An investigational targeted therapy designed to block a common genetic driver 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 on July 3.
The Phase I/II multicenter study, led by researchers from Dana-Farber Cancer Institute in Boston, evaluated zoldonrasib in patients with metastatic pancreatic cancer whose tumors carried a KRAS G12D mutation. The findings showed high rates of tumor shrinkage, substantial reductions in cancer DNA detected in the bloodstream, and no unexpected safety concerns.
Pancreatic cancer remains one of the world's deadliest cancers and is often diagnosed at a metastatic stage when curative surgery is not possible. Chemotherapy is currently the standard first-line treatment for metastatic disease, but its effectiveness is limited and five-year survival rates remain around 3%. Scientists have long known that mutations in the KRAS gene drive most cases of pancreatic cancer. About 90% of cases harbor a KRAS mutation and approximately 40% carry the G12D subtype.
Zoldonrasib represents 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 abnormal KRAS G12D protein that drives tumor growth. Researchers are studying whether combining this targeted approach with chemotherapy can improve outcomes compared to chemotherapy alone.
Dr. Teresa Macarulla, Head of Medical Oncology at Hospital Clínic Barcelona and Congress Co-chair who was not involved in the study, said, "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." The study enrolled 81 patients across multiple centers in the United States; objective response rates reached 82% for those receiving zoldonrasib plus modified FOLFIRINOX and 61% for those receiving it plus gemcitabine/nab-paclitaxel. Disease control was achieved in up to 96% and strong molecular responses were observed across both groups.
The safety profile matched known side effects from chemotherapy regimens without additional toxicities identified. No treatment-related deaths were reported. These results supported launching RASolute 305—a global Phase III trial comparing zoldonrasib plus chemotherapy versus placebo plus chemotherapy for previously untreated patients with KRAS G12D metastatic pancreatic cancer.
Looking ahead, Dr. Macarulla said, "If these findings are confirmed, this approach could represent an important advance towards more personalised treatment for pancreatic cancer. It could also be explored in earlier stages of disease, where greater tumor shrinkage before surgery may improve patient outcomes."
