A novel KRAS G12D inhibitor produced disease control in almost 80% of patients with heavily pretreated advanced or metastatic KRAS G12D–mutated pancreatic cancer in an early-phase study reported at the 2026 ASCO Gastrointestinal (GI) Cancers Symposium.1
Of 41 evaluable patients treated with single-agent INCB161734 at the recommended phase II dose of 1,200 mg/day, 15 (37%) achieved objective responses, and 32 had stable disease, representing a disease control rate of 78%. All the patients had received at least two prior lines of therapy, and many had received at least three. In a separate, smaller cohort, the drug was shown to be feasible and safe when combined with gemcitabine plus nab-paclitaxel or modified FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin), demonstrating that this combination can be administered without compromising chemotherapy dose intensity, said Zev Wainberg, MD, MSc, of University of California, Los Angeles (UCLA) Health.
Zev Wainberg, MD, MSc
“Deep molecular responses were observed in patients with pancreatic ductal adenocarcinoma who received INCB161734 as monotherapy and in combination with chemotherapy,” he said. “The encouraging clinical efficacy supports the initiation of a phase III trial in patients with first-line metastatic pancreatic ductal adenocarcinoma.”
At a median follow-up of about 5 months, the median duration of response and progression-free survival in the single-agent study had not been reached. “The swimmer plot indicated the clinical benefit was durable in heavily pretreated patients with pancreatic ductal adenocarcinoma,” Dr. Wainberg added.
About INCB161734 and This Study
KRAS G12D mutations are among the most common oncogenic drivers for pancreatic ductal adenocarcinoma. With the recognition that RAS is no longer an undruggable mutation, RAS inhibitors have proliferated, with drug development advancing down two pathways: nonselective (pan-RAS) inhibitors and allele-specific inhibitors. INCB161734 targets KRAS G12D. Phase I results revealed a manageable safety profile in patients with KRAS G12D–mutated advanced or metastatic solid tumors, Dr. Wainberg said.
In the current study, 61 patients were treated with single-agent INCB161734 and 44 received the KRAS inhibitor plus one of two standard-of-care chemotherapy regimens—gemcitabine plus nab-paclitaxel or mFOLFIRINOX. This followed an evaluation of multiple dose levels of INCB161734, which established 1,200 mg/day as the recommended phase II dose.
“By and large, this represented a greater-than-third-line patient population, with the majority of patients having received two prior lines,” Dr. Wainberg noted. As of the data cutoff in November 2025, treatment was ongoing in 69% of patients. The median duration of response and progression-free survival data, he said, are “unfortunately” not yet available.
Safety Profile in Combination with Chemotherapy
The recommended phase II dose was generally well tolerated, according to Dr. Wainberg, with few dose interruptions or reductions and two discontinuations because of treatment-related adverse events. Preliminary data from the ongoing expansion phase of the trial also indicated an acceptable safety profile when INCB161734 was administered in combination with chemotherapy, he said.
In the 16 evaluable patients who received 1,200 mg/day of the KRAS inhibitor in combination with gemcitabine plus nab-paclitaxel, treatment-related adverse events leading to dose interruptions of the novel agent were observed in 43.8% and those leading to dose reductions in 6.3%; no patients discontinued the drug. Chemotherapy interruptions were observed in 37.5% and dose reductions in 43.8%, and no patient discontinued chemotherapy for a drug-related reason. The primary toxicity was neutropenia, which was grade 3 or higher in approximately 40% of patients. Approximately 50% to 60% of patients experienced gastrointestinal side effects of grade 1 to 2. The median relative dose intensity of gemcitabine plus nab-paclitaxel was 75%, “consistent with what we might expect with standard chemotherapy,” Dr. Wainberg said.
Of the seven evaluable patients who received 1,200 mg/day of INCB161734 plus mFOLFIRINOX, three experienced a treatment-related adverse event leading to treatment interruption; no patients required dose reductions or discontinued treatment. Adverse events led to chemotherapy interruptions in four patients, reductions in four patients, and discontinuations in two patients. The median relative dose intensity of mFOLFIRINOX was 76%, which Dr. Wainberg noted is “comparable to previous reports.”
‘Large’ Molecular Response
“We are also looking at variant allele frequency with these KRAS inhibitors,” Dr. Wainberg continued. “INCB161734 caused rapid molecular responses after only a few weeks of dosing, and in patients with detectable KRAS G12D in plasma [circulating tumor] DNA (80% of the population), two-thirds treated at 1,200 mg had an early molecular response (90% reduction in variant allele frequency). The combination of the drug with chemotherapy similarly showed a large molecular response.”
The global phase III DAWN-303 trial will enroll patients with previously untreated metastatic pancreatic ductal adenocarcinoma, randomly assigning them to mFOLFIRINOX or gemcitabine plus nab-paclitaxel in combination with either INCB161734 or placebo. Additionally, multiple trials are exploring combination therapy with the agent in colorectal cancer.
DISCLOSURE: Dr. Wainberg reported relationships with Alligator Bioscience, Amgen, Arcus Biosciences, Astellas, AstraZeneca/MedImmune, Bayer, BridgeBio, Bristol Myers Squibb, Daiichi Sankyo, EMD Serono, Ipsen, Janssen Oncology, Lilly, Merck, Novartis, Pfizer, Phanes Therapeutics, Revolution Medicines, and Seagen.
REFERENCE
1. Wainberg ZA, Henry JT, Park H, et al: Preliminary phase 1 results of INCB161734, a novel oral Kirsten rat sarcoma G12D inhibitor, as monotherapy or in combination with chemotherapy for advanced/metastatic pancreatic duct adenocarcinoma. 2026 ASCO GI Cancers Symposium. Abstract 654. Presented January 9, 2026.
EXPERT POINT OF VIEW
Invited discussant for the study of the novel KRAS G12D inhibitor INCB161734 in heavily pretreated advanced or metastatic KRAS G12D–mutated pancreatic cancer, Andrew H. Ko, MD, FASCO, Professor of Clinical Medicine and Associate Division Chief of Oncology in the Division of Hematology/Oncology at the University of California, San Francisco (UCSF), expressed enthusiasm about the findings.1
He stated that the study has “generated a lot of justifiable excitement” and added that, “at the risk of hyperbole and getting too far ahead of ourselves,” these results, along with other recent studies, suggest that “we’re on the cusp of a potentially transformative time in the treatment of pancreatic cancer with the development of a number of novel RAS inhibitors.”
Advances in KRAS Inhibitor Development
After many steps in the development of drugs inhibiting RAS—once considered “undruggable”—several novel agents now fall into two categories: pan-(K)RAS inhibitors and allele-specific compounds, including those targeting G12D, G12C and G12V. These inhibitors bind RAS in the “off” state (GDP-bound), the “on” state (GTP-bound), or both (“on/off” state). INCB161734 binds both the “on” and “off” states of KRAS.
In his remarks, he first applauded several aspects of the study design: evaluating the compound as both a single agent and in combination with standard chemotherapy regimens at full doses, across various lines of treatment, and allowing assessment of KRAS mutational status by either tissue- or blood-based assays. “This is going to be of practical relevance, because the rapid turnaround and readout of RAS mutational status is going to be key if and when these RAS inhibitors find their way into frontline treatment paradigms.”
Key Insights from the Study
Speaking to efficacy, Dr. Ko observed, “The waterfall plot for INCB161734 monotherapy was very encouraging. The objective response rate of 37%—which was mainly in patients on their third-line-plus of treatment—compares very favorably with what we expect in the standard-of-care chemotherapy second-line setting,” he said, referencing the 17% response rate with chemotherapy in the NAPOLI-1 trial.2 “The swimmer’s plot was also encouraging, but we do need to see the median duration of response as well as other oncologically meaningful outcomes. For the combination cohort, it’s a little premature to talk about the signal of efficacy. Certainly, by proof of principle, the deep and early molecular responses by [circulating tumor] DNA are encouraging.”
“The agent’s toxicity profile is perhaps even more interesting,” Dr. Ko continued. Consisting primarily of gastrointestinal and constitutional effects, he noted that the adverse events differed from those associated with existing pan-RAS inhibitors. For example, rash and stomatitis were not observed here, possibly reflecting INCB161734’s specificity for the G12D allele.
“But I think it’s worth noting that close to half of patients did require some interruption of either study drug or chemotherapy,” he pointed out. “Now, that’s not a deal breaker, but I think it highlights some of the potential practical challenges and overlapping toxicities when we start thinking about combining these RAS inhibitors with chemotherapy or other agents.”
Looking to the future, Dr. Ko predicted, “Certainly, we anticipate using these agents for advanced or metastatic chemo-resistant disease, but obviously, there is a lot of interest in moving these agents into the frontline setting—in combination with chemotherapy, or, maybe if the results are good enough, as monotherapy, which would completely transform the way we treat our patients with advanced or metastatic disease…. I think the sky’s the limit.”
DISCLOSURE: Dr. Ko reported relationships with Aptitude Health, MJH Life Sciences, Research To Practice, Astellas, Corcept Therapeutics, FibroGen (now Kyntra Bio), Gilead Sciences, GRAIL, Jazz Pharmaceuticals, Legend Biotech, Merus, Pfizer, RenovoRx, Revolution Medicines, Roche/Genentech, Tango Therapeutics, Apexigen (acquired by Pyxis Oncology), Arcus Biosciences, Biomed Valley Discoveries, CrystalGenomics, Leap Therapeutics, Novartis, and Verastem.
REFERENCES
1. Wainberg ZA, Henry JT, Park H, et al: Preliminary phase 1 results of INCB161734, a novel oral Kirsten rat sarcoma G12D inhibitor, as monotherapy or in combination with chemotherapy for advanced/metastatic pancreatic duct adenocarcinoma. 2026 ASCO GI Cancers Symposium. Abstract 654. Presented January 9, 2026.
2. Wang-Gillam A, Hubner RA, Siveke JT, et al: NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Eur J Cancer 108:78-87, 2019.
