Genmab and Incyte team up on KRAS G12D colorectal cancer trial

Genmab and Incyte have announced a clinical trial collaboration to evaluate a novel combination regimen in patients with metastatic colorectal cancer harbouring a KRAS G12D mutation, one of the most common and difficult-to-treat molecular subtypes of the disease.

Under the agreement, Genmab will sponsor and conduct a Phase 1/2 study testing its investigational bispecific antibody petosemtamab alongside Incyte's oral KRAS G12D inhibitor INCB161734 and standard-of-care chemotherapy in the first-line setting. Incyte will co-fund the trial and supply INCB161734.

The science behind the combination

Petosemtamab (GEN1158) is an IgG1-based bispecific antibody that targets both the epidermal growth factor receptor (EGFR) and LGR5, a marker associated with cancer stem-like cells. It works by blocking EGFR-mediated signalling at a distinct ligand-binding site, promoting EGFR degradation in cells that co-express both targets, and engaging macrophages and natural killer cells to stimulate innate immune activity. The candidate is already being assessed in two Phase 3 trials in RAS/BRAF wild-type metastatic colorectal cancer, as well as in head and neck squamous cell carcinoma.

INCB161734 is a selective, orally bioavailable small molecule designed as an ON/OFF KRAS G12D inhibitor. Incyte is currently enrolling patients with previously untreated KRAS G12D-mutated pancreatic ductal adenocarcinoma in the global Phase 3 DAWN-303 study, and the compound is under evaluation as monotherapy and in combination in an ongoing Phase 1 basket trial across KRAS G12D-mutated solid tumours.

The rationale for pairing the two agents rests on their mechanistic complementarity. KRAS G12D mutations occur in roughly 15% of colorectal cancer cases and, together with other KRAS alterations, account for approximately 40% of the disease overall. These tumours are associated with poor prognosis and, in the RAS-mutant population, are ineligible for the approved anti-EGFR antibodies cetuximab and panitumumab, leaving patients reliant on chemotherapy doublets and bevacizumab. Adding direct KRAS G12D inhibition to an EGFR-LGR5-targeting bispecific could address both the canonical driver mutation and the tumour-promoting stem-cell compartment simultaneously.

Market context and competitive landscape

The KRAS inhibitor space has grown rapidly since sotorasib and adagrasib established proof of concept for KRAS G12C inhibition in non-small cell lung cancer and colorectal cancer. The G12D variant, though more prevalent across solid tumours, has proved harder to drug given differences in nucleotide cycling dynamics, and no G12D-specific agent is yet approved. Several companies, including Mirati Therapeutics (now part of Bristol Myers Squibb), Revolution Medicines, and Relay Therapeutics, are pursuing G12D programmes at various stages, making Incyte's INCB161734 one of a competitive cohort vying for first-mover advantage.

Genmab's decision to combine petosemtamab with a KRAS inhibitor rather than relying on EGFR blockade alone reflects a broader industry recognition that single-pathway inhibition is rarely durable in RAS-driven colorectal cancer. Whether the triple combination with chemotherapy can improve on current standards without an unacceptable toxicity burden will be the central question for the Phase 1/2 study. Investors will watch for dose-escalation safety data and early efficacy signals, including objective response rates in the KRAS G12D-selected population, as the trial matures.

Judith Klimovsky, Executive Vice President and Chief Development Officer at Genmab, said the collaboration "reflects our commitment to research collaborations aimed at expanding potential treatment options for more patients." No timeline for trial initiation or first data readout was provided in the announcement.