KRAS G12D Early Responses Impress but Randomization Will Decide PDAC Value

Incyte Presents Positive Data for Gastrointestinal Cancer Portfolio at ESMO 2026

Incyte presented new clinical data at ESMO 2026 for its gastrointestinal cancer portfolio, highlighting the KRAS G12D inhibitor INCB161734 in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), and the TGFβR2×PD-1 bispecific antibody INCA338901 in microsatellite stable CRC (MSS CRC). Phase 1 results for INCB161734 in metastatic KRAS G12D-mutated PDAC showed encouraging efficacy with objective response rates up to 89% and disease control rates of 100% when combined with standard-of-care chemotherapies. Similarly, INCA338901 demonstrated a 71% ORR and 100% DCR in first-line MSS CRC patients. These data reinforce ongoing and planned Phase 3 registrational trials, including DAWN-303 for INCB161734 in PDAC and NEXERA-303 for INCA338901 in MSS CRC, with manageable safety profiles observed across studies.

• New Phase 1 data for INCB161734 (1,200 mg QD) in metastatic KRAS G12D-mutated PDAC (n=54) demonstrated deep and durable responses. In combination with mFOLFIRINOX, patients achieved an 89% ORR and 100% DCR, with a 90% six-month PFS rate. With GEMNabP, ORR was 69% and DCR 96%, showing an 80% six-month PFS. The safety profile was manageable, consistent with SoC regimens, with GI-related TRAEs being mostly Grade 1/2.
• In advanced/metastatic KRAS G12D-mutated CRC, INCB161734 combined with cetuximab (n=22) achieved a 36% ORR and 100% DCR in heavily pretreated patients, with a median PFS of 7.2 months. A Phase 3 study (DAWN-302) is planned for H1 2027. Additionally, Incyte announced new collaborations with Bristol Myers Squibb and Synnovation to evaluate INCB161734 in combination with navlimetostat (PRMT5 inhibitor) and SNV1521 (PARP1 inhibitor), respectively, for advanced PDAC.
• Phase 1 data (n=94) for INCA338901 (900 mg IV Q2W) in advanced or MSS CRC showed notable clinical activity. In the first-line setting, INCA338901 combined with FOLFOX and bevacizumab (n=42) yielded a 71% ORR and 100% DCR, with an 81% six-month PFS. Responses were observed across subgroups, including those with liver and peritoneal metastases. The Phase 3 NEXERA-303 study for this combination in first-line metastatic MSS CRC is ongoing, with topline data anticipated in 2029.

Early Efficacy and Safety of INCB161734 in KRAS G12D PDAC

Recent studies in pancreatic ductal adenocarcinoma have evaluated KRAS G12D inhibition, CCR2 inhibition with chemotherapy, and PARP inhibition in BRCA-mutant disease. These trials report recommended doses, adverse events, and response and survival outcomes in defined populations.

• Oral KRAS G12D inhibitor GFH375 for previously treated advanced solid tumors with KRASG12D mutations: a phase 1 trial evaluated GFH375 administered orally once or twice daily in 74 heavily treated patients including 43 patients with PDAC. The maximum tolerated dose was not reached with no dose-limiting toxicity observed among the 22 patients in the dose-escalation part, the recommended phase 2 dose of GFH375 was declared as 600 mg once daily, Grade ≥3 treatment-related adverse events occurred in 36.5% (27/74), and one (1.4%) grade 5 treatment-related adverse event was reported as septic shock. In patients with PDAC, the confirmed ORR was 35.1% (13/37), with a median duration of response of 5.6 months, and the median PFS and median OS were 5.5 months and 9.9 months, respectively.

• Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial evaluated oral PF-04136309 at a starting dose of 500 mg twice daily plus FOLFIRINOX (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion). This dose was established as the recommended phase 2 dose, no treatment-related deaths occurred, and Grade 3 or higher adverse events in patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Among 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging, 16 (49%) of 33 patients achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients.

• Rucaparib Monotherapy in Patients With Pancreatic Cancer and a Known Deleterious BRCA Mutation (RUCAPANC) evaluated oral rucaparib (600 mg twice daily) in 19 patients with measurable locally advanced/metastatic pancreatic cancer who had received one to two prior chemotherapy regimens. The objective response rate was 15.8% (3 of 19) with two partial responses and one complete response confirmed, and the disease control rate (CR, partial response, or stable disease for ≥ 12 weeks) was 31.6% (6 of 19). Treatment-emergent adverse events included nausea (63.2%) and anemia (47.4%), and Grade ≥ 3 adverse events included anemia (31.6%), fatigue (15.8%), and ascites (15.8%).

Addressing Unmet Needs in KRAS G12D-Mutated PDAC

Pancreatic ductal adenocarcinoma remains characterized by late-stage diagnosis, aggressive biology, and limited responsiveness to conventional cytotoxic therapies, with a 5-year survival rate of only 12% and fewer than 9% of patients surviving beyond 5 years. Despite representing only 3% of new cancer cases, it is projected to become the second leading cause of cancer-related deaths by 2030. Over 80% of patients present with unresectable disease, while only 10-15% of patients are diagnosed with potentially resectable disease, and surgical resection has been historically considered the only curative treatment. Screening the general population is not currently viable owing to overall low incidence and lack of specific tests, making early detection in high-risk individuals a central unmet need addressed through surveillance with endoscopic ultrasound in combination with magnetic resonance imaging/magnetic resonance cholangiopancreatography, artificial intelligence assisted EUS, AI-driven imaging, and liquid biopsies incorporating circulating tumour DNA, circulating tumour cells, microRNAs, exosomes, and volatile organic compounds.

A second unmet need centers on high-risk individuals defined by genetic and familial susceptibility, which accounts for 10% of pancreatic ductal adenocarcinoma cases. Pathogenic germline variants in susceptibility genes, such as BRCA2/ATM/CDKN2A/STK11/PALB2/TP53, as well as mismatch repair genes, BRCA1, BRCA2, PALB2, Lynch syndrome, hereditary breast and ovarian cancer syndrome, hereditary pancreatitis, familial adenomatous polyposis, Peutz-Jeghers syndrome, familial pancreatic cancer mutation, and ataxia telangiectasia, confer a substantially higher lifetime risk, while families fulfilling the criteria for familial pancreatic cancer exhibit disease clustering in the absence of an identifiable pathogenic germline variant. Data from the international CAPS consortium, the Dutch nationwide surveillance program, and the IRFARPC consistently demonstrate a stage shift toward earlier, resectable disease and improved survival among cancers detected under surveillance, with surveillance strategies demonstrating increased detection of Stage I pancreatic ductal adenocarcinoma. In prospective surveillance, pancreatic ductal adenocarcinoma was detected in 11 individuals (4.6%), with 73% diagnosed at an early stage, alongside 4 (1.67%) with pancreatic neuroendocrine tumor, 6 (2.5%) with main-duct intraductal papillary neoplasm, and 41 (17.15%) with side-branch intraductal papillary neoplasm.

Therapeutic resistance in advanced or metastatic disease defines an additional targeted population, where combination therapy protocols such as FOLFIRINOX and gemcitabine/nab-paclitaxel define standard-of-care and median progression-free survival upon first palliative chemotherapy was 4.1 (3.1-5.9) months. Research has focused on molecularly defined subpopulations who may benefit from targeted therapies matched to molecular profile, including maintenance PARP inhibition in tumors harboring deleterious BRCA1, BRCA2, and PALB2 alterations, KRAS G12C inhibition with sotorasib and adagrasib, KRAS G12D targeting, and KRAS wild-type pancreatic ductal adenocarcinoma enriched for targetable alterations such as oncogenic BRAF alterations, mismatch repair deficiency, and FGFR2, ALK, NTRK, ROS1, NRG1, and RET rearrangements. Complementary strategies include immune checkpoint blockade with dostarlimab and pembrolizumab in cancers harboring mismatch repair deficiency or high microsatellite instability, HER2-directed antibody-drug conjugates including trastuzumab deruxtecan and RC48 in HER2-positive disease, liposomal irinotecan plus fluorouracil and leucovorin in patients who progressed after gemcitabine-based chemotherapy, and tailored approaches for elderly patients where individuals aged ≥65 years now represent 64% of new cancer cases and 71.3% of cancer-related deaths and where deficit accumulation frailty index assessment identified 61.2% as frail with median overall survival of 7.13 months compared with 16.1 months in nonfrail patients.

Incyte's Dual Oncology Advances: Reshaping 'Undruggable' KRAS and 'Cold' CRC

The recent ESMO presentation from Incyte has sent a clear signal to the oncology community: the landscape for historically challenging cancers is on the cusp of significant change. Two investigational agents, INCB161734 and INCA338901, have delivered early-phase data that suggest a powerful shift in therapeutic possibilities for pancreatic ductal adenocarcinoma (PDAC) and microsatellite stable colorectal cancer (MSS CRC).

For INCB161734, a KRAS G12D inhibitor, the reported objective response rates of up to 89% and 100% disease control rates in metastatic PDAC patients, when combined with standard chemotherapy, are particularly striking. PDAC is an aggressive malignancy with a dire prognosis, and KRAS G12D mutations are a prevalent driver that has long eluded effective targeted therapies. While these Phase 1 results are highly promising, the aggressive nature of PDAC and the emergence of adaptive resistance mechanisms to KRAS inhibitors mean that the true test will be in the ongoing DAWN-303 Phase 3 trial. The competitive landscape for KRAS G12D inhibitors is also intensifying, with several compounds vying for market share, underscoring the need for INCB161734 to demonstrate sustained, differentiated benefits.

Equally compelling are the data for INCA338901, a TGFβR2×PD-1 bispecific antibody, which achieved a 71% ORR and 100% DCR in first-line MSS CRC. MSS CRC represents the majority of colorectal cancer cases and is notoriously 'cold' to conventional immunotherapies. This bispecific approach, by simultaneously blocking PD-1 and modulating the TGF-β pathway—a known contributor to immune suppression in the tumor microenvironment—offers a novel strategy to 'heat up' these tumors. The complexity of TGF-β signaling, however, means that the precise balance of its modulation alongside PD-1 blockade will be critical to optimize efficacy and manage potential immune-related adverse events in the larger NEXERA-303 Phase 3 study. If these results hold, INCA338901 could unlock immunotherapy for a vast, underserved patient population, fundamentally altering the treatment paradigm for MSS CRC. These dual advancements position Incyte as a significant player in precision oncology, addressing critical unmet needs with innovative, mechanistically distinct therapies.