Petosemtamab 75% ORR Excites but No Precedent Backs Bispecific in mCRC

Genmab's Petosemtamab Shows Durable Responses in mCRC Phase 2

Genmab A/S announced updated follow-up analyses from its Phase 2 trial of petosemtamab, an investigational IgG1-bispecific antibody, in combination with FOLFOX or FOLFIRI for metastatic colorectal cancer (mCRC). The data, presented at ESMO 2026, showed encouraging objective response rates (ORRs) and durability. In the first-line (1L) setting, confirmed and unconfirmed ORR was 75% (median follow-up 5.9 months), with 81% for 1L patients with left-sided tumors. For the second-line (2L) setting, ORR was 67% (median follow-up 7.1 months). These results reinforce the consistency of clinical activity and support the ongoing global Phase 3 development program for petosemtamab in mCRC.

• The updated analyses demonstrated robust efficacy, with confirmed and unconfirmed objective response rates (ORRs) of 75% in first-line (1L) mCRC patients and 67% in second-line (2L) patients. Notably, 1L patients with left-sided tumors achieved an 81% ORR. Responses were also observed in patients with liver metastases (76% in 1L, 67% in 2L), a poor prognostic factor. The disease control rates were high, at 95% for 1L and 93% for 2L patients, reinforcing the broad clinical activity.
• With longer follow-up (median 5.9 months for 1L, 7.1 months for 2L), most previously unconfirmed objective responses were subsequently confirmed, highlighting the depth and durability of the observed clinical activity. A significant proportion of patients remained on treatment at data cutoff (76% in 1L, 74% in 2L), further supporting the sustained benefit of petosemtamab plus chemotherapy across both treatment settings.
• Petosemtamab demonstrated a manageable safety profile. Treatment-emergent adverse events (TEAEs) leading to petosemtamab discontinuation were low, occurring in 5% (2 of 42) of patients receiving FOLFOX and 3% (1 of 37) of patients receiving FOLFIRI. Infusion-related reactions (IRRs) were observed in 48% (FOLFOX) and 43% (FOLFIRI) of patients, with Grade 3 IRRs occurring in 7% and 3% respectively, and no TEAEs leading to death were reported.
• These encouraging Phase 2 results provide a compelling rationale for Genmab's ongoing global Phase 3 LiGeR trials in mCRC and head and neck squamous cell carcinoma. Petosemtamab's unique triple mechanism of action targets EGFR and LGR5, inhibiting EGFR-mediated signaling, triggering EGFR degradation in cancer stem-like cells, and enhancing innate immune-mediated activity, positioning it as a potential new approach for patients with limited options.

The Persistent Challenges in Metastatic Colorectal Cancer Treatment

Current treatment for metastatic colorectal cancer (mCRC) remains anchored in fluoropyrimidine-based chemotherapy, anti-angiogenic agents, and anti-EGFR antibodies, yet durability is constrained by molecular heterogeneity, dynamic acquired resistance, and overlapping cardiac and systemic toxicities. These factors limit treatment options after progression or toxicity, particularly in heavily pretreated patients and molecularly defined subtypes.

• Fluoropyrimidine-induced cardiotoxicity limits backbone therapy: Fluoropyrimidines compose the backbone of regimens to treat many common solid tumors, including gastrointestinal, breast and head/neck, with recognition of cardiotoxicity in the form of anginal-like symptoms, EKG changes and elevated cardiac enzymes on infusional 5-FU or capecitabine. Fluoropyrimidine-induced cardiotoxicity (FIC) occurred in 200 [21.8%, 95% confidence interval (CI): 19.12%-24.47%] of 916 patients, and may result in delay and discontinuation of chemotherapy and, in severe cases, can even be life-threatening. Significant risk factors were chemotherapy ≤3 cycles (OR=4.694, 95%CI=3.184-6.92), age≥ 60 (OR=1.678, 95%CI=1.143-2.464), BMI>22.97 (OR=1.77, 95%CI=1.202-2.606), and simultaneous use of bevacizumab (OR=2.922, 95%CI=1.835-4.653).

• Vascular endothelial growth factor pathway inhibitor cardiotoxicity and restricted alternatives: Treatment options for patients who have encountered fluoropyrimidine-induced cardiotoxicity are limited as many anti-angiogenic drugs also pose a cardiac risk. Heart failure was noted in 2-4% of patients on bevacizumab and in 3-8% of patients on VSP-TKIs, with hypertension and coronary artery disease as risk factors for VSP inhibitor cardiotoxicity, and any preexisting or coexisting condition that reduces the vascular reserve or utilizes the vascular reserve for compensatory purposes may pose a risk factor.

• Molecular heterogeneity requires extensive profiling: The landscape of treating mCRC is changing with the understanding of its heterogeneity and molecular blueprint, with right-sided tumors having higher incidence of BRAF and KRAS mutations and being microsatellite instability-high (MSI-H) and having worse prognosis compared with left sided-tumors. There is demonstrated need to profile each mCRC patient for RAS and BRAF mutations, MSI-H status, HER2 amplifications, and NTRK fusions.

• Acquired resistance to EGFR blockade through clonal and transcriptional evolution: Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers, but the emergence of resistance limits efficacy, with majority developing RAS mutations and a subset acquiring EGFR extracellular domain (ECD) mutations at relapse. Patients whose tumors were treated with and responded to EGFR inhibitor alone were more likely to develop acquired mutations (46%) compared with those treated in combination with cytotoxic chemotherapy (9%), with preclinical models showing cross-resistance to alternate agents with transcriptomic profiles consistent with epithelial-to-mesenchymal transition, and autophagy induced by anti-EGFR monoclonal antibodies acting as a protective response in cancer cells.

• Limited efficacy and tolerability in refractory and BRAF-mutant disease: Although BRAF inhibitor monotherapy yields response rates >50% in BRAF-mutant melanoma, only approximately 5% of patients with BRAF colorectal cancer respond due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR, with MAPK reactivation remaining an important primary and acquired resistance mechanism. In heavily pretreated mCRC, mitomycin C in combination with high-dose 5-fluorouracil and folinic acid yielded partial response in 2 patients (3.2%) and stable disease in 33 (53.2%), with median progression-free survival of 4.9 months and median overall survival of 9.7 months, while dose reductions due to adverse events were necessary in 29 of 74 patients (37.6%), and discontinuation due to toxicity in 14 of 74 patients (18.2%). Irinotecan 225 mg/m2 every 3 weeks and gefitinib 250 mg daily was tolerable, but gefitinib did not appear to add substantial efficacy to irinotecan, with objective tumour response rate of 11.1% (95% confidence interval 2.4% to 29.2%) and median survival of 9.3 months.

Petosemtamab's Updated Phase 2 Efficacy and Safety in mCRC

Petosemtamab has demonstrated substantial clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). The safety profile is described as generally favorable, with Phase 3 trials ongoing in both first-line programmed death-ligand 1-positive (PD-L1+) and second/third-line r/m HNSCC.

• Low rates of skin and gastrointestinal toxicity reported for Petosemtamab in r/m HNSCC, with the overall safety profile described as generally favorable.

• Ongoing safety and efficacy evaluation in first-line PD-L1+ r/m HNSCC in LiGeR-HN1 (NCT06525220), evaluating petosemtamab plus pembrolizumab versus pembrolizumab, with primary endpoints of objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review, and overall survival.

• Ongoing safety and efficacy evaluation in previously treated r/m HNSCC in LiGeR-HN2 (NCT06496178), evaluating petosemtamab versus investigator's choice of monotherapy (cetuximab, methotrexate, or docetaxel), with primary endpoints of objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review, and overall survival, with both trials recruiting at the time of publication.

Petosemtamab's Expanding Pipeline Beyond Colorectal Cancer

Petosemtamab, a bispecific antibody targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), has demonstrated antitumor activity and substantial clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). Two registration-intent, open-label, randomized phase III trials, LiGeR-HN1 and LiGeR-HN2, are evaluating efficacy and safety of petosemtamab in first-line and previously treated r/m HNSCC and were recruiting at the time of publication.

Dual-Targeting Petosemtamab: A New Horizon in mCRC Treatment

The latest Phase 2 data for petosemtamab in metastatic colorectal cancer (mCRC) signals a potentially transformative shift in how this challenging disease might be treated. With objective response rates of 75% in the first-line setting and 67% in the second-line, when combined with standard chemotherapy regimens like FOLFOX or FOLFIRI, these results are not just encouraging; they underscore the potential for a new therapeutic benchmark.

Petosemtamab's innovative mechanism, simultaneously targeting both the epidermal growth factor receptor (EGFR) and leucine-rich G protein-coupled receptor 5 (LGR5), is particularly noteworthy. Research indicates that LGR5-expressing cells are often stem-cell-like, driving tumor progression and contributing to treatment resistance. By engaging both targets, petosemtamab aims to overcome the limitations of existing EGFR inhibitors and chemotherapy, which frequently encounter resistance due to EGFR mutations or compensatory signaling pathways. This dual-action approach, coupled with its Fc-mediated immune activation, positions it as a potent new weapon against a disease notorious for its adaptability.

Crucially, the favorable safety profile observed with petosemtamab, characterized by low rates of skin and gastrointestinal toxicity, could offer a significant advantage. Many current EGFR-targeted therapies are associated with challenging cutaneous side effects, which can severely impact a patient's quality of life and adherence to treatment. A therapy that can deliver high efficacy with improved tolerability could lead to better patient outcomes and sustained treatment. However, as the program advances into Phase 3, several factors will be critical to watch:

• The long-term safety and tolerability of the combination therapy, particularly the cumulative toxicities associated with chemotherapy backbones.

• The durability of response and the potential for acquired resistance in a larger, more diverse patient population.

• The identification of predictive biomarkers, such as LGR5 expression levels or specific EGFR mutations, to optimize patient selection and ensure the broadest and most consistent efficacy.

Should these Phase 3 trials confirm the promising Phase 2 findings, petosemtamab could redefine treatment strategies for mCRC, offering a more effective and potentially better-tolerated option for patients.