New ADC Trastuzumab Rezetecan Reduced Progression Risk by 67% in HER2+ Colorectal Cancer
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HORIZON-CRC01: Trastuzumab Rezetecan in HER2-Positive Colorectal Cancer
Why Are New Treatments Needed in HER2-Positive Colorectal Cancer?
HER2 positivity in colorectal cancer defines a subgroup seen particularly in RAS wild-type tumors, with both biological and therapeutic significance. HER2 amplification or overexpression can provide growth signals to the tumor cell and may also be associated with resistance to anti-EGFR therapies in some patients.
In recent years, HER2-targeted therapies have become increasingly prominent in colorectal cancer. The combination of tucatinib + trastuzumab received FDA accelerated approval after chemotherapy in RAS wild-type, HER2-positive metastatic colorectal cancer. Trastuzumab deruxtecan demonstrated through trials such as DESTINY-CRC01 and DESTINY-CRC02 that a HER2-targeted ADC approach can show clinical activity in this disease.
HER2 is a growth-signaling receptor that supports proliferation in some cancer cells. In colorectal cancer, HER2 positivity is generally defined as IHC 3+ or IHC 2+ with positive in situ hybridization. This may indicate that the patient could benefit from HER2-targeted therapies.
What Kind of Medicine Is Trastuzumab Rezetecan?
Trastuzumab rezetecan is a HER2-targeted antibody–drug conjugate. It combines an antibody component that binds to a tumor cell expressing HER2 with a potent cytotoxic payload delivered inside the cell. The aim is to selectively target HER2-positive tumor cells and deliver a chemotherapy-like effect more directly to the tumor cell.
In the phase 1 study preceding HORIZON-CRC01, trastuzumab rezetecan showed tolerable safety and preliminary efficacy in advanced HER2-expressing gastric/GEJ and colorectal cancers. An ORR of approximately 40% was reported in the colorectal cancer subgroup, providing the rationale for the phase 3 HORIZON-CRC01 trial.
An antibody–drug conjugate combines an antibody that binds to a specific target on the tumor cell with a potent chemotherapy-like toxic payload. Although targeted, it is not free of side effects; cytopenias, gastrointestinal toxicity, changes in liver tests, and lung toxicity with some ADCs must be monitored carefully.
Study Design: How Was HORIZON-CRC01 Conducted?
HORIZON-CRC01 is a randomized, open-label phase 3 trial conducted in China. It enrolled patients with HER2-positive, RAS/RAF wild-type advanced colorectal cancer whose disease had progressed despite prior chemotherapy containing fluoropyrimidine, oxaliplatin, and irinotecan.
A total of 130 patients were enrolled and randomized 2:1 to trastuzumab rezetecan or standard treatment. In the standard-treatment arm, TAS-102, fruquintinib, or regorafenib could be used at the investigator's discretion. Crossover from standard treatment to trastuzumab rezetecan was permitted after progression.
| Item | Trastuzumab rezetecan arm | Standard-treatment arm | Clinical significance |
|---|---|---|---|
| Number of patients | 86 patients | 44 patients | 130 patients in total, randomized 2:1. |
| Treatment | Trastuzumab rezetecan 4,8 mg/kg IV every 3 weeks | TAS-102, fruquintinib, or regorafenib | A HER2-targeted ADC was compared with standard later-line options. |
| Patient selection | HER2-positive, RAS/RAF wild-type advanced CRC | A biomarker-selected, treatment-resistant patient group. | |
| Previous treatment | Progression after fluoropyrimidine, oxaliplatin, and irinotecan | A later-line population with limited treatment options. | |
| Stratification | HER2 status: IHC 3+ vs IHC 2+/ISH+; ECOG 0 vs 1 | HER2 intensity and performance status were balanced. | |
| Crossover | None | Could receive trastuzumab rezetecan after progression | May affect the maturity and interpretation of the OS analysis. |
Patient Characteristics: A Heavily Pretreated, Biomarker-Selected Group
The median age of the enrolled patients was 58 and 64% of patients were male. A substantial proportion had also received targeted therapies or immunotherapy previously: immunotherapy %20, anti-HER2 therapy %18,5, anti-VEGF antibodies %53,8 and anti-EGFR antibodies %86,2 were the respective rates of previous use.
Main Efficacy Results: PFS and ORR Improved Markedly
Median follow-up was 9,6 months . According to the independent review committee, median PFS was 5,5 monthswith trastuzumab rezetecan and 2,8 months with standard treatment. HR was 0,33, with p<0,0001. Investigator-assessed PFS was similar: 5,6 vs 2,8 months, HR 0,31.
The difference in response rates was even more striking. According to the independent review committee, the objective response rate in the trastuzumab rezetecan arm was %40,7, compared with only %4,5 in the standard-treatment arm. This is an important tumor-shrinkage signal in chemotherapy-resistant, HER2-positive CRC previously treated in later lines.
| Outcome | Trastuzumab rezetecan | Standard treatment | Clinical interpretation |
|---|---|---|---|
| IRC median PFS | 5,5 months | 2,8 months | The primary endpoint was positive; HR 0,33. |
| Investigator-assessed median PFS | 5,6 months | 2,8 months | Consistent with the independent assessment. |
| IRC ORR | %40,7 | %4,5 | The tumor-shrinkage rate was markedly higher. |
| Median duration of response | 4,4 months | 3,4 months | Response duration was longer, but still modest. |
| OS | Not mature | It is too early to interpret OS because of crossover and short follow-up. | |
Safety: Hematological Toxicity Stands Out
Rates of treatment-related adverse events of grade 3 or higher were similar between the arms: with trastuzumab rezetecan, %48,8, and with standard treatment, %50,0. However, the toxicity profiles differed. The most common high-grade adverse events in the trastuzumab rezetecan arm were hematological: decreased neutrophil count, low white-cell count, anemia, and low platelets stood out.
Two treatment-related deaths were reported in the trastuzumab rezetecan arm: septic shock and myelosuppression. In contrast, no treatment-related adverse event leading to discontinuation of the study medicine was reported. Although this safety profile suggests that the medicine may be manageable, careful monitoring is needed, particularly for neutropenia, infection, and bone marrow suppression.
Practical Safety Message
Although this treatment is “HER2-targeted”, hematological toxicity is substantial. In particular, because of neutropenia and infection risk, complete blood counts, education about fever, early assessment for antibiotics, and supportive treatments when needed should be part of center practice.
Historical Context: Where Does It Fit in HER2-Targeted CRC?
The treatment landscape in HER2-positive metastatic colorectal cancer has developed rapidly in recent years. Tucatinib + trastuzumab became one of the first targeted combinations approved after chemotherapy in RAS wild-type, HER2-positive mCRC. Trastuzumab deruxtecan supported the concept of a HER2-targeted ADC through strong response rates in DESTINY-CRC trials. HORIZON-CRC01 makes an important contribution by testing a different HER2 ADC, trastuzumab rezetecan, against standard later-line options in a randomized phase 3 trial.
| Approach | Patient group | Key message | Relationship to HORIZON-CRC01 |
|---|---|---|---|
| Tucatinib + trastuzumab | RAS wild-type, HER2-positive mCRC after chemotherapy | The HER2 TKI + antibody combination received FDA accelerated approval. | One of the main references showing the clinical relevance of HER2 targeting in mCRC. |
| Trastuzumab deruxtecan | HER2-positive advanced mCRC | High response rates with the ADC approach and strong efficacy particularly in IHC 3+ patients. | Strengthened the biological rationale for the HER2 ADC class in CRC. |
| Trastuzumab rezetecan | HER2-positive, RAS/RAF wild-type, chemotherapy-resistant advanced CRC | Showed a PFS and ORR advantage in a randomized phase 3 trial. | Under regulatory review in China; ADC sequencing and global positioning will be discussed. |
Critical Reading: How Should the Data Be Interpreted in a Balanced Way?
Strong Data, but Questions Remain
- PFS and ORR are strong: HR 0,33 and ORR 40,7% provide a clear efficacy signal compared with standard later-line options.
- OS is not yet mature: Because crossover was allowed and follow-up was short, the overall-survival effect will become clearer over time.
- The trial was conducted in China: Global generalizability must be assessed separately in different patient populations and treatment sequences.
- The standard-treatment arm was heterogeneous: Although TAS-102, fruquintinib, and regorafenib can be used in the same clinical setting, they have different toxicity and efficacy profiles.
- Prior anti-HER2 treatment was limited: 18,5% of patients had previously received anti-HER2 treatment. Efficacy after prior tucatinib–trastuzumab or T-DXd therefore requires separate analysis.
- Hematological toxicity is substantial: Neutropenia and infection risk must be managed carefully, particularly in later-line, heavily pretreated patients.
- HER2 ADC sequencing is uncertain: The optimal sequence among trastuzumab deruxtecan, trastuzumab rezetecan, TKI + trastuzumab combinations, and first-line studies is not yet clear.
Message for Clinical Practice
The most important practical message of HORIZON-CRC01 is the value of comprehensive molecular and immunohistochemical assessment in advanced colorectal cancer. HER2 positivity, particularly in RAS/RAF wild-type patients, can change treatment selection even in later lines. In metastatic colorectal cancer, therefore, not only RAS, BRAF, and MSI but also HER2 status should be an important part of the treatment roadmap.
If approved through regulatory processes, trastuzumab rezetecan could be a new ADC option in HER2-positive, chemotherapy-resistant advanced CRC. However, its place in global practice will be determined together with sequencing relative to existing HER2-targeted therapies, efficacy after prior anti-HER2 exposure, and its safety profile.
How to Explain It to a Patient
“If a target called HER2 is highly expressed in your colon or rectal cancer, medicines directed at that target may be considered. In this trial, a new treatment that binds to HER2 and carries a potent medicine into the cancer cell delayed disease progression and increased tumor-shrinkage rates compared with standard later-line medicines. However, it requires regular monitoring because of side effects such as low blood counts and infection risk.”
Drozdogan Academic Commentary
HORIZON-CRC01 is important ASCO 2026 evidence that strengthens the clinical relevance of the ADC class in HER2-positive colorectal cancer at the level of a randomized phase 3 trial.
The marked differences, including a PFS HR of 0,33 and ORR of 40,7% versus 4,5%, again show that HER2 in this patient group is not merely a prognostic or resistance-associated marker, but an actively treatable target.
However, the medicine's definitive place in global treatment algorithms will not become clear until questions about immature OS, validation outside China, efficacy after previous anti-HER2 therapies, and the sequencing of HER2-targeted TKIs/ADCs are answered.
Conclusion
HORIZON-CRC01 showed that trastuzumab rezetecan significantly improved PFS and ORR compared with standard later-line options in HER2-positive, RAS/RAF wild-type, chemotherapy-resistant advanced colorectal cancer. Median PFS was 5,5 months versus 2,8 months, HR 0,33; ORR 40,7% versus 4,5% .
Although the safety profile appeared manageable, hematological toxicity was substantial; two treatment-related deaths show that infection and myelosuppression risks must be taken seriously in later-line patients. These data increase the importance of ADCs in HER2-positive colorectal cancer and further strengthen the role of HER2 testing in the metastatic CRC treatment roadmap.
- ASCO Daily News. Phase 3 HORIZON-CRC01 Trial Shows PFS Benefit With Trastuzumab Rezetecan in HER2-Positive, Chemotherapy-Refractory Advanced CRC. May 31, 2026.
- ASCO 2026 Abstract 3505. HORIZON-CRC01: trastuzumab rezetecan vs standard of care in HER2-positive advanced CRC.
- Liu T et al. Trastuzumab Rezetecan in HER2-expressing advanced gastric/GEJ adenocarcinoma and colorectal cancer: phase 1 trial. Journal of Clinical Oncology. 2026.
- FDA. Tucatinib with trastuzumab accelerated approval for RAS wild-type HER2-positive metastatic colorectal cancer. 2023.
- Yoshino T et al. Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in HER2-expressing metastatic colorectal cancer. Nature Communications. 2023.
- Raghav K et al. DESTINY-CRC02 primary results: trastuzumab deruxtecan in HER2-positive advanced colorectal cancer. 2024.
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