NCT07059338

Dual EGFR/HER2 Blockade Combined With Irinotecan for the Treatment of HER2-Positive Metastatic Colorectal Cancer

Trastuzumab in Combination With Cetuximab and Irinotecan for the Treatment of HER2-Positive Metastatic Colorectal Cancer：A Phase II, Open-Label Trial

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 34 (estimated)
• Sponsor: Sun Yat-sen University · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

In colorectal cancer (CRC), HER2 has emerged as a critically targeted biomarker in recent years. Although multiple clinical trials have demonstrated the potential of HER2-targeted therapies in HER2-positive (overexpressed/amplified) metastatic CRC (mCRC), the duration of treatment response remains short with rapid disease progression. This underscores the urgent need to develop novel therapeutic strategies for HER2-positive mCRC. The EGFR pathway is constitutively activated in CRC and mediates resistance to HER2-targeted therapies through the formation of EGFR-HER2 heterodimers. Notably, EGFR-targeting antibodies combined with irinotecan can reverse irinotecan chemoresistance. Building upon these mechanisms, this study proposes to evaluate the combination of trastuzumab (anti-HER2), cetuximab beta (anti-EGFR), and irinotecan in chemotherapy-refractory HER2-positive mCRC.

Detailed description

In colorectal cancer (CRC), HER2 has emerged as a significant therapeutic target, with clinical studies demonstrating promising yet transient responses to HER2-targeted therapies in HER2-positive (overexpressed/amplified) advanced cases, highlighting the need for improved strategies. Mechanistically, in the 65-75% of CRCs exhibiting EGFR overexpression, HER2 promotes heterodimerization with EGFR, impairing internalization of HER2-targeted ADCs and reducing drug uptake. Preclinical evidence suggests EGFR monoclonal antibodies (cetuximab/panitumumab) may overcome this limitation by inducing EGFR internalization and enhancing HER2-targeted drug efficacy. However, HER2-positive advanced CRC lacks validated predictive biomarkers and thorough translational research. Our study will clinically evaluate trastuzumab plus cetuximab and irinotecan in this population, while performing longitudinal biomarker analyses of paired blood and tumor samples to identify response predictors, elucidate resistance mechanisms, and optimize this promising therapeutic approach.

Conditions

• HER2 Positive
• Colorectal Cancer (CRC)

Interventions

Type	Name	Description
DRUG	Trastuzumab +Cetuximab β+Irinotecan	Trastuzumab 4 mg/kg , Cetuximab β: 500 mg/m² ,Irinotecan 180 mg/m², repeat once every 2 weeks

Timeline

• Start date: 2025-07-11
• Primary completion: 2027-12-30
• Completion: 2028-12-30
• First posted: 2025-07-10
• Last updated: 2025-07-10

Locations

1 site across 1 country: China