An investigational targeted therapy designed to block one of the most common genetic drivers of pancreatic cancer has shown promising early results when combined with standard first-line chemotherapy, according to research presented at the ESMO Gastrointestinal Cancers Congress 2026 (Abstract 340O).
The phase I/II multicenter study, led by researchers from Dana-Farber Cancer Institute, evaluated zoldonrasib in patients with metastatic pancreatic cancer whose tumors carried a KRAS G12D mutation. The early findings showed high rates of tumor shrinkage, substantial reductions in cancer DNA detected in the bloodstream, and no unexpected safety concerns.
For decades, scientists have known that pancreatic cancer is driven by mutations in the KRAS gene, which produces a protein that regulates normal cell growth. When KRAS is mutated, it continuously signals cancer cells to grow and divide. Around 90% of pancreatic cancers harbor a KRAS mutation, and approximately 40% carry the KRAS G12D subtype, the most common KRAS mutation found in the disease.
Until recently, KRAS G12D was widely regarded as an “undruggable” target. Zoldonrasib is one of a new generation of investigational medicines designed to selectively inhibit this mutation. Unlike chemotherapy, which affects rapidly dividing cells throughout the body, zoldonrasib acts directly on the abnormal KRAS G12D protein that drives tumor growth. Researchers are investigating whether combining this targeted approach with chemotherapy can improve patient outcomes compared with chemotherapy alone.
Teresa Macarulla, MD, PhD, Head of the Medical Oncology Department at Hospital Clínic Barcelona, Spain, and Congress Co-chair, who was not involved in the study, commented: “The emergence of therapies designed specifically against KRAS G12D represents one of the most promising areas of research in pancreatic cancer today. For many years, this mutation was considered impossible to target, making these early findings particularly important.”
Study Details and Results
The study enrolled 81 patients with previously untreated metastatic pancreatic cancer harboring a KRAS G12D mutation at multiple cancer centers in the United States. Of these, 41 received zoldonrasib in combination with modified leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and 40 received zoldonrasib plus gemcitabine and nab-paclitaxel.
Among patients with sufficient follow-up for efficacy assessment, objective response rates reached 82% in patients receiving zoldonrasib plus modified FOLFIRINOX and 61% in those receiving zoldonrasib plus gemcitabine plus nab-paclitaxel. Disease control was achieved in 96% and 90% of patients, respectively.
Strong molecular responses were also observed. Every evaluable patient experienced at least a 50% reduction in circulating tumor DNA (ctDNA) carrying the KRAS G12D mutation. Complete clearance of detectable ctDNA was achieved in 47% of evaluable patients receiving modified FOLFIRINOX and 71% receiving gemcitabine plus nab-paclitaxel.
The safety profile was consistent with known chemotherapy-related adverse events, with no additional toxicities identified. The most common treatment-related adverse events were diarrhea, nausea, and fatigue with zoldonrasib plus modified FOLFIRINOX, and fatigue, nausea, and decreased neutrophil counts with zoldonrasib plus gemcitabine/nab-paclitaxel. Grade 3 or higher treatment-related adverse events occurred in 61% and 80% of patients, respectively, and no treatment-related deaths were reported.
“These findings are encouraging because they suggest that targeting KRAS G12D can be combined with standard chemotherapy without introducing unexpected safety concerns,” added Dr. Macarulla. “However, this remains an early study involving a relatively small number of patients and it will now be important to confirm these results in the ongoing randomized phase III trial.”
These findings supported the launch of RASolute 305 (ClinicalTrials.gov identifier NCT07621718), a global, randomized phase III trial comparing zoldonrasib plus chemotherapy with placebo plus chemotherapy in patients with previously untreated KRAS G12D–mutated metastatic pancreatic cancer.
Looking ahead, Dr. Macarulla said, “If these findings are confirmed, this approach could represent an important advance towards more personalized treatment for pancreatic cancer. It could also be explored in earlier stages of disease, where greater tumor shrinkage before surgery may improve patient outcomes.”
DISCLOSURE: For full disclosures of the study authors, visit cslide.ctimeetingtech.com.
