Dr Wainberg on INCB161734 Activity in Refractory Pancreatic Cancer

“[INCB161734] is changing the landscape in real time.”

Zev A. Wainberg, MD, a professor of medicine at UCLA and co-director of the UCLA GI Oncology Program, discussed data from a phase 2 trial (NCT06179160) presented at the 2026 Gastrointestinal Cancers Symposium for INCB161734, a novel oral KRAS G12D inhibitor, in patients with refractory pancreatic ductal adenocarcinoma (PDAC), as well as how the ongoing phase 3 DAWN-303 trial (NCT07522073) may affect the evolving landscape of RAS-targeted therapy.

In the phase 1 study, patients with refractory PDAC who had already received several prior lines of therapy were treated with INCB161734 monotherapy, Wainberg began. Among evaluable patients treated at the recommended phase 2 dose of 1200 mg daily (n = 41), the objective response rate was 37%, and the disease control rate was 78%. Wainberg called the single-agent activity encouraging and in line with the performance publicly reported for other KRAS G12D inhibitors.

INCB161734 was also combined safely with chemotherapy without compromising chemotherapy dose intensity, Wainberg noted. As a class, KRAS G12D inhibitors have shown notable gastrointestinal toxicities, chiefly nausea and vomiting that are predominantly grade 1 or 2 and more pronounced when the drug is combined with chemotherapy; as such, anti-emetics are indicated when dosing the agent, according to Wainberg.

The value of DAWN-303 lies in testing whether its investigational strategy can improve the current standard of care, which remains chemotherapy in the frontline setting, Wainberg said. DAWN-303 is a randomized, double-blind study evaluating investigator’s choice of chemotherapy with or without INCB161734 in patients with previously untreated, KRAS G12D-mutated metastatic PDAC.

Several RAS inhibitors are in development, some further along than others, Wainberg noted. He pointed to daraxonrasib (RMC-6236), an oral pan-RAS inhibitor that already has a positive second-line study, the phase 3 RASolute 302 trial (NCT06625320), and for which regulatory approval is anticipated shortly. No KRAS G12D inhibitor is yet approved for pancreatic cancer, Wainberg said; the promise of the allele-specific KRAS G12D–directed agents is their potential for less toxicity than pan-RAS inhibitors, which makes safely combining a KRAS G12D inhibitor with chemotherapy a feasible goal, he concluded.