Dr Huffman on the Mechanism of Action of INCB161734 in KRAS G12D–Mutated Metastatic Pancreatic Cancer

“[INCB161734] binds the switch II pocket of mutant KRAS with a G12D mutation with picomolar affinity, and it shows a greater than 80-fold selectivity over wild-type KRAS.”

Brandon Huffman, MD, an assistant professor of medicine at Harvard Medical School and a physician at Dana-Farber Cancer Institute, discussed the mechanism of action of the KRAS G12D inhibitor INCB161734 and the design of the phase 3 DAWN-303 trial (NCT07522073) evaluating the inhibitor in patients with previously untreated, KRAS G12D–mutated metastatic pancreatic ductal adenocarcinoma (PDAC).

INCB161734 is a selective, noncovalent KRAS G12D inhibitor that binds the switch II pocket of mutant KRAS with picomolar affinity and has demonstrated greater than 80-fold selectivity over wild-type KRAS, according to Huffman. He noted that the agent works as a dual ON/OFF inhibitor, a mechanism he said distinguishes it from other KRAS G12D–targeted agents with reported clinical activity, such as molecular glue degraders or PROTAC-based agents. In findings from the phase 1 INCB161734-101 trial (NCT06179160) presented at the 2026 Gastrointestinal Cancers Symposium, single-agent INCB161734 produced an overall response rate (ORR) of 37% and a disease control rate of 78% in heavily pretreated patients with KRAS G12D–mutated PDAC at the recommended phase 2 dose of 1200 mg once daily (n = 41).

DAWN-303 is a randomized, double-blind trial enrolling patients with previously untreated, KRAS G12D–mutated metastatic PDAC, Huffman said. Investigators will first select either mFOLFIRINOX (modified leucovorin, fluorouracil, irinotecan, and oxaliplatin) or gemcitabine plus nab-paclitaxel (Abraxane) as the chemotherapy backbone, after which patients will be randomly assigned to receive that selected chemotherapy regimen with either INCB161734 or placebo, Huffman explained. The primary end points are overall survival, as well as progression-free survival and ORR by blinded independent central review, he said.

Huffman noted that preliminary data showed that INCB161734 combined with chemotherapy was well tolerated, without an increase in the expected toxicity profile of either agent. He said he is hopeful that adding a KRAS inhibitor to chemotherapy in this setting will improve outcomes for patients, and that DAWN-303 will help clarify whether KRAS G12D inhibition combined with chemotherapy outperforms chemotherapy alone in the first-line treatment of patients with metastatic PDAC.