INCB161734 Plus Chemotherapy Continues to Elicit Responses in KRAS G12D–Mutated PDAC

INCB161734 plus chemotherapy was tolerable and generated responses in patients with KRAS G12D–mutated advanced or metastatic pancreatic ductal adenocarcinoma (PDAC), according to updated data from a phase 1 trial (NCT06179160) presented at the 2026 ESMO Congress.¹

Among efficacy-evaluable patients who received INCB161734 at 1200 mg once daily with gemcitabine and nab-paclitaxel (Abraxane; n = 26) or with modified FOLFIRINOX (mFOLFIRINOX; modified oxaliplatin, leucovorin, irinotecan, and fluorouracil; n = 27), the objective response rates (ORRs), which included unconfirmed responses, were 69% and 89%, respectively. The respective disease control rates (DCRs) were 96% and 100%. When confirmed responses and responses pending confirmation were counted, the ORRs were 58% and 81%, respectively. The 6-month progression-free survival (PFS) rate was 80% with gemcitabine plus nab-paclitaxel and 90% with mFOLFIRINOX, and the median efficacy follow-ups were 7.2 months and 5.6 months, respectively.

A plasma circulating tumor DNA (ctDNA) analysis showed molecular responses, defined as a reduction of at least 90% in KRAS G12D variant allele frequency by week 8, in 74% of patients receiving gemcitabine plus nab-paclitaxel and 69% of patients receiving mFOLFIRINOX.

“We observed a favorable safety and tolerability of [INCB161734] at 1200 mg daily in combination with standard chemotherapy,” Antoine Hollebecque, MD, of Institut Gustave Roussy in Villejuif, France, stated in a presentation of the data.

What was the design of the phase 1 trial of INCB161734 plus chemotherapy in advanced or metastatic PDAC?

INCB161734 is a selective, orally administered inhibitor that targets KRAS G12D in both its active and inactive states. Hollebecque noted that KRAS G12D mutations are the most common oncogenic driver in PDAC, found in approximately 40% of patients with the disease.

The trial enrolled patients with locally advanced or metastatic PDAC and a locally confirmed KRAS G12D mutation who had an ECOG performance status of 0 or 1 and had not previously received a KRAS G12D inhibitor. In the dose-escalation portion, patients could have received up to 1 prior systemic regimen in the metastatic setting; in the dose-expansion portion, no prior systemic therapies were permitted. Patients received INCB161734 at 600 mg or 1200 mg once daily with gemcitabine plus nab-paclitaxel (gemcitabine at 1000 mg/m² and nab-paclitaxel at 125 mg/m² on days 1, 8, and 15 of a 28-day cycle) or mFOLFIRINOX (oxaliplatin at 85 mg/m², leucovorin at 400 mg/m², irinotecan at 150-180 mg/m², and fluorouracil at 2400 mg/m² on days 1 and 15 of a 28-day cycle). The 1200-mg dose was selected as the recommended dose for expansion, and the expansion cohorts enrolled 21 patients each to the gemcitabine/nab-paclitaxel and mFOLFIRINOX arms. Patients continued to receive treatment until they started another anticancer therapy, experienced disease progression or unacceptable adverse effects, died, withdrew consent, or the study ended. The key end points were safety and tolerability along with efficacy measures, including ORR, DCR, duration of response (DOR), and PFS.

As of the July 6, 2026, data cutoff, 54 patients had received INCB161734 at 1200 mg once daily with chemotherapy: 26 with gemcitabine plus nab-paclitaxel and 28 with mFOLFIRINOX. The median age was 62 years (range, 35-77) in the gemcitabine plus nab-paclitaxel arm and 63 years (range, 37-77) in the mFOLFIRINOX arm. In total, 50% and 43% of patients, respectively, had an ECOG performance status of 0, and 85% and 86% of patients had liver metastases. In the metastatic setting, 92% and 93% of patients had received no prior systemic therapy. The median durations of INCB161734 treatment were 7.6 months (range, 0.5-9.1) and 7.0 months (range, 0.6-11.7), and treatment was ongoing in 62% and 82% of patients. Disease progression was the primary reason for discontinuation in 31% (n = 8) and 14% (n = 4) of patients.

What did earlier phase 1 results show for INCB161734 in PDAC?

Earlier results from the same phase 1 trial were presented at the 2026 Gastrointestinal Cancers Symposium, with a data cutoff of November 11, 2025.² INCB161734 monotherapy at 1200 mg once daily, the recommended phase 2 dose, was evaluated in 61 patients with PDAC. Among efficacy-evaluable patients (n = 41), who were mainly in the third-line or later setting, the ORR was 37%, and the DCR was 78%. TRAEs of any grade occurred in 90.2% of patients, grade 3 or higher TRAEs were reported in 19.7% of patients, and 2 patients (3%) discontinued treatment because of TRAEs. Among patients with detectable KRAS G12D mutations in plasma ctDNA who received the 1200-mg dose (n = 32), 66% had a molecular response by week 8.

The trial also evaluated INCB161734 at 600 mg or 1200 mg once daily plus gemcitabine and nab-paclitaxel (n = 28) or mFOLFIRINOX (n = 16). Among patients receiving the chemotherapy combinations with INCB161734 at 600 mg (n = 15), the ORR was 27%, and the DCR was 87%; at an INCB161734 dose of 1200 mg (n = 8), the ORR was 50%, and the DCR was 88%. Molecular responses occurred in 80% of patients receiving a combination (n = 10). The investigators reported that the combinations did not compromise chemotherapy dose intensity, with a median relative dose intensity of 74% for both gemcitabine and nab-paclitaxel and 76% for fluorouracil in the mFOLFIRINOX combination.

What was the safety profile of INCB161734 plus chemotherapy in advanced or metastatic PDAC?

In the updated analysis, all patients in the safety population (gemcitabine plus nab-paclitaxel arm, n = 26; mFOLFIRINOX arm, n = 28) experienced TRAEs of any grade.¹ With gemcitabine plus nab-paclitaxel, the most common TRAEs were diarrhea (65%; grade ≥ 3, 4%), nausea (65%; 4%), decreased neutrophil count (65%; 58%), and anemia (58%; 38%). With mFOLFIRINOX, the most common TRAEs were diarrhea (68%; 11%), nausea (64%; 4%), vomiting (57%; 7%), decreased neutrophil count (57%; 36%), and fatigue (54%; 11%). Most gastrointestinal TRAEs were grade 1 or 2 and lessened over the course of treatment, and no TRAEs resulted in death.

TRAEs led to INCB161734 interruption in 73% of patients receiving gemcitabine plus nab-paclitaxel and 39% of those receiving mFOLFIRINOX, dose reduction in 23% and 21% of patients, respectively, and discontinuation in 4% and 0% of patients. TRAEs led to chemotherapy interruption in 85% and 79% of patients, dose reduction in 69% and 57% of patients, and discontinuation in 31% and 32% of patients. The median relative dose intensity of INCB161734 was 85% with gemcitabine plus nab-paclitaxel and 77% with mFOLFIRINOX. The median relative dose intensity of chemotherapy over the full treatment period was 49% with gemcitabine plus nab-paclitaxel and 53% with mFOLFIRINOX.

What are the next steps for developing INCB161734 in first-line metastatic PDAC?

The investigators pointed to the findings as support for the ongoing phase 3 DAWN-303 trial (NCT07522073), a randomized, double-blind study of standard chemotherapy with or without INCB161734 in previously untreated patients with KRAS G12D–mutated metastatic PDAC. The trial is currently enrolling, with a target enrollment of 588 patients.³ Patients will receive investigator’s choice of chemotherapy plus either INCB161734 or placebo. The primary end points are overall survival, PFS by blinded independent central review (BICR), and objective response by BICR. Secondary end points include DOR, disease control, safety, and quality of life. The estimated primary completion date is September 15, 2028, and the estimated study completion date is March 19, 2029.

Disclosures: Hollebecque reported serving in consulting or advisory roles for Amgen, Basilea Pharmaceutica, Bristol-Myers Squibb, Incyte Corporation, Merck Sharp & Dohme, Relay Therapeutics, Sanofi, Seagen Inc., Servier, and Taiho Oncology, Inc.; receiving institutional research funding from Incyte Corporation; and receiving travel support from F. Hoffmann-La Roche AG and Pierre Fabre Pharmaceuticals.

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

References

1. 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: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 3137RO.
2. Wainberg Z, Henry J, 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 ductal adenocarcinoma (PDAC). Paper presented at: 2026 ASCO Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA. Abstract 654
3. A study to evaluate chemotherapy with or without INCB161734 in previously untreated, KRAS G12D-mutated metastatic pancreatic ductal adenocarcinoma (DAWN-303). ClinicalTrials.gov. Updated October 8, 2026. Accessed October 26, 2026. https://clinicaltrials.gov/study/NCT07522073