DAWN-303 Trial Set to Advance INCB161734 in First-Line KRAS G12D–Mutated Metastatic Pancreatic Cancer

INCB161734, an investigational oral KRAS G12D inhibitor, may build on the efficacy of chemotherapy alone in the first-line treatment of patients with KRAS G12D–mutated metastatic pancreatic ductal adenocarcinoma (PDAC), according to Zev A. Wainberg, MD.

The phase 3 DAWN-303 trial (NCT07522073) is randomly assigning patients with previously untreated, KRAS G12D–mutated metastatic PDAC to receive investigator’s choice of chemotherapy (modified leucovorin, fluorouracil, irinotecan, and oxaliplatin [mFOLFIRINOX] or gemcitabine plus nab-paclitaxel [Abraxane]) in combination with either INCB161734 or placebo.¹ The trial continues the development of INCB161734 that was the focus of the phase 1 INCB161734-101 trial (NCT06179160), findings from which were presented at the 2026 Gastrointestinal Cancers Symposium.²

“[INCB161734] is a KRAS noncovalent oral inhibitor of G12D specifically, what we are calling now an allele-specific inhibitor,” Wainberg said in an interview with OncLive®. “[It has] one of the largest data sets for any [KRAS] G12D inhibitor, as it’s gone through phase 1 and completed dose escalation [studies] and now [is being investigated in] a number of expansion arms in various cancers.”

Wainberg is a professor of medicine at UCLA and co-director of the UCLA GI Oncology Program in Los Angeles, California.

What is the rationale for targeting KRAS G12D in pancreatic cancer?

KRAS G12D mutations are some of the most common oncogenic drivers in PDAC, making the alteration an attractive and prevalent target. INCB161734 is a selective ON/OFF oral KRAS G12D inhibitor that binds both the active, GTP-bound and inactive, GDP-bound forms of KRAS G12D. In preclinical models, this agent demonstrated greater than 80-fold selectivity for KRAS G12D over wild-type KRAS.

The rationale for studying this agent is set against a rapidly evolving competitive landscape. The RAS(ON) multiselective inhibitor daraxonrasib (Rasonque) was FDA approved on August 26, 2026, for the treatment of patients with metastatic PDAC.³ Additionally, pan-RAS agents, such as the molecular glue ERAS-0015, have advanced into development for the disease.⁴

Wainberg drew a distinction between selective and pan-RAS approaches, saying, “There are a number of RAS inhibitors in development, some further along than others. The promise of these is that they will perhaps [be associated with] less toxicity than a pan-RAS inhibitor and are more specific. The idea that we can combine [INCB161734] with chemotherapy would be the end point we’re looking for.”

What phase 1 trial findings have previously been shown with INCB161734 in pancreatic cancer?

The first-in-human INCB161734-101 trial enrolled patients with locally advanced or metastatic solid tumors harboring a KRAS G12D mutation.² Patients needed to have an ECOG performance status of 0 or 1 and no prior treatment with a KRAS G12D–selective inhibitor.

INCB161734 monotherapy dose escalation spanned 200 mg to 1600 mg once daily; dose expansion evaluated the agent at doses of 600 mg and 1200 mg once daily. Additionally, combination cohorts paired INCB161734 with gemcitabine/nab-paclitaxel or mFOLFIRINOX, with dose-escalation doses of INCB161734 at 600 mg and 1200 mg once daily, the latter of which was selected as the recommended dose for expansion in the combination cohorts. The primary end point was safety and tolerability, with secondary end points of overall response rate (ORR), disease control rate (DCR), duration of response (DOR), and pharmacokinetics.

Among evaluable patients with heavily pretreated PDAC who received INCB161734 monotherapy at 1200 mg once daily (n = 41), the ORR was 37%, and the DCR was 78%. In patients with first- or second-line metastatic PDAC, INCB161734 at 1200 mg once daily plus chemotherapy (n = 8) produced an ORR of 50% and a DCR of 88%, whereas the 600-mg once-daily plus chemotherapy cohort (n = 15) achieved an ORR of 27% and a DCR of 87%. The median relative dose intensity of chemotherapy was maintained in both combinations, comparable with historical reports, and deep molecular responses in plasma circulating tumor DNA were observed with both the monotherapy and the combination regimens.

Any-grade treatment-related adverse effects (TRAEs) occurred in 90.2% of patients receiving INCB161734 monotherapy at 1200 mg once daily (n = 61), with grade 3 or higher TRAEs reported in 19.7% of patients; 3% of patients discontinued due to TRAEs. The most common TRAEs in this group were nausea (59.0%), vomiting (57.4%), diarrhea (54.1%), and fatigue (32.8%). Notably, gastrointestinal (GI) AEs were mostly grade 1 and improved after the first cycle.

“[The ORR with INCB161734 hit] 37% as a single agent, [this is] quite encouraging. This is in line with [the activity of] other KRAS G12D inhibitors,” Wainberg said. “[INCB161734] was combined with chemotherapy safely. There have been some toxicities of note in general with KRAS G12D inhibitors, mainly focusing on GI symptoms…predominantly nausea and vomiting, particularly when combined with chemotherapy. Anti-emetics are indicated when dosing [INCB161734].”

What is the design of the DAWN-303 trial?

DAWN-303 is a randomized, double-blind trial enrolling approximately 588 patients with histologically or cytologically confirmed metastatic PDAC harboring a KRAS G12D mutation who have received no prior systemic treatment in the metastatic setting, have an ECOG performance status of 0 or 1, and have adequate organ function; prior treatment with any KRAS inhibitor is exclusionary.¹ The trial is enrolling internationally across more than 200 sites. Investigators will first select the chemotherapy backbone (mFOLFIRINOX or gemcitabine/nab-paclitaxel), after which patients will be randomly assigned 1:1 to receive that chemotherapy regimen in combination with INCB161734 or placebo, continuing treatment until disease progression.

OS, as well as progression-free survival (PFS) and ORR by blinded independent central review, serve as the primary end points. Secondary end points include DOR; DCR; investigator assessed PFS, ORR, DOR, and DCR; safety, and quality-of-life outcomes.

Wainberg underscored that biomarker confirmation is a prerequisite for patient enrollment.

“The big caveat is patients have to [have KRAS G12D mutations]. This represents approximately 40% of metastatic pancreatic cancers, so it’s a good number of patients,” he said. “[Mutation status] has to be confirmed prior to enrollment based on either a liquid biopsy or a tissue biopsy. Nowadays we’re testing this in a lot of patients anyway, so turnaround time has shortened quite a bit.”

How might INCB161734 influence the pancreatic cancer treatment paradigm?

Wainberg framed the DAWN-303’s central question as whether a selective, chemotherapy-combinable agent can move frontline outcomes.

“The study’s value is in seeing if we can improve on the standard of care [SOC], which currently remains chemotherapy in the frontline setting,” he said.

He noted that KRAS G12D–selective inhibitors are being positioned to combine with chemotherapy and may spare patients the added toxicity associated with broader RAS blockade.

Looking further out, Wainberg anticipated that KRAS inhibitors may become embedded across lines of therapy.

"These drugs are now going to be SOC across the board, [with] many studies ongoing that will take a number of years to clarify exactly which drug [we should use] when,” he said. “We’re going to probably be looking at a number of approvals of KRAS inhibitors over the next number of years in pancreatic cancer, [with] studies ongoing to combine these drugs with chemotherapy before surgery, [as well as] after surgery in the adjuvant context. It’s going to take us a number of years to sort out exactly when and how [we should use these agents], but [they] will be part and parcel of every patient’s treatment.”

References

1. A study to evaluate chemotherapy with or without INCB161734 in previously untreated, KRAS G12D-mutated metastatic pancreatic ductal adenocarcinoma (DAWN-303). ClinicalTrials.gov. Updated August 6, 2026. Accessed August 27, 2026. https://clinicaltrials.gov/study/NCT07522073
2. 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
3. FDA approves first in class targeted therapy for metastatic pancreatic cancer. FDA. August 26, 2026. Accessed August 28, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-class-targeted-therapy-metastatic-pancreatic-cancer?utm_medium=email&utm_source=govdelivery
4. Erasca granted FDA fast track designation for pan-RAS molecular glue ERAS-0015 in patients with metastatic pancreatic adenocarcinoma. News release. Erasca, Inc. August 24, 2026. Accessed August 28, 2026. https://investors.erasca.com/news-releases/news-release-details/erasca-granted-fda-fast-track-designation-pan-ras-molecular-glue