INCB161734 Combination Data Shape DAWN-303’s All-Comers Design in Frontline KRAS G12D-Mutated PDAC

INCB161734, an investigational KRAS G12D inhibitor, has shown antitumor activity both as monotherapy and in combination with standard chemotherapy regimens in patients with KRAS G12D–mutated pancreatic ductal adenocarcinoma (PDAC), according to Davide Melisi, MD, PhD. He noted that the combination activity builds on earlier single-agent findings, with the combined regimens producing considerably higher response rates than monotherapy alone.

“We are seeing a revolution in the management of pancreatic cancer with the development of all these RAS inhibitors,” Melisi said in an exclusive interview with OncLive^®. “If the [phase 3 DAWN-303 trial (NCT07522073) findings are] positive, we will find ourselves distinguishing those patients with a KRAS G12D mutation vs those patients with any other mutation of RAS. Patients with any other mutation will receive chemotherapy in the first-line setting and daraxonrasib [Rasonque] in the second-line setting. Patients with KRAS G12D–mutated tumors, based on the results of the DAWN-303 trial, could be treated initially with a combination of a RAS inhibitor and chemotherapeutic treatment.”

In a phase 1 trial (NCT06179160), INCB161734 monotherapy at 1200 mg once daily produced an objective response rate (ORR) of 37% and a disease control rate (DCR) of 78% among efficacy-evaluable patients with KRAS G12D–mutated PDAC (n = 41).¹ In the chemotherapy cohorts, INCB161734 produced an ORR of 89% (confirmed ORR [cORR], 81%) and a DCR of 100% with modified FOLFIRINOX (mFOLFIRINOX; leucovorin, fluorouracil, irinotecan, and oxaliplatin; n = 27), and an ORR of 69% (cORR, 58%) and a DCR of 96% with gemcitabine plus nab-paclitaxel (Abraxane; n = 26).²

In the interview, Melisi discussed INCB161734’s mechanism of action, the phase 1 trial’s safety and efficacy findings, the design and eligibility criteria for the DAWN-303 trial, and where the agent may fit into the KRAS G12D–mutated PDAC treatment paradigm amid the recent FDA approval of daraxonrasib for the treatment of patients with metastatic pancreatic adenocarcinoma who have received at least 1 prior systemic therapy or are not eligible to receive multi-agent systemic therapy.³

Melisi is an associate professor of medical oncology at the University of Verona in Italy.

OncLive: What is the mechanism of action of INCB161734, and what makes it unique in the PDAC field?

Melisi: [INCB161734] is a small-molecule inhibitor of RAS in its G12D mutation, in both the ON and OFF states. This agent is active and selective for inhibiting RAS proteins with the G12D mutation, which is the reason for its tolerable safety profile, because this agent does not affect the activation of wild-type RAS in any state and does not inhibit this protein in the wild-type state. It is not associated with any adverse effects that are, on the other hand, quite common with other kinds of agents, such as pan-RAS(ON) inhibitors, which inhibit both mutated RAS in the active state and wild-type RAS in the active state in normal tissue and can lead to unique, peculiar toxicities, especially skin toxicity; these are completely absent with INCB161734.

What have preliminary phase 1 efficacy and safety findings shown with INCB161734 in pancreatic cancer?

INCB161734 is a promising agent. We were involved in the development of this inhibitor in the phase 1 trial, and the preliminary efficacy and safety results are promising. In terms of efficacy, the drug demonstrated important activity, with an ORR as monotherapy of 37%.¹ In the same trial, we also combined the drug with standard chemotherapeutic regimens, and the combination of chemotherapy and INCB161734’s KRAS G12D inhibition was promising, with a combination ORR exceeding half of the patients.

In terms of safety, being a selective inhibitor of KRAS G12D, INCB161734 is a safe agent. It doesn’t interfere with the activity of wild-type RAS in the ON state, so the class toxicities associated with pas-RAS inhibitors are not present with INCB161734. The only toxicity worth commenting on is nausea, but this was limited to approximately 10% of the patients. In summary, [we have seen] a good safety profile and a promising signal for activity [with INCB161734] as a single agent and in combination with chemotherapeutic agents, something that is not a given with other [RAS] inhibitors.

What is important to note about the design of the phase 3 DAWN-303 trial?

This is going to be an important trial because it is the first trial exploring the combination of a KRAS G12D inhibitor with chemotherapy. It is a randomized trial comparing one of the standard regimens for first-line treatment in metastatic pancreatic cancer, either mFOLFIRINOX or gemcitabine plus nab-paclitaxel, in combination with [INCB161734] in the experimental arm. Toxicity is not going to be a major concern.

Differently from the designs of other trials with other inhibitors in the first-line setting, for instance, with pan-RAS inhibitors, this trial doesn’t have a separate single-agent arm. The trial uses a classical randomized design of adding or not adding the experimental agent, because for KRAS G12D inhibitors, there is no need to consider monotherapy, since the safety profile in combination with chemotherapy remains acceptable. In case of toxicity related to the chemotherapeutic part of the treatment, there is the possibility to reduce or even completely interrupt the treatment with the chemotherapeutic agents and move forward with only the KRAS G12D inhibitor, in a sort of long-term or maintenance treatment. The idea is that the 2 components of the treatment, chemotherapy and the RAS inhibitor, are considered separate, and based on the safety profile of the experimental agent, the plan would be to continue [treatment with INCB161734] even if the patient develops cumulative toxicities related to the chemotherapeutic part of the combination strategy.

What enrollment criteria for DAWN-303 should colleagues keep in mind?

There are no specifics among the inclusion and exclusion criteria. [The trial is enrolling a] standard profile of patients in the metastatic setting. Patients allowed for enrollment must have measurable metastatic disease, be newly diagnosed, or have recurrence after a previous resection. As always, it is important to have a sufficiently long period of time between the end of adjuvant treatment and the recurrence of disease, which is 12 months. It will also be important to demonstrate the [presence of a] mutation in KRAS G12D.

Given that daraxonrasib and other RAS-targeted agents are in development and entering the PDAC treatment paradigm, where might INCB161734 fit if trial data remain positive?

This is an important topic. [INCB161734] will be positioned [as a therapy for use] at the beginning of the [treatment] history of patients diagnosed with metastatic pancreatic cancer. This is important for patients with KRAS G12D–mutated tumors, because the idea, if the [DAWN-303] trial is positive, is to have an initial treatment option with the RAS inhibitor.

Additionally, the fact that the safety profile of [INCB161734], as well as other KRAS G12D inhibitors, is much safer than that demonstrated by [earlier pan-RAS] inhibitors will probably increase the possibility of combining these agents with chemotherapy. This is going to be important for patients with metastatic disease. The possibility of this KRAS G12D inhibitor being combined with chemotherapy, even if this combination does not turn out to be fully synergistic but is at least additive, will overall represent the combination regimen with the highest ORR we could ever consider, adding the activity given by chemotherapy and the activity given by the RAS inhibitor. If this is successful for he first-line treatment, I foresee that it will be even more important in the earliest stages of disease in the future, such as in immediately resectable or borderline resectable pancreatic cancer, where you want to see a rapid response at the beginning of treatment.

Considering all the ongoing trials with RAS inhibitors, including the pan-RAS(ON) inhibitor [daraxonrasib] in the first-line setting in the phase 3 RASolute 304 trial [NCT07252232], [INCB161734 in] the DAWN-303 trial, and the imminent future development of zoldonrasib [RMC-9805/RM-036], another KRAS G12D inhibitor, we will probably see a difference in the future between the treatment of patients with KRAS G12D–mutated tumors and all the others. For KRAS G12D–mutated tumors, we will probably see the addition of KRAS G12D inhibitors to the standard treatment sequence we have today, added to first-line chemotherapeutic treatment. For patients with other, rarer mutations for which no selective inhibitors have yet been developed, based on the results that could come from ongoing trials, such as the phase 3 RASolute 303 trial [NCT07491445] with daraxonrasib in the first-line [metastatic pancreatic adenocarcinoma] setting, we will probably see daraxonrasib monotherapy given as monotherapy at the very beginning of treatment to all patients who do not have KRAS G12D–mutated disease. Then, given the difficulties in combining daraxonrasib with other chemotherapeutic regimens, we will maintain the same therapeutic sequence we have now in the first- or second-line settings. In the future, we will start to distinguish patients with KRAS G12D–mutated tumors from patients with any other mutation, and the 2 therapeutic strategies will be quite different: for the [former], by adding [KRAS G12D inhibitors to standard therapy]; for the [latter], by shifting what we are used to [adopting later in the treatment sequence] by adding daraxonrasib to the beginning of the treatment sequence.

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 KRAS G12D inhibitor, as monotherapy or in combination with chemotherapy for advanced/metastatic pancreatic duct adenocarcinoma. J Clin Oncol. 2026;44(suppl 2):654. doi:10.1200/JCO.2026.44.2_suppl.654
2. Hollebecque A, Park H, Henry J, et al. Safety and efficacy of INCB161734, a novel oral KRAS G12D inhibitor, in combination with chemotherapy in patients with advanced/metastatic pancreatic ductal adenocarcinoma. Presented at: ESMO Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract 3137RO.
3. FDA approves first in class targeted therapy for metastatic pancreatic cancer. FDA. August 26, 2026. Accessed October 30, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-class-targeted-therapy-metastatic-pancreatic-cancer?utm_medium=email&utm_source=govdelivery