INCB161734 / Incyte - LARVOL DELTA

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). (ASCO-GI 2026) - P1 | "The study is evaluating INCB161734 monotherapy including a PDAC-specific expansion cohort and INCB161734 combination therapies, including with mFOLFIRINOX or GEMNabP in pts with PDAC and ≤1 prior treatment (tx) in the metastatic setting. INCB161734 monotherapy has a manageable safety profile, with promising early clinical efficacy and evidence of molecular response in pts with advanced/metastatic PDAC harboring KRASG12D mutation. Ongoing dose escalation of INCB161734 in combination with chemotherapy shows an encouraging safety profile. INCB161734 monotherapy outcomes at selected doses in pts with PDAC and ≥1 post-baseline scan."

Combination therapy • First-in-human • Metastases • Monotherapy • P1 data • Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Safety and Efficacy of INCB161734, a Novel Oral KRAS G12D Inhibitor, in Combination with Chemotherapy in Patients (pts) with Advanced/Metastatic Pancreatic Ductal Adenocarcinoma (PDAC) (ESMO 2026) - No abstract available

Clinical • Combination therapy • Metastases • Oncology • Pancreatic Ductal Adenocarcinoma • KRAS

Safety and Efficacy of Oral KRAS G12D Inhibitor INCB161734 as Monotherapy or in Combination with Cetuximab (Cetux) in Patients (pts) with Advanced/Metastatic Colorectal Cancer (CRC) (ESMO 2026) - No abstract available

Clinical • Combination therapy • Metastases • Monotherapy • Colorectal Cancer • Oncology • Solid Tumor • KRAS

A Study to Assess the Mass Balance, Pharmacokinetics, and Metabolite Profiles of a Single Oral Dose of [14C]-INCB161734 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=10 | Not yet recruiting | Sponsor: Incyte Corporation

New P1 trial

Preliminary phase I results of INCB161734, a novel oral KRAS G12D inhibitor, in patients with advanced or metastatic solid tumors (ESMO 2025) - P1 | "Monotherapy expansion at 600 and 1200 mg qd is ongoing, and combinations with standard therapies in CRC and PDAC are enrolling. Updated data will be presented."

Clinical • Metastases • P1 data • Colorectal Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • KRAS

Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies. (PubMed, Future Med Chem) - "Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805...Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment."

IO biomarker • Journal • Review • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS

The ongoing first-line treatment race for metastatic pancreatic ductal adenocarcinomas: will a tough disease lose its horror? (PubMed, Future Oncol) - "PDACs are K-RAS addicted (incidence >90%), however, RAS oncogenes have been regarded to be "undruggable." Several highly specific inhibitors have been developed with atebimetinib (MEK inhibitor), daraxonrasib (tri-complex pan-K-RAS inhibitor), zoldonrasib (tri-complex K-RAS G12D inhibitor), INCB161734 (non-covalent ON/OFF inhibitor specific for K-RAS G12D), HRS-4642 (liposomal G12D inhibitor), and setidegrasib (G12D degrader) currently undergoing phase III evaluation in first-line PDACs. Since the benefits provided by chemotherapy regimens are limited, it is conceivable that the novel targeted approaches may have the potential to overcome these limitations. Of note, outcomes for some of these compounds numerically exceeded the historical benchmarks with standard chemotherapy suggesting that a chemotherapy backbone might no longer be needed in the future."

Journal • Oncology • Palliative care • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Path less travelled: Discovery of INCB161734, a selective KRAS G12D inhibitor (ACS-Fall 2026) - "A second round of optimization focused on removing the ubiquitous second basic amine present in most clinical KRAS G12D inhibitors via a strategy centered on rigidification of the structure. These changes led to INCB161734, which demonstrated a balanced profile, efficacy in murine models of KRAS G12D driven tumors and excellent cross species and clinical phramacokinetics."

KRAS

Incyte Data to Be Highlighted in Four Rapid Oral Presentations at the European Society for Medical Oncology (ESMO) Congress 2026 Support Efforts to Improve Outcomes in Difficult-to-Treat Cancers (Incyte Press Release) - "Rapid oral presentations will highlight new Phase 1 data across Incyte’s solid tumor portfolio; Both INCB161734, an investigational, potent, selective and orally bioavailable KRAS G12D inhibitor, and INCA33890, a TGFβR2×PD-1 bispecific antibody, are being evaluated in ongoing Phase 3 programs as first-line treatments for patients with advanced pancreatic ductal adenocarcinoma (PDAC) and microsatellite stable (MSS) colorectal cancer, respectively."

First-in-human • P1 data • P3 data • Anal Squamous Cell Carcinoma • Colorectal Cancer • Epithelial Ovarian Cancer • Fallopian Tube Cancer • Pancreatic Ductal Adenocarcinoma • Peritoneal Cancer

Key Business Updates (Incyte Press Release) - "The Company initiated a Phase 3 study (DAWN-303) evaluating INCB161734 as a first-line treatment in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) in combination with standard-of-care chemotherapy (mFOLFIRINOX or GEMNabP) versus chemotherapy alone in the first quarter of 2026; Additional data from the ongoing Phase 1 trial evaluating INCB161734 in combination with standard-of-care chemotherapy as a first-line treatment in patients with metastatic PDAC are anticipated in the second half of 2026...The Phase 3 study evaluating INCA33890 in....patients with microsatellite stable colorectal cancer (MSS CRC) is ongoing; Additional data from the ongoing Phase 1 study evaluating INCA33890...in patients with solid tumors is expected in the second half of 2026."

P1 data • Trial status • Colorectal Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

DAWN-303: A Study to Evaluate Chemotherapy With or Without INCB161734 in Previously Untreated, KRAS G12D-Mutated Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P3 | N=588 | Recruiting | Sponsor: Incyte Corporation

New P3 trial • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

INCB161734: A novel, potent, and orally bioavailable KRAS G12D selective inhibitor demonstrates antitumor activity in KRAS G12D mutant tumors (AACR 2024) - "INCB161734 is efficacious against multiple types of G12D-mutated tumors and xenografts, resulting in significant tumor growth inhibition, growth arrest and/or regression in multiple PDAC (HPAC, Panc0403, and 2838c3) and CRC (CT26, GP2D, and LS513) mouse tumor models.These preclinical results demonstrate that INCB161734 is a potent, selective, and orally bioavailable KRAS G12D inhibitor, strongly efficacious against KRAS G12D mutant tumors. The potential benefit of INCB161734 for patients with KRAS G12D mutant disease is under investigation in ongoing clinical trials."

Colorectal Cancer • Oncology • CASP3 • CASP7 • KRAS

Preclinical evaluation of potential therapeutic combinations with the Kirsten Rat Sarcoma (KRAS)G12D inhibitor INCB161734 with chemotherapy, growth factor disruption, or immunotherapy in pancreatic cancer (ESMO-TAT 2026) - P1 | "Combinations included INCB161734 with chemotherapy (gemcitabine + nab-paclitaxel or 5-fluorouracil + irinotecan + oxaliplatin + leucovorin), the epidermal growth factor receptor (EGFR) antagonist cetuximab, or anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies. These results demonstrate that KRAS G12D blockade via INCB161734 combined with chemotherapy, EGFR signalling disruption, or immune checkpoint blockade via PD-1/PD-L1 may have the potential to improve therapeutic efficacy in PDAC."

IO biomarker • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • KRAS

...the initiation of a Phase 3 study evaluating INCB161734 in first-line patients with metastatic PDAC in combination with chemotherapy versus chemotherapy alone is anticipated in the first quarter of 2026. (Businesswire)

New P3 trial • Pancreatic Ductal Adenocarcinoma

INCB161734 at ASCO GI 2026: Early Clinical Data in KRASG12D-Mutated Pancreatic Cancer (OncoDaily) - "Antitumor activity was observed with INCB161734 monotherapy in heavily pretreated patients with PDAC. Among evaluable patients treated with INCB161734 1200 mg daily (n=41), the disease control rate was 78% (32 patients), and the objective response rate was 37% (15 patients). Tumor shrinkage was observed in multiple patients, with several responses ongoing at the time of data cutoff."

P1 data • Pancreatic Cancer

Incyte…Provides Updates on Key Clinical Programs (Businesswire) - "The Phase 1 data in patients with myelofibrosis (MF) as monotherapy and in combination with ruxolitinib are anticipated in the second half of 2025...A Phase 1 study evaluating JAK2V617Fi in MPNs is ongoing. Initial proof of concept data are anticipated in the first half of 2026...Incyte plans to initiate Phase 3 studies for its potentially first-in-class CDK2 inhibitor (INCB123667), in ovarian cancer in 2025 and is also evaluating INCB123667 in combination with other treatments; The Phase 3 study evaluating tafasitamab as first-line treatment for diffuse large B-cell lymphoma (DLBCL) is ongoing. The Phase 3 data are anticipated in the second half of 2025; The Phase 1 studies evaluating KRASG12D and TGFßR2×PD-1 in solid tumors are ongoing. Initial proof of concept data for both studies are anticipated in the second half of 2025."

Clinical data • JAK2V617F • New P3 trial • Diffuse Large B Cell Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm • Ovarian Cancer • Solid Tumor

A Study to Assess the Effect of Itraconazole, Rifampin, and Acid-Reducing Agents on INCB161734 Pharmacokinetics When Administered Orally in Healthy Participants (clinicaltrials.gov) - P1 | N=63 | Completed | Sponsor: Incyte Corporation | Recruiting ➔ Completed

Trial completion

INCB161734-101: A Study to Evaluate INCB161734 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation (clinicaltrials.gov) - P1 | N=710 | Recruiting | Sponsor: Incyte Corporation | N=466 ➔ 710

Enrollment change • Solid Tumor • KRAS

Data from Incyte’s TGFβR2×PD-1 Bispecific Antibody and KRAS G12D Inhibitor to be Presented at the European Society of Medical Oncology (ESMO) Congress 2025 (Businesswire) - "...Results from Phase 1 proof-of-concept studies of INCA33890, a promising TGFβR2×PD-1-directed bispecific antibody, and INCB161734, a novel, selective and orally bioavailable KRAS G12D inhibitor, will be highlighted as oral presentations..."

P1 data • Solid Tumor

Incyte…announced the first clinical data evaluating its…potent, selective and orally bioavailable KRAS G12D inhibitor (INCB161734) for patients with KRAS G12D mutations, specifically pancreatic ductal adenocarcinoma (PDAC). (Businesswire) - "PDAC patients receiving 600 mg (n=25) and 1,200 mg (n=29) INCB161734 daily demonstrated objective response rates (ORR; 20% and 34%) and high DCRs (64% and 86%). The study is ongoing for the majority of patients; data on durability of response is expected in the first half of 2026."

P1 data • Pancreatic Ductal Adenocarcinoma

A Study to Assess the Effect of Itraconazole, Rifampin, and Acid-Reducing Agents on INCB161734 Pharmacokinetics When Administered Orally in Healthy Participants (clinicaltrials.gov) - P1 | N=72 | Recruiting | Sponsor: Incyte Corporation | Not yet recruiting ➔ Recruiting

Enrollment open

Incyte To Present Initial Data for its TGFβR2×PD-1-directed Bispecific Antibody (INCA33890) and its Selective Inhibitor of G12D-mutated KRAS (INCB161734) at the European Society of Medical Oncology (ESMO) Congress 2025 (Incyte Press Release) - "Details on the abstracts accepted for oral presentation at ESMO include: (i) INCB161734 (KRAS G12D)​: Preliminary Phase 1 Results Of INCB161734, A Novel Oral KRAS G12D Inhibitor, In Patients With Advanced Or Metastatic Solid Tumors​ (...Abstract #916O); (ii) INCA33890 (PD-1/TGFβR2): A Phase 1 Study Of INCA33890, A PD-1/Tgfβr2 Bispecific Antibody, For Advanced Solid Tumours​ (...Abstract #1522); (iii) INCAGN2385 (LAG-3)​: Retifanlimab (Anti–PD-1 Mab) Alone Or In Combination With Anti-LAG3 ± Anti-TIM3 Mabs In Previously Untreated, Recurrent And/Or Metastatic (R/M) PD-L1+ HNSCC: A Double-Blind Randomised Controlled Phase 2 Trial (...Abstract #1325)."

Clinical data • Squamous Cell Carcinoma of Head and Neck

A Study to Assess the Effect of Itraconazole, Rifampin, and Acid-Reducing Agents on INCB161734 Pharmacokinetics When Administered Orally in Healthy Participants (clinicaltrials.gov) - P1 | N=72 | Not yet recruiting | Sponsor: Incyte Corporation

New P1 trial

Incyte Reports 2025 First Quarter Financial Results and Provides Updates on Key Clinical Programs (Businesswire) - "The Phase 3 study evaluating tafasitamab as first-line treatment for DLBCL is ongoing. The Phase 3 data are anticipated in the second half of 2025. The Phase 1 studies evaluating KRASG12D and TGFßR2×PD-1 in solid tumors are ongoing and enrolling patients. Initial proof of concept data for both studies are anticipated in the second half of 2025."

P1 data • P3 data • Diffuse Large B Cell Lymphoma • Solid Tumor

Incyte Reports 2024 Fourth Quarter and Year-End Financial Results, Provides 2025 Financial Guidance and Highlights 2025 R&D Milestones (Businesswire) - "Other Hematology/Oncology – key highlights: Incyte plans to initiate Phase 3 studies for its potentially first-in-class CDK2 inhibitor (INCB123667), in ovarian cancer in 2025 and is also evaluating INCB123667 in combination with other treatments. The Phase 3 study evaluating tafasitamab in first-line DLBCL is ongoing. The Phase 3 data are anticipated in the first half of 2025. The Phase 1 studies evaluating KRASG12D and TGFßR2×PD-1 in solid tumors are ongoing and enrolling patients. Initial proof of concept data for both studies are anticipated in 2025."

New P3 trial • P1 data • P3 data • Diffuse Large B Cell Lymphoma • Ovarian Cancer • Solid Tumor