Clinical Summary:

• Design/Population: A phase 3 trial assessed trastuzumab rezetecan in patients with HER2-positive, RAS/RAF wild-type advanced colorectal cancer who experienced disease  progression on second-line therapy.
• Key Outcomes: Trastuzumab rezetecan improved progression-free survival and objective response compared to standard options with a manageable safety profile. 
• Clinical Relevance: These findings support trastuzumab rezetecan as a potential new treatment option for heavily pretreated patients with HER2-positive advanced colorectal cancer. 

According to results from a phase 3 trial, trastuzumab rezetecan significantly improved survival and response compared to standard options among patients with chemotherapy-refractory HER2-positive advanced colorectal cancer (CRC). 

These results were presented by Jin Li, MD, Shanghai GoBroad Cancer Hospital, Shanghai, China, at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 

In this multicenter, open-label trial, 130 patients with HER2-positive, RAS and RAF wild-type advanced CRC who experienced disease progression following standard second-line therapy were randomized 2:1 to receive either 4.8 mg/kg of intravenous trastuzumab rezetecan once every 3 weeks (n = 86) or physician’s choice of TAS-102, fruquintinib, or regorafenib. Patients were stratified based on HER2 status and performance status. The primary end point was progression-free survival (PFS), assessed via independent review committee.  Key secondary end points included objective response rate (ORR), overall survival (OS), duration of response, and safety. 

At a median follow-up of 9.6 months, median independent review committee-assessed PFS was 5.5 months in the trastuzumab rezetecan arm and 2.8 months in the physician’s choice arm (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.21 to 0.53; P < .0001). Investigator-assessed median PFS was 5.6 months and 2.8 months, respectively (HR, 0.31; 95% CI, 0.20 to 0.50; P < .0001). 

Independent review committee-assessed median ORR was 40.7% in the trastuzumab rezetecan arm and 4.5% in the physician’s choice arm (P < .001), and investigator-assessed median ORR was 32.6% and 4.5%, respectively (P = .0002). Independent review committee-assessed duration of response was 4.4 months in the trastuzumab rezetecan arm and 3.4 months in the physician’s choice arm, and investigator-assessed duration of response was 5.8 months and 1.4 months, respectively. Median OS was not reached in either treatment arm, although trastuzumab rezetecan reduced the risk of death by 23% (HR, 0.77; 95% CI, 0.35 to 1.73; one-sided P = .2651). 

Grade ≥3 treatment-related adverse events were reported in 48.8% of patients in the trastuzumab rezetecan arm and 50% of patients in the physician’s choice arm. Treatment-related adverse events did not lead to any treatment discontinuations. There were 2 treatment-related deaths reported in the trastuzumab rezetecan arm due to septic shock and myelosuppression.

“Trastuzumab rezetecan achieved prolonged PFS and improved ORR in chemotherapy-refractory HER2-positive advanced CRC, with a tolerable safety profile,” concluded Dr Li. 

Source:

Li J, Yuan Y, Liu T, et al. Phase 3 trial of trastuzumab rezetecan vs standard of care (SOC) for chemotherapy-refractory, HER2-positive, advanced colorectal cancer (CRC). Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 3505.