cell lung cancer.
A comprehensive review of KRAS drug development in pancreatic cancer highlighted the shift towards G12D inhibitors like MRTX1133 and pan-RAS inhibitors like daraxonrasib, with numerous agents in clinical trials.
Verastem's KRAS G12D inhibitor VS-7375 demonstrated a 41% overall response rate in a clinical trial with heavily pre-treated pancreatic cancer patients, with 91.5% experiencing disease control. Separately, a new study suggests resistance to MRTX1133 is associated with increased sensitivity to BET inhibition, with combination therapy showing extended survival in murine models.
Incyte presented preliminary Phase 1 data for its KRAS G12D inhibitor, INCB161734, in advanced pancreatic ductal adenocarcinoma, with a data cut-off of August 1, 2025. The data showed evidence of clinical benefit in 83 patients and a manageable safety profile with mostly Grade 1 gastrointestinal toxicities. The trial is ongoing, with results expected in 2026.
A review article emphasized the critical role of KRAS in pancreatic cancer and noted that the recent approval of KRAS inhibitors for other cancers has shattered the "undruggable" perception, fueling hope for breakthroughs in PDAC therapy.
Verastem Oncology's oral KRAS G12D inhibitor, VS-7375, received FDA Fast Track designation for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) with KRAS G12D mutation, for both first-line treatment and after prior systemic therapy.
MRTX1133, a reversible KRAS G12D inhibitor, was discontinued from Phase 1 trials in March 2025 due to formulation challenges and suboptimal pharmacokinetics. Additionally, Daraxonrasib (RMC-6236), a pan-RAS(ON) inhibitor, is showing encouraging early clinical results for RAS-driven cancers and is undergoing a large international Phase 3 trial.
Initial safety and efficacy findings for VS-7375 in advanced solid tumors, including PDAC, were presented at the ASCO Annual Meeting, showing a 52% overall response rate and 100% disease control rate in PDAC patients with KRAS G12D mutation.
The FDA approved an investigational new drug (IND) application for VS-7375, an oral KRAS G12D inhibitor, for the treatment of patients with advanced solid tumors, including pancreatic cancer.
2024
3 updates
2024
3 updatesFurther research highlighted that chemotherapy could enhance the effectiveness of KRAS inhibitors in pancreatic cancer by shutting down different cellular instructions that drive cancer cell growth, potentially preventing resistance.
Memorial Sloan Kettering Cancer Center researchers published findings on a new mechanism of resistance to KRAS inhibitors in pancreatic cancer models, identifying opportunities to improve treatment effectiveness, particularly for the aggressive 'basal' subtype.
Studies published in Cancer Discovery demonstrated that combining chemotherapy with experimental KRAS inhibitors, such as MRTX1133, significantly reduced tumor growth and spread in mouse models of pancreatic cancer, suggesting a strategy to overcome resistance.
2023
3 updates
2023
3 updatesRevolution Medicines presented promising anti-tumor and safety data for its RAS inhibitor RMC-6236 in patients with previously treated non-small cell lung cancer and pancreatic ductal adenocarcinoma. In 40 efficacy-evaluable NSCLC patients, the objective response rate was 38% and the disease control rate was 85%. For pancreatic ductal adenocarcinoma patients, median progression-free survival was 8.5 months and median overall survival was 14.5 months.
Mirati Therapeutics announced that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application for MRTX1133, a potential first-in-class oral KRASG12D selective inhibitor. This clearance allows for the initiation of Phase 1 clinical evaluation of MRTX1133, which targets KRASG12D mutations found in approximately 180,000 patients in the US and Europe, for whom there are currently no targeted treatment options.
Despite the success of G12C inhibitors in lung cancer, it became clear that these drugs had limited applicability in pancreatic cancer, where the G12C mutation is rare (1-2% of cases), shifting research focus to other prevalent mutations like G12D.
2022
1 update
2022
1 updateAdagrasib (Krazati), another KRAS G12C inhibitor, received accelerated FDA approval for NSCLC, further expanding treatment options for this specific KRAS mutation.
2021
1 update
2021
1 updateSotorasib (Lumakras), the first KRAS G12C inhibitor, received accelerated FDA approval for treating non-small cell lung cancer (NSCLC), validating the concept of directly targeting KRAS mutations.
2013
1 update
2013
1 updateAfter decades of KRAS being considered "undruggable," a pivotal discovery was made regarding a cryptic allosteric site in KRAS G12C, opening the door for the development of direct KRAS inhibitors.
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