A Global Trial of Trastuzumab Rezetecan (SHR-A1811) in Combination With Chemotherapy and Bevacizumab as First-Line Treatment in Patients With Advanced Colorectal Cancer Expressing HER2

A Global, Multicenter, Randomized, Dose-Optimization Phase II Study of Trastuzumab Rezetecan (SHR-A1811) in Combination With mFOLFOX6 (-1) and Bevacizumab as First-Line Treatment in Patients With HER2-Positive Advanced Colorectal Cancer (HORIZON-CRC221)

This global study is being conducted to evaluate the safety and determine the recommended phase 3 dose of trastuzumab rezetecan in combination with mFOLFOX6 chemotherapy (dose level -1) and bevacizumab as first-line treatment in participants with advanced colorectal cancer that expresses HER2, including but not limited to HER2 immunohistochemistry (IHC) 2+ "equivocal" or 3+ "positive" based on gastric cancer criteria, focused on the Western population. Encouraging data in efficacy and safety with trastuzumab rezetecan in a similar setting in China (NCT06015048) were presented at 2026 American Society of Clinical Oncology annual meeting.

Inclusion Criteria:

1. ECOG performance status score of 0 or 1.
2. Histologically or cytologically confirmed unresectable, recurrent, or metastatic colorectal adenocarcinoma that is HER2-positive. "HER2-positive" indicates IHC 2+ or 3+, or HER2 (ERBB2) amplification by NGS at a CLIA-certified or ISO-accredited laboratory. HER2 IHC 2+/3+ should be based on gastric cancer criteria.
3. Either have not received any prior systemic anti-tumor therapy (including, but not limited to, systemic chemotherapy, molecular targeted drug therapy, immunotherapy, biotherapy, or other investigational agents), or, if previously treated with neoadjuvant or adjuvant therapy, have first documented recurrence or metastasis >6 months after the last dose of neoadjuvant or adjuvant therapy. Participants known to have dMMR or high-level MSI-H are excluded unless the investigator determines they are unsuitable for anti-PD-1/PD-L1 therapy. Participants known to have BRAF V600 mutation are excluded unless the investigator determines they are unsuitable for BRAF-targeting therapy. Note that participants may have received a maximum of 2 doses of mFOLFOX6 with or without bevacizumab in the locally advanced/unresectable or metastatic setting prior to randomization.
4. Have at least one measurable lesion according to the RECIST version 1.1. Measurable lesions should not have received prior local therapy such as radiotherapy (lesions located within a previous radiotherapy field can be considered as target lesions if progression is confirmed).

Exclusion Criteria:

1. Prior Treatments:

   1. Prior treatment with anti-HER2 ADCs featuring exatecan or its derivatives as the payload (a topoisomerase I inhibitor), such as trastuzumab deruxtecan (Enhertu®, DS-8201a).
   2. Treatment with any investigational drug or therapy not yet approved for marketing within 4 weeks prior to the first dose of the IMP.
   3. Systemic anti-tumor therapy within 4 weeks prior to the first dose of the IMP, including chemotherapy, biotherapy, targeted therapy, or immunotherapy. For small molecule targeted therapies, a washout period of at least 5 half-lives or 7 days (whichever is longer) from the last dose is required before the first dose of the IMP. Note that participants may have received a maximum of 2 doses of mFOLFOX6 with or without bevacizumab in the locally advanced/unresectable or metastatic setting prior to randomization.
   4. Palliative radiotherapy completed within 2 weeks prior to the first dose of the IMP.
   5. Major surgery within 4 weeks prior to the first dose of the IMP or planned elective surgery during the trial period. Minor traumatic procedures (e.g., needle biopsy, endoscopy, drainage) within 7 days prior. Presence of non-healed wounds (severe, non-healing, or dehisced) or untreated fractures.
   6. Use of aspirin (>325 mg/day), dipyridamole, ticlopidine, clopidogrel, cilostazol, or other drugs known to inhibit platelet function within 1 week prior to the first dose of the IMP.
   7. Administration of live attenuated vaccines within 4 weeks prior to the first dose of the IMP, or anticipated requirement for such vaccines during the study treatment period.

2. History of hypersensitivity to monoclonal antibodies, any component of the trastuzumab rezetecan formulation, fluorouracil, levo-leucovorin (or leucovorin), oxaliplatin, bevacizumab, or related drugs.

3. Presence of Grade >1 peripheral sensory neuropathy.

4. History of hemoptysis (approximately ≥2.5 mL of fresh blood in one episode) within 3 months prior to the first dose of the IMP.

5. Tumor encasement or invasion of major blood vessels (e.g., pulmonary artery, superior vena cava) as indicated by CT or MRI.