Phase 1 Data Support DAWN-303’s Evaluation of INCB161734 in Frontline KRAS G12D–Mutated PDAC

INCB161734 monotherapy produced an objective response rate (ORR) of 37% (n = 15/41) and a disease control rate (DCR) of 78% (n = 32/41) in heavily pretreated patients with KRAS G12D–mutated pancreatic ductal adenocarcinoma (PDAC) treated at the recommended phase 2 dose (RP2D) of 1200 mg once daily (n = 41), according to Brandon Huffman, MD.¹

“This is a heavily pretreated population of patients; in many cases, this was the third line of treatment for pancreatic cancer, which is typically a refractory population, [thus] a 37% ORR is quite significant,” Huffman said in an exclusive interview with OncLive®.

The ongoing phase 3 DAWN-303 trial (NCT07522073) is evaluating INCB161734 plus investigator-selected chemotherapy in patients with previously untreated, KRAS G12D–mutated metastatic PDAC.² Patients will be randomly assigned to receive INCB161734 or placebo added to either modified FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin; mFOLFIRINOX) or gemcitabine plus nab-paclitaxel (Abraxane), with a target enrollment of approximately 588 patients across primary end points of overall survival (OS), progression-free survival (PFS), and ORR by blinded independent central review.

In the interview, Huffman discussed the mechanism of action of INCB161734, phase 1 safety and efficacy findings from the phase 1 INCB161734-101 trial (NCT06179160) presented at the 2026 Gastrointestinal Cancers Symposium, the design and eligibility criteria for DAWN-303, and where INCB161734 could fit into the pancreatic cancer treatment paradigm if the phase 3 data are positive.

Huffman is an assistant professor of medicine at Harvard Medical School and a physician at Dana-Farber Cancer Institute in Boston, Massachusetts.

OncLive: What is the mechanism of action of INCB161734, and what makes it unique among KRAS G12D-targeted agents in pancreatic cancer?

Huffman: INCB161734 is a targeted KRAS G12D inhibitor. It’s a selective, noncovalent inhibitor that specifically targets KRAS G12D. It binds the switch II pocket of mutant KRAS that has a G12D mutation with picomolar affinity, and it shows a greater than 80-fold selectivity over the non-mutant, or wild-type, KRAS. It is distinct in that we call it a dual ON and OFF inhibitor, which is different from a few other KRAS G12D–targeted agents that have shown clinical activity, such as molecular glue or PROTAC degraders.

What have phase 1 data shown about the safety and efficacy of INCB161734 in KRAS G12D-mutated pancreatic cancer?

We have data from a phase 1 study. In the dose-escalation portion, there were no dose-limiting toxicities, and the RP2D was established at 1200 mg once daily.¹ In pancreatic cancer, 41 patients with KRAS G12D-mutated pancreatic cancer received the RP2D of 1200 mg once daily. Of those patients, 15 achieved an objective response, which correlates to a 37% objective response rate, and 32 of the 41, or 78%, achieved disease control.

In terms of adverse effects [AEs], INCB161734 was generally well tolerated, with mostly grade 1 and grade 2 AEs reported. One known class effect of KRAS inhibitors is gastrointestinal-related symptoms, such as nausea, vomiting, and diarrhea. INCB161734 was associated with similar AEs, causing nausea in 59.0% of patients, vomiting in 57.4% of patients, diarrhea in 54.1% of patients, and fatigue in 32.8% of patients. Notably, rash, which is seen in the setting of multi-RAS inhibition, was not common in this cohort.

What is important to know about the design of the phase 3 DAWN-303 trial evaluating INCB161734 in patients with frontline pancreatic cancer?

[DAWN-303] is a randomized, double-blind trial in patients with previously untreated metastatic pancreatic cancer with a KRAS G12D mutation. What is unique about this study is that it allows the investigator to choose either mFOLFIRINOX or gemcitabine plus nab-paclitaxel as the chemotherapy backbone and then combines that regimen with either INCB161734 or placebo. It’s blinded, so neither the patients nor the investigators know which treatment the patients are receiving.

The target enrollment is approximately 600 patients globally.² The primary end points are OS, PFS, and ORR by blinded independent central review, which will help us understand the responses and survival outcomes that we’re hoping the addition of a RAS inhibitor to chemotherapy in this setting will improve. Preliminary data suggest that the chemotherapy in combination with INCB161734 is well tolerated without an increase in the expected [AE] profiles of each of the therapies. We’re hopeful that [DAWN-303] will move the needle and help us determine whether KRAS G12D inhibition combined with chemotherapy is [more effective] than chemotherapy alone in the first-line setting.

What enrollment criteria are relevant when considering patient referral to the DAWN-303 trial?

The treatment population [requires] a known metastatic diagnosis of PDAC and a known KRAS G12D mutation identified on either circulating tumor DNA or tumor tissue testing. Notably, no prior systemic therapy is allowed for metastatic disease. Patients have to be fit enough with an [ECOG] performance status of 0 or 1. They need to have measurable disease, because one of the primary end points is ORR. Notably, no [patients with] prior RAS inhibitor [treatment are] allowed on the study.

Where might INCB161734 fit into the pancreatic cancer treatment paradigm if DAWN-303 data are positive?

If this study is positive, meaning it significantly improves OS, PFS, and ORR [with INCB161734 plus chemotherapy], this combination will have been proven to be better than the standard of care, which is currently systemic chemotherapy. [If the trial is positive], it will position the chemotherapy combination with INCB161734 as the frontline therapy for KRAS G12D–mutated pancreatic cancer, and that is a large population of patients with pancreatic cancer. KRAS G12D is the most common genetic mutation in pancreatic cancer, affecting approximately 40% to 45% of pancreatic cancers, so this is a large population. About 50% of patients with pancreatic cancer have metastatic disease at first diagnosis. This is an important study to understand whether [KRAS G12D inhibition] truly benefits patients, and this could change the treatment landscape over the next 1 to 5 years. The paradigm could shift substantially over that time, largely because of RAS inhibitor–targeted therapies.

The pancreatic cancer treatment landscape is changing rapidly, and what we’re doing today is going to be less effective than what we’re going to be doing in 5 years because of trials like the DAWN-303 study. We’re all hopeful. It’s a clinical trial, [so] it’s an experiment, and it will be a bit of time before we know [the findings], but we’re excited about the future of pancreatic cancer management.

Editor’s Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

This article was supported in part by Incyte. Content independently developed and published by OncLive.

References

1. Wainberg ZA, Henry JT, Park H, et al. Preliminary phase 1 results of INCB161734, a novel oral Kirsten rat sarcoma (KRAS) G12D inhibitor, as monotherapy or in combination with chemotherapy for advanced/metastatic pancreatic duct adenocarcinoma (PDAC). J Clin Oncol. 2026;44(suppl 2):654. doi:10.1200/JCO.2026.44.2_suppl.654
2. A study to evaluate chemotherapy with or without INCB161734 in previously untreated, KRAS G12D-mutated metastatic pancreatic ductal adenocarcinoma (DAWN-303). ClinicalTrials.gov. Updated September 15, 2026. Accessed September 16, 2026. https://clinicaltrials.gov/study/NCT07522073