Pyrotinib Plus Trastuzumab as an Effective Later-Line Therapeutic Strategy for HER2-Positive Metastatic Colorectal...

Dual human epidermal growth factor receptor 2 (HER2) blockade demonstrates promising yet limited clinical activity in HER2-positive metastatic colorectal cancer (mCRC). This study was initiated to evaluate the novel combination of trastuzumab (anti-HER2 monoclonal antibody) and pyrotinib (a pan-HER tyrosine kinase inhibitor) in this molecularly defined population.

This exploratory single-arm phase II trial enrolled HER2-positive mCRC patients refractory to standard first- and second-line therapies. Participants received intravenous trastuzumab (8 mg/kg loading dose on cycle 1 day 1, then 6 mg/kg every 3 weeks) plus oral pyrotinib 400 mg once daily in 21-day cycles. The primary endpoint was objective response rate (ORR).

Between December 1, 2019, and March 31, 2025, 20 patients were enrolled, with 17 evaluable for efficacy. The objective response rate (ORR) was 23.5% (4 partial responses), and the disease control rate (DCR) reached 88.2%. Median progression-free survival (PFS) was 6.2 months (95% CI, 0.42-11.98), and median overall survival (OS) was 21.1 months (95% CI, 15.84-26.36). Responses occurred exclusively in RAS/BRAF wild-type patients (ORR 28.6%; DCR 92.9%), who showed significantly longer median PFS (8.5 vs 2.6 months; HR 0.32; P=0.008) and OS (22.6 vs 4.9 months; P=0.022) versus KRAS-mutant counterparts. Treatment-related adverse events (TRAEs) included diarrhea (75%), fatigue (40%), and nausea (35%). Diarrhea accounted for all grade 3 TRAEs (30%). No grade ≥4 TRAEs were observed.

Pyrotinib plus trastuzumab demonstrates clinically meaningful efficacy and a manageable safety profile in heavily pretreated HER2-positive metastatic colorectal cancer. These findings support advancing this regimen as a potential alternative in refractory HER2-positive mCRC, particularly in the RAS/BRAF wild-type subgroup.