An investigational targeted therapy designed to block one of the most common genetic drivers of pancreatic cancer has shown promising initial results when used in combination with standard first-line chemotherapy, according to research presented today at the ESMO Gastrointestinal Cancer Conference 2026.
A phase I/II multicenter study led by researchers at Dana-Farber Cancer Institute in Boston evaluated zordonrasib in patients with metastatic pancreatic cancer whose tumors carry the KRAS G12D mutation. Initial findings showed high tumor shrinkage rates, significant reductions in cancer DNA detected in the bloodstream, and no unexpected safety concerns.
Pancreatic cancer is one of the most deadly cancers in the world and remains one of the most difficult to treat. Because pancreatic cancer often has few specific symptoms in its early stages, many patients are diagnosed only after the disease has spread and curative surgery is usually no longer possible. Chemotherapy remains the standard first-line treatment for metastatic pancreatic cancer, but its ability to control disease is limited, with 5-year survival rates for metastatic disease remaining at approximately 3%.
Scientists have known for decades that pancreatic cancer is caused by mutations in the KRAS gene, which produces a protein that regulates normal cell growth. When KRAS is mutated, cancer cells are continuously sent signals to grow and divide. Approximately 90% of pancreatic cancers have KRAS mutations, and approximately 40% carry the KRAS G12D subtype, the most common KRAS mutation in this disease.
Until recently, KRAS G12D was widely considered to be an “untreatable” target. Zordonrasib is one of a new generation of investigational drugs designed to selectively inhibit this mutation. Unlike chemotherapy, which affects rapidly dividing cells throughout the body, zordonrasib acts directly on the abnormal KRAS G12D protein, which promotes tumor growth. Researchers are investigating whether combining this targeted approach with chemotherapy can improve patient outcomes compared to chemotherapy alone.
Dr. Teresa Macalula, Head of Medical Oncology at Barcelona Hospital in Spain and Council Co-President, who was not involved in the study, commented: “The emergence of treatments specifically designed for KRAS G12D is one of the most promising areas of pancreatic cancer research today. For many years, it was considered impossible to target this mutation, so these early findings are particularly important.”
The study enrolled 81 patients with previously untreated metastatic pancreatic cancer with the KRAS G12D mutation at multiple cancer centers in the United States. Of these, 41 received zordonradib in combination with modified FOLFIRINOX, and 40 received zordonradib in combination with gemcitabine and nab-paclitaxel.
Among patients with adequate follow-up for efficacy evaluation, objective response rates reached 82% in patients who received zordonradib plus modified forfirinox and 61% in patients who received zoldonradib plus gemcitabine and nab-paclitaxel. Disease control was achieved in 96% and 90% of patients, respectively.
Strong molecular reactions were also observed. All evaluable patients experienced at least a 50% reduction in circulating tumor DNA harboring the KRAS G12D mutation. Complete elimination of detectable mutated circulating tumor DNA was achieved in 47% of evaluable patients receiving modified FOLFIRINOX and 71% receiving gemcitabine and nab-paclitaxel.
The safety profile was consistent with known chemotherapy-related adverse events, and no additional toxicities were observed. The most common treatment-related adverse events were diarrhea, nausea, and fatigue with zordonradib plus modified forfilinox, and fatigue, nausea, and decreased neutrophil count with zoldonradib plus gemcitabine/nab-paclitaxel. Grade 3 or higher treatment-related adverse events occurred in 61% and 80% of patients, respectively, but no treatment-related deaths were reported.
These findings are encouraging as they suggest that targeting KRAS G12D can be combined with standard chemotherapy without raising unexpected safety concerns. However, this is still an early study with a relatively small number of patients, and it will be important to confirm these results in ongoing randomized phase III trials. ”
Dr. Teresa Macalula, Head of Oncology, Hospital Clinic Barcelona, Spain
These findings supported the initiation of RASolute 305, a global randomized phase III trial comparing zordonradib plus chemotherapy versus placebo plus chemotherapy in patients with previously untreated KRAS G12D metastatic pancreatic cancer.
Looking ahead, Dr. Macalula said, “If these findings are confirmed, this approach could be an important step forward toward more personalized treatment of pancreatic cancer. It could also be studied in earlier stages of the disease, potentially improving patient outcomes by shrinking tumors to a greater extent before surgery.”
sauce:
European Society of Medical Oncology (ESMO)
