Genmab petosemtamab hits 75% ORR in Phase 2 mCRC update
Genmab has reported updated follow-up data from its Phase 2 trial of petosemtamab in metastatic colorectal cancer (mCRC), with the bispecific antibody demonstrating confirmed and unconfirmed objective response rates (ORRs) of 75% in first-line (1L) patients and 67% in second-line (2L) patients when combined with standard FOLFOX or FOLFIRI chemotherapy regimens. The data were presented at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid.
The dataset, cut as of 15 May 2026, covered 79 patients in total: 45 in the 1L setting and 34 in the 2L setting. Among 1L patients with left-sided tumours, the ORR reached 81%. Disease control rates were 95% in the 1L cohort and 93% in the 2L cohort, and the majority of patients remained on treatment at the data cutoff: 76% and 74% in 1L and 2L settings respectively. Genmab also noted that most previously unconfirmed responses had since been confirmed with longer follow-up, supporting what the company characterised as durable clinical activity across both treatment lines.
Mechanism and safety profile
Petosemtamab is an investigational IgG1-based bispecific antibody targeting two receptors: the epidermal growth factor receptor (EGFR) and LGR5, a marker expressed on stem-like cancer cells thought to drive tumour recurrence. Genmab says the molecule acts through three mechanisms simultaneously, inhibiting EGFR signalling, triggering degradation of cancer stem-like cells that co-express EGFR and LGR5, and engaging innate immune effectors including macrophages and natural killer cells. The combination of EGFR inhibition with LGR5-targeted activity is the key differentiator the company is positioning against existing EGFR-directed therapies such as cetuximab and panitumumab, both of which are established in RAS/BRAF wild-type mCRC but do not address stem-cell-driven resistance.
The safety readout showed manageable tolerability at this stage. Infusion-related reactions (IRRs) occurred in 48% of patients receiving petosemtamab plus FOLFOX and 43% of those on FOLFIRI, though grade 3 IRRs were limited to 7% and 3% of patients in each group respectively. Treatment-emergent adverse events led to petosemtamab discontinuation in 5% of the FOLFOX group and 3% of the FOLFIRI group. No treatment-emergent deaths were reported.
Ruth Vera, a medical oncologist at the Hospital Universitario de Navarra and a study investigator, said the results "suggest that treatment with petosemtamab plus chemotherapy may offer a potential new approach" for patients with RAS/BRAF wild-type mCRC, a group that faces limited options once first-line standard-of-care regimens are exhausted.
Phase 3 programme and market context
Genmab has initiated four Phase 3 trials under the LiGeR programme: two in head and neck squamous cell carcinoma and two in mCRC, targeting both 1L RAS/BRAF wild-type left-sided disease (LiGeR-CRC1) and 2L RAS/BRAF wild-type disease (LiGeR-CRC2). All four are actively enrolling. The Phase 2 data presented at ESMO provide the clinical rationale underpinning those trials, though response rate data from a single-arm, open-label study of this size cannot substitute for the randomised, controlled evidence the Phase 3 programme will need to generate.
Colorectal cancer remains the third most commonly diagnosed cancer globally, with approximately 1.9 million new cases each year. Five-year survival in late-stage metastatic disease sits at roughly 15%, underlining the unmet need. The competitive landscape in EGFR-targeted mCRC is well established, but no approved bispecific currently combines EGFR and LGR5 targeting. How durably petosemtamab's stem-cell mechanism translates into long-term survival benefit is the central question the LiGeR-CRC trials will need to answer. Median follow-up of under eight months in the Phase 2 cohort means overall survival data remain immature, and analysts and clinicians will focus on progression-free and overall survival readouts from Phase 3 as the critical inflection points for the asset.