Incyte and Genmab plan a Phase 1/2 trial combining petosemtamab, INCB161734 and chemotherapy in first-line KRAS G12D-mutated metastatic colorectal cancer.
Written By: Rishabh Sonawane, BPharm
Reviewed By: Pharmacally Editorial Team
Genmab A/S and Incyte announced a clinical trial collaboration on October 24, 2026, to evaluate a three-component treatment regimen in previously untreated patients with KRAS G12D-mutated metastatic colorectal cancer (mCRC). The planned Phase 1/2 study will combine petosemtamab, Genmab’s investigational bispecific antibody targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), with INCB161734, Incyte’s investigational KRAS G12D inhibitor, and standard-of-care chemotherapy.
Under the agreement, Genmab will conduct the study, while Incyte will co-fund the trial and provide clinical supplies of INCB161734. The companies have not disclosed the planned enrolment, study initiation date, financial terms or anticipated completion timeline.
Scientific Rationale for the Combination
KRAS mutations occur in approximately 40% of colorectal cancers, with G12D representing the most common KRAS mutation. Incyte estimates that KRAS G12D accounts for approximately 15% of colorectal cancer cases, identifying a substantial molecularly defined population for targeted treatment development.
INCB161734 is an investigational, orally bioavailable small-molecule inhibitor designed to selectively target KRAS G12D. Petosemtamab is an investigational human IgG1-based bispecific antibody that inhibits EGFR-mediated signalling by preventing ligand binding. It is also designed to promote EGFR degradation in cancer stem-like cells expressing both EGFR and LGR5 and enhance innate immune-mediated activity involving macrophages and natural killer cells.
The combination is intended to investigate whether direct KRAS G12D inhibition, EGFR/LGR5-directed antibody activity and chemotherapy can provide complementary antitumour effects. However, this scientific rationale does not establish that the three-component regimen will improve clinical outcomes. Its safety, tolerability and efficacy will need to be demonstrated in prospective clinical studies.
Existing Clinical Development Programmes
The collaboration extends the investigation of both agents in oncology, although their existing clinical programmes address different settings.
Petosemtamab is being studied in head and neck squamous cell carcinoma and other solid tumours, including colorectal cancer. Its development programme includes two Phase 3 trials evaluating combinations with chemotherapy in first- and second-line RAS/BRAF wild-type mCRC. These studies involve a different molecular population from the KRAS G12D-mutated patients targeted by the newly announced collaboration.
INCB161734 is being evaluated in the global Phase 3 DAWN-303 study (NCT07522073) in previously untreated patients with KRAS G12D-mutated pancreatic ductal adenocarcinoma. It is also being investigated as monotherapy and in combination with standard-of-care chemotherapy in an ongoing Phase 1 study of KRAS G12D-mutated solid tumours (NCT06179160).
These programmes provide context for the agents’ broader clinical development but do not establish the efficacy of the proposed combination in colorectal cancer.
Clinical and Development Implications
For Genmab, the collaboration supports the broader development strategy for petosemtamab by introducing another combination and treatment setting. For Incyte, it provides an opportunity to investigate INCB161734 alongside an antibody targeting EGFR and LGR5 in a molecularly defined colorectal cancer population.
The central clinical question is whether combining these targeted approaches with chemotherapy can produce sufficient antitumour activity with an acceptable safety profile to justify further development. The early-stage study will need to establish the regimen’s safety, tolerability and preliminary activity before subsequent clinical development decisions can be made.
Both targeted agents remain investigational, and no regulatory approval has been announced for the proposed combination. The collaboration therefore represents an early clinical development strategy rather than an established treatment advance. Its significance will ultimately depend on the clinical evidence generated in patients with KRAS G12D-mutated metastatic colorectal cancer.
Reference
Genmab and Incyte Announce Clinical Trial Collaboration in Metastatic Colorectal Cancer, Genmab, 24 October 2026
Incyte and Genmab Announce Clinical Trial Collaboration in Metastatic Colorectal Cancer, Incyte, 24 October 2026
About the Writer
Rishabha Sonawane, B.Pharm (LinkedIn) is healthcare writer with a strong interest in medical writing, regulatory affairs, clinical research, and AI-driven drug discovery. He has completed specialized training from the NIH and ICMR in clinical pharmacology, clinical research, and scientific writing. Passionate about evidence-based healthcare communication, he focuses on translating complex scientific research into clear, accurate, and engaging medical content.