RAS(ON) Inhibitor Zoldonrasib Is Safe, Shows Early Activity Signals in KRAS G12D–Mutated PDAC

Zoldonrasib (RMC-9805), an investigational RAS(ON) inhibitor, was well tolerated and associated with manageable adverse effects (AEs) and preliminary antitumor activity in patients with KRAS G12D–mutated pancreatic ductal adenocarcinoma (PDAC), according to data from an ongoing phase 1 trial (NCT06040541) presented at the 2025 Gastrointestinal Cancers Symposium.1

At the September 2, 2024, data cutoff and a median time on treatment of 2.8 months (range, 0.2-6.7) for patients with PDAC who received zoldonrasib at 1200 mg daily (1200 mg once daily, n = 60; 600 mg twice daily, n = 39), the most common treatment-related AEs (TRAEs) included nausea (any-grade, 27%; grade 1, 23%; grade 2, 4%), diarrhea (20%; 16%; 4%), vomiting (15%; 13%; 2%), and rash (10%; 10%; 0%). Other select TRAEs included increased alanine aminotransferase (ALT) levels (grade 1, 5%; grade 2, 0%; grade 3, 1%) and increased aspartate aminotransferase (AST) levels (3%; 1%; 0%). TRAEs led to dose reduction in 4% of patients and were all grade 1.

At a median time on treatment of 2.8 months (range, 0.1-8.9) among all patients with various tumor types who received zoldonrasib at any dose (n = 179), the most common TRAEs included nausea (any-grade, 30%; grade 1, 27%; grade 2, 3%), diarrhea (16%; 13%; 3%), and vomiting (15%; 11%; 3%). Other select TRAEs included increased ALT levels (grade 1, 7%; grade 2, 0%; grade 3, 1%), increased AST levels (6%; 1%; 0%), and rash (6%; 0%; 0%). TRAEs led to dose reduction in 3% of patients and were all grade 1.

Overall, no instances of stomatitis occurred, no TRAEs led to treatment discontinuation, and no grade 4/5 TRAEs or serious AEs were reported.

Background and Trial Design

Zoldonrasib is a potent, orally bioavailable, tri-complex, covalent RAS(ON) inhibitor selective for KRAS G12D. Previously, a pan-cancer analysis of KRAS-altered samples from adult patients with cancer showed that 43% of PDAC cases harbored KRAS G12D mutations.2 Furthermore, prior research has shown that molecular response in the form of on-treatment circulating tumor DNA (ctDNA) reductions could predict antitumor activity in select solid tumors.1

This ongoing phase 1 study is evaluating zoldonrasib with or without daraxonrasib (RMC-6236) in patients at least 18 years of age with advanced solid tumors harboring KRAS G12D mutations. To enroll, patients need to have received prior standard therapy appropriate for their tumor type and stage; have an ECOG performance status of 0 or 1; and have no active brain metastases.

During part 1 of the trial, which served as the dose-escalation portion, patients received zoldonrasib orally in 21-day treatment cycles at daily doses of 150 mg, 300 mg, 600 mg, 900 mg, or 1200 mg; or twice-daily doses of 300 mg, 450 mg, or 600 mg. Part 2 of the trial is serving as the dose-expansion and -optimization portion of the trial for patients with PDAC.

The trial objectives included safety/tolerability, pharmacokinetics, pharmacodynamic changes in ctDNA, and antitumor activity. Investigators analyzed plasma samples at baseline and during treatment on day 1 of cycles 2 or 3 to assess changes in KRAS G12D variant allele frequency (VAF) in ctDNA.

Additional Study Findings

Among all disease histologies (n = 179), which included PDAC, colorectal cancer, non–small cell lung cancer, sinonasal adenocarcinoma, melanoma of the vulva, metastatic small bowel carcinoma, ovarian cancer, uterine adenocarcinoma, high-grade mucinous carcinoma peritonei, ampullary cancer, duodenal cancer, signet ring gastric carcinoma, uterine cancer, and appendiceal cancer, patients had a median age of 62 years (range, 25-86). Fifty-five percent of patients were male, 70% had an ECOG performance status of 1, 75% had baseline liver metastases, and 59% had stage IV metastatic disease at diagnosis. Patients in this population had received a median of 2 prior lines of anticancer therapies (range, 0-9).

In the population of patients with PDAC (n = 104), the median age was 65 years (range, 30-86), 55% were male, 71% had an ECOG performance status of 1, 86% had baseline liver metastases, and 57% had stage IV metastatic disease at diagnosis. Patients in this population had received a median of 2 prior lines of anticancer therapies (range, 0-6).

Pharmacokinetic data from the phase 1 trial showed that exposure to zoldonrasib generated dose-dependent increases in the whole blood concentration of the agent that reached levels predicted to induce tumor regression, based on preclinical data. Based on the phase 1 findings, 1200 mg daily was identified as a candidate for the recommended phase 2 dose and schedule of zoldonrasib in patients with PDAC.

Among response-evaluable patients with KRAS G12D–mutated PDAC who received zoldonrasib at 1200 mg daily (once-daily dosing schedule, n = 20; twice-daily dosing schedule, n = 20), the overall response rate was 30%, and the disease control rate was 80%. Among those who received the agent at 1200 mg daily (either once-daily or twice-daily dosing), best responses included 16 partial responses (PRs). Among patients who received the agent at a lower daily dose, best responses included 6 PRs.

Marked reductions in KRAS G12D VAF in ctDNA from pretreatment levels were observed among 28 evaluable patients with PDAC who received zoldonrasib at 1200 mg daily. In total, 86% of these patients experienced a KRAS G12D VAF decrease of greater than 50%, and 39% of patients achieved a 100% decrease.

“Preliminary safety and clinical activity data support the ongoing development of zoldonrasib as a single agent and in combination with other therapies, including the RAS(ON) multi-selective inhibitor daraxonrasib,” the study authors concluded in a poster presentation of the data.

References

1. Spira A, Papadopoulos K, Kim D, et al. 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. J Clin Oncol. 2025;43(4):724. doi:10.1200/JCO.2025.43.4_suppl.724
2. Lee JK, Sivakumar S, Schrock AB, et al. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol. 2022;6(1):91. doi:10.1038/s41698-022-00334-z