At the ESMO GI Cancers Congress 2026, Brian M. Wolpin presented preliminary phase 1/2 results of zoldonrasib plus chemotherapy in patients with first-line RAS G12D-mutant metastatic pancreatic adenocarcinoma.
The presentation, titled “Safety and efficacy of zoldonrasib (RMC-9805) plus chemotherapy in patients with 1L RAS G12D metastatic pancreatic adenocarcinoma,” was presented as abstract 340O.
Background
Metastatic pancreatic ductal adenocarcinoma remains a difficult-to-treat disease, with a 5-year survival rate of approximately 3%. Standard first-line chemotherapy provides limited benefit, and new targeted approaches are needed.
RAS G12D mutations occur in approximately 40% of pancreatic ductal adenocarcinomas. There is currently no approved targeted therapy for this molecular subgroup.
Zoldonrasib is an oral RAS(ON) G12D-selective inhibitor. It has previously shown manageable safety and encouraging activity in patients with previously treated RAS G12D-mutant metastatic pancreatic ductal adenocarcinoma.
You can also read about Zoldonrasib in Previously Treated KRAS G12D NSCLC on OncoDaily.
Methods
RMC-GI-102 is a phase 1/2 platform study evaluating zoldonrasib-based combinations in patients with metastatic PDAC and RAS G12D mutations. Eligible patients had no prior systemic therapy for metastatic disease and ECOG performance status 0–1.
Patients received zoldonrasib 1200 mg once daily in combination with either modified FOLFIRINOX or gemcitabine plus nab-paclitaxel. The chemotherapy backbone was selected by the investigator, and the dose-escalation and dose-expansion cohorts were not randomized.
Zoldonrasib was administered once daily on a 28-day treatment cycle. No dose-limiting toxicities were observed in part 1 for either regimen, and zoldonrasib 1200 mg once daily was selected as the recommended phase 2 dose in combination with both chemotherapy regimens.
The study evaluated safety and tolerability, antitumor activity, and the recommended phase 2 dose of zoldonrasib in combination with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel. The clinical trial identification number was NCT06445062.
Key Findings
As of the February 8, 2026 data cutoff, the response-evaluable population included 22 patients treated with zoldonrasib plus modified FOLFIRINOX and 31 patients treated with zoldonrasib plus gemcitabine/nab-paclitaxel. In this analysis, median follow-up was 6.1 months and 5.7 months, respectively.
With zoldonrasib plus modified FOLFIRINOX, the objective response rate was 82% and the disease control rate was 96%. With zoldonrasib plus gemcitabine/nab-paclitaxel, the objective response rate was 61% and the disease control rate was 90%.
Progression-free survival and overall survival estimates remained immature because of limited follow-up at the time of data cutoff.
In the safety population, 41 patients received zoldonrasib plus modified FOLFIRINOX and 40 received zoldonrasib plus gemcitabine/nab-paclitaxel. Treatment-related adverse events were broadly consistent with the established safety profiles of modified FOLFIRINOX and gemcitabine/nab-paclitaxel, with no new or unexpected safety findings reported.
With zoldonrasib plus modified FOLFIRINOX, any-grade treatment-related adverse events occurred in 98% of patients, and grade 3 or higher treatment-related adverse events occurred in 61%. The most common events included diarrhea, nausea, fatigue, decreased neutrophil count, and vomiting. No grade 5 treatment-related adverse events were reported.
With zoldonrasib plus gemcitabine/nab-paclitaxel, any-grade treatment-related adverse events occurred in 100% of patients, and grade 3 or higher treatment-related adverse events occurred in 80%. The most common events included fatigue, nausea, decreased neutrophil count, anemia, rash, diarrhea, and peripheral sensory neuropathy. No grade 5 treatment-related adverse events were reported.
Zoldonrasib maintained mean dose intensities of 86% with modified FOLFIRINOX and 90% with gemcitabine/nab-paclitaxel.
You can also read about Vopimetostat Plus Daraxonrasib Shows 92% ORR in MTAP-Deleted, RAS-Mutant mPDAC on OncoDaily.
Conclusions
Zoldonrasib plus chemotherapy showed a favorable safety and tolerability profile and compelling preliminary antitumor activity in patients with first-line RAS G12D-mutant metastatic pancreatic ductal adenocarcinoma.
Additional follow-up is needed to assess durability, including progression-free survival and overall survival. Observed differences in baseline characteristics limited direct comparison of antitumor activity between the chemotherapy regimens.
These preliminary data support the ongoing global phase 3 RASolute 305 study evaluating zoldonrasib plus chemotherapy versus placebo plus chemotherapy in first-line KRAS G12D-mutant metastatic pancreatic ductal adenocarcinoma.
Expert Highlight
Osman Köstek, from Marmara University Department of Medical Oncology, shared on his LinkedIn page:
“Exciting early results for KRAS G12D-mutant pancreatic cancer from ESMO GI 2026!
The combination of zoldonrasib with standard chemotherapy demonstrated encouraging activity in the frontline setting:
- ORR 82% with mFOLFIRINOX
- ORR 61% with gemcitabine/nab-paclitaxel
- 100% of evaluable patients achieved >50% reduction in KRAS G12D ctDNA levels
With a median follow-up of only ~6 months, longer-term PFS and OS data are eagerly awaited, but these findings further strengthen KRAS G12D as a promising therapeutic target in PDAC.
The era of precision oncology in pancreatic cancer is rapidly evolving.”
Angela Lamarca, who also commented on the presentation on X, wrote:
“Non-randomised Zoldonrasib + FOLFIRINOX/GemNab in 1L mKRAS G12D aPDAC data at ESMO GI 26 by Brian Wolpin
Poor(er) px charact in mFOLFIRINOX
Less rash; good tolerance – good dose intensity
ORR 82% mFOLFIINOX; 61% GN
Ph III RASolute 305 coming”
More details are available in the official ESMO Gastrointestinal Cancers Congress 2026 programme.