Phase 3 trial of trastuzumab rezetecan vs standard of care (SOC) for chemotherapy-refractory, HER2-positive, advanced colorectal cancer (CRC).

3505 Background: Antibody-drug conjugate (ADC) targeting HER2 represents standard therapy for HER2-positive gastric cancer and breast cancer. This study aimed to assess trastuzumab rezetecan (an HER2-targeted ADC) vs SOC in patients (pts) with chemotherapy-refractory, HER2-positive, RAS and RAF wild-type advanced CRC. Methods: In this randomized, open-label, multicenter, phase 3 trial, pts with HER2-positive, RAS and RAF wild-type, advanced CRC who have progressed after standard 2nd-line therapy were randomized 2:1 to receive trastuzumab rezetecan (4.8 mg/kg, d1, iv, q3w) or SOC (TAS-102 [35 mg/m 2 , bid, d1-5 and d8-12], fruquintinib [5 mg, qd, d1-21], or regorafenib [160 mg, qd, d1-21]; po, q4w). Randomization was stratified by HER2 status (IHC 3+ vs IHC 2+/ISH+) and ECOG PS (0 vs 1). Primary endpoint was PFS per RECIST v1.1 by independent review committee (IRC). Key secondary endpoint was OS. Results: As of data cutoff (Oct 31, 2025), 130 pts were randomly assigned to trastuzumab rezetecan (N=86) or SOC (N=44). 70.8% of pts had HER2 IHC 3+, and 57.7% had an ECOG PS of 1. Median follow-up was 9.6 mo (95% CI 7.4-10.7). PFS per IRC was significantly increased with trastuzumab rezetecan vs SOC (median 5.5 mo [95% CI 4.8-6.7] vs 2.8 mo [95% CI 2.2-4.2]; HR 0.33 [95% CI 0.21-0.53]; 1-sided p