The human epidermal growth factor receptor 2 (HER2)–directed antibody-drug conjugate trastuzumab rezetecan significantly improved progression-free survival and produced higher response rates compared with standard-of-care therapy in patients with chemotherapy-refractory, HER2-positive, RAS/RAF wild-type advanced colorectal cancer, according to results from the phase III HORIZON-CRC-01 trial presented at the 2026 ASCO Annual Meeting.

Jin Li, MD

At a median follow-up of 9.6 months, median progression-free survival by independent review was 5.5 months with trastuzumab rezetecan vs 2.8 months with standard of care, representing a 67% reduction in the risk of disease progression or death. Overall survival data were immature, but the hazard ratio numerically favored trastuzumab rezetecan (hazard ratio [HR] = 0.77, 95% confidence interval = 0.35–1.73), corresponding to a 23% reduction in the risk of death compared with standard of care.

Presenting the findings, Jin Li, MD, of Shanghai GoBroad Cancer Hospital and China Pharmaceutical University, said the agent “could be a novel treatment option for chemotherapy-refractory, HER2-positive metastatic colorectal cancer.”

HER2-Positive Colorectal Cancer

HER2 expression or amplification is an established oncogenic driver in approximately 3% to 5% of patients with advanced colorectal cancer. HER2-positive disease is associated with a poor prognosis and limited treatment options, particularly after progression on standard therapies.

HER2-targeted therapy is well established in breast and gastric cancers, and HER2-directed strategies have increasingly become part of the treatment landscape in colorectal cancer. Trastuzumab rezetecan is an investigational HER2-directed antibody-drug conjugate designed to deliver cytotoxic therapy directly to HER2-expressing tumor cells. In earlier studies involving patients with HER2-positive colorectal cancer, trastuzumab rezetecan demonstrated antitumor activity and a manageable safety profile, supporting its evaluation in a randomized phase III trial.

Study Design

HORIZON-CRC-01 was a randomized, open-label, multicenter phase III trial that enrolled patients with HER2-positive, RAS/RAF wild-type advanced colorectal cancer whose disease had progressed after standard second-line therapy. HER2-positive disease was defined as immunohistochemistry 3+ or immunohistochemistry 2+ with in situ hybridization positivity.

Patients were randomly assigned 2:1 to receive trastuzumab rezetecan at 4.8 mg/kg intravenously every 3 weeks or investigator’s choice of standard-of-care therapy, which included TAS-102 (oral combination chemotherapy of trifluridine/tipiracil); fruquintinib (an oral VEGFR tyrosine kinase inhibitor), or regorafenib (an oral multikinase inhibitor that targets multiple signaling pathways involved in tumor growth and angiogenesis).

Randomization was stratified by HER2 status and Eastern Cooperative Oncology Group (ECOG) performance status. The primary endpoint was progression-free survival according to RECIST version 1.1, as assessed by an independent review committee. Overall survival was a key secondary endpoint.

As of the October 31, 2025, data cutoff, 130 patients had been randomly assigned: 86 to trastuzumab rezetecan and 44 to standard of care. Overall, 70.8% of patients had HER2 immunohistochemistry 3+ disease, and 57.7% had an ECOG performance status of 1.

Efficacy Findings

Trastuzumab rezetecan significantly improved progression-free survival by independent review. Median progression-free survival was 5.5 months with trastuzumab rezetecan vs 2.8 months with standard of care (HR = 0.33; P < .0001).

Investigator assessment yielded similar results. Median investigator-assessed progression-free survival was 5.6 months with trastuzumab rezetecan vs 2.8 months with standard of care (HR = 0.31; P < .0001).

Tumor response rates also favored trastuzumab rezetecan. The objective response rate by independent review was 40.7% with trastuzumab rezetecan vs 4.5% with standard of care. Investigator-assessed objective response rates were 32.6% vs 4.5%, respectively. Median duration of response was 4.4 months with trastuzumab rezetecan vs 3.4 months with standard of care.

Overall survival data were not yet mature, and median overall survival was not reached in either treatment arm. Although the hazard ratio numerically favored trastuzumab rezetecan, corresponding to a 23% reduction in the risk of death compared with standard of care, the confidence interval was wide, and longer follow-up is needed.

Dr. Li emphasized the consistency of the progression-free survival benefit observed across independent and investigator assessments, and noted that subgroup analyses generally favored trastuzumab rezetecan.

Adverse Events and Treatment Discontinuation

Treatment-emergent adverse events occurred in all patients in both treatment arms. Treatment-related adverse events occurred in 98.8% of patients treated with trastuzumab rezetecan and 97.7% of those who received standard of care.

Grade 3 or higher treatment-related adverse events were reported in 48.8% of patients in the trastuzumab rezetecan arm and 50.0% of those in the standard-of-care arm. No patients discontinued treatment because of treatment-related adverse events.

The most common toxicities associated with trastuzumab rezetecan were myelosuppression events, including neutropenia, thrombocytopenia, and anemia. Two treatment-related deaths occurred in the trastuzumab rezetecan arm: one from septic shock and one from myelosuppression.

Discussant Perspective

Discussing the study, Filippo Pietrantonio, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, said treatment of HER2-positive colorectal cancer is evolving from dual HER2 blockade toward HER2-directed antibody-drug conjugates. He described HORIZON-CRC-01 as important randomized evidence supporting trastuzumab rezetecan as a potential new standard-of-care option for chemotherapy-refractory HER2-positive disease.

Filippo Pietrantonio, MD

Dr. Pietrantonio noted that antibody-drug conjugates and dual HER2 blockade may ultimately serve complementary roles. Dual HER2 blockade may offer a more tolerable, chemotherapy-free option for some patients, whereas antibody-drug conjugates may provide broader cytotoxic activity, including after prior HER2-targeted therapy.

He also highlighted several limitations of HORIZON-CRC-01, including immature overall survival data, lack of quality-of-life data, myelosuppression-related toxicity, and questions about the generalizability of the findings outside China.

Finally, Dr. Pietrantonio noted that the activity seen in later-line disease supports evaluating HER2-directed strategies earlier, where the optimal role of dual HER2 blockade, antibody-drug conjugates, and combination approaches remains to be defined. 

DISCLOSURE: For full disclosures of the study authors, visit coi.asco.org. Dr. Li reported no conflicts of interest. Dr. Pietrantonio reported honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Incyte, Ipsen, Johnson & Johnson, Merck Serono, MSD Oncology, Pierre Fabre, Rottapharm Biotech, Seagen, Servier, and Takeda; consulting or advisory roles with Agenus, Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Gilead Sciences, GlaxoSmithKline, Incyte, Jazz Pharmaceuticals, Johnson & Johnson/Janssen, Merck Serono, MSD Oncology, Pfizer, Pierre Fabre, Revolution Medicines, Rottapharm Biotech, Servier, and Takeda; institutional research funding from Agenus, Amgen, AstraZeneca, BeOne, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Johnson & Johnson/Janssen, Lilly, and Rottapharm Biotech; and travel, accommodations, or expenses from Amgen, Astellas Pharma, Johnson & Johnson/Janssen, Merck Serono, Pierre Fabre, and Takeda Science Foundation. The study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

REFERENCE

1. 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). 2026 ASCO Annual Meeting. Abstract 3505. Presented May 31, 2026.