A Landmark Approval: Filling a Critical Treatment Gap
On August 6, 2026, the National Medical Products Administration (NMPA) of China announced that trastuzumab rezetecan (SHR-A1811, trade name: Aivida), an anti-HER2 antibody-drug conjugate (ADC) independently developed by Hengrui Medicine, received its third indication approval following lung cancer and breast cancer. The new indication covers adult patients with HER2-positive colorectal cancer who have failed prior treatment with oxaliplatin, fluorouracil, and irinotecan[1].
As the world's first anti-HER2 therapeutic agent to achieve positive results in a randomized, controlled, Phase 3 study in the field of HER2-positive colorectal cancer, this approval not only fills the long-standing gap of high-level evidence-based medicine support for this patient population but also ushers in a new era of precision treatment for patients with HER2-positive colorectal cancer in China.
HORIZON-CRC01: The Study That Made Approval Possible
HER2 is an important target in oncology. Anti-HER2 therapies have been widely used in breast and gastric cancers and have significantly improved patient survival. However, in colorectal cancer, no anti-HER2 treatment had previously been formally approved in China, leaving a significant unmet clinical need.
Against this backdrop, Professor Li Jin, President of China Pharmaceutical University Affiliated Shanghai GOBROAD Cancer Hospital, and Professor Yuan Ying from the Second Affiliated Hospital of Zhejiang University School of Medicine co-led the landmark HORIZON-CRC01 study, breaking through the treatment impasse and laying a solid foundation for regulatory approval.
HORIZON-CRC01 Study Design:
- Type: Randomized, open-label, active-controlled, multicenter Phase 3 trial
- Eligibility: Patients with HER2-positive (IHC 3+ or IHC 2+/ISH+) advanced colorectal cancer who had failed prior fluorouracidine, oxaliplatin, and irinotecan treatment. dMMR or MSI-H patients must have failed prior anti-PD-1 or anti-PD-L1 monoclonal antibody therapy. Prior anti-HER2 therapy was permitted[2].
- Enrollment: 130 patients randomized 2:1 to trastuzumab rezetecan (n=86) versus standard-of-care (n=44)
- Control arm: Investigator's choice of trifluridine/tipiracil (TAS-102), fruquintinib, or regorafenib, with crossover to trastuzumab rezetecan allowed upon progression[2]
Efficacy Results: Near-Doubling of Progression-Free Survival
At the 2026 ASCO Annual Meeting, results presented onsite by Professor Li Jin demonstrated that the study achieved its primary endpoint. At a median follow-up of 9.6 months, assessment by the Independent Review Committee (IRC) showed:
Key Efficacy Findings from HORIZON-CRC01:
- Median PFS (IRC): 5.5 months (trastuzumab rezetecan) vs. 2.8 months (standard-of-care) — nearly double, representing a 67% reduction in disease progression risk (HR 0.33, 95% CI: 0.21–0.53, p<0.0001)[2]
- Median OS: Not yet reached in either arm, but a favorable survival trend was observed (HR 0.77)[2]
- ORR (IRC): 40.7% vs. 4.5% (risk difference 36.2, 95% CI: 24.1–48.2, p<0.0001)[2]
- DoR (IRC): 4.4 months vs. 3.4 months, showing improvement trend[2]
- Subgroup consistency: Benefit was consistent regardless of HER2 expression status (IHC 3+ or IHC 2+/ISH+), prior lines of therapy, prior anti-HER2 treatment history, primary tumor location, or number of metastatic lesions[2]
The substantial improvement in objective response rate (from 4.5% to 40.7%) means that nearly four out of ten patients who had exhausted all standard chemotherapy options experienced meaningful tumor shrinkage with trastuzumab rezetecan — a transformative outcome in the later-line setting.
Safety Profile: Controllable Tolerability, No Interstitial Lung Disease
Safety analysis showed that compared with the standard-of-care group, the incidence of Grade 3 or higher treatment-related adverse events (TRAEs) was actually lower in the trastuzumab rezetecan group (48.8% vs. 50.0%), with hematologic toxicity being predominant. Importantly, no interstitial lung disease (ILD) events were observed, and no patient discontinued treatment due to TRAEs[2]. These findings demonstrate controllable safety and favorable tolerability, providing a solid foundation for patients to complete full treatment cycles.
Innovative Design: How Structure Drives Efficacy and Safety
The outstanding efficacy and safety profile of trastuzumab rezetecan are inseparable from its innovative structural design. The agent consists of a humanized anti-HER2 antibody (trastuzumab) conjugated via a cleavable tetrapeptide linker to a DNA topoisomerase I inhibitor payload called ruze-tecan (SHR169265, also known as DXh)[3]. Data show that compared with DXd (the payload of trastuzumab deruxtecan), ruze-tecan demonstrates superior lipophilicity, membrane permeability, and cytotoxic potency across multiple tumor cell lines[3,4].
Three Pillars of Structural Optimization:
- High-potency payload (ruze-tecan/DXh): More lipophilic and membrane-permeable than DXd, with stronger cytotoxic activity against diverse tumor cell lines[3,4]
- Optimized drug-to-antibody ratio (DAR = 6:1): Lower DAR reduces circulating levels of cytotoxic payload, improving safety margins[3]
- High-stability linker with chiral cyclopropyl group: Prevents uncontrolled toxin release and reduces adverse events caused by premature release[3]
Preclinical studies confirmed that in multiple xenograft tumor models including SK-BR-3 (HER2-high), JIMT-1 (HER2-moderate), and Capan-1 (HER2-low), trastuzumab rezetecan significantly and sustainably inhibited tumor growth while demonstrating good tolerability[4]. This combination of high-activity payload, optimized DAR, and high-stability linker achieves a better balance between antitumor activity and safety — a design philosophy validated clinically by the HORIZON-CRC01 results.
From Later-Line to First-Line: Reshaping the Treatment Landscape
Based on Phase 1 results published in the Journal of Clinical Oncology (JCO), trastuzumab rezetecan has been recommended in the CSCO Colorectal Cancer Diagnosis and Treatment Guidelines (2026 Edition) for later-line treatment of HER2-positive colorectal cancer[5]. Its colorectal cancer indication was included in both the breakthrough therapy designation list and the priority review program. The time from New Drug Application (NDA) submission to formal approval was only six months, reflecting broad recognition of this original Chinese drug and embodying the regulatory philosophy of centering on patient needs.
First-Line Combination: SHR-A1811-208 Shows Remarkable Early Results
Data from the phase Ib/II SHR-A1811-208 study, presented at ASCO 2026, explored first-line trastuzumab rezetecan combined with bevacizumab and mFOLFOX for HER2-positive colorectal cancer. Preliminary results showed an ORR of 90.5%, disease control rate (DCR) of 100%, and 12-month PFS rate of 94.7%, with overall manageable safety[6]. Based on these highly encouraging findings, the pivotal Phase 3 SHR-A1811-317 study has been initiated to evaluate the efficacy and safety of trastuzumab rezetecan-based combination therapy in the first-line HER2-positive colorectal cancer setting.
As trastuzumab rezetecan advances toward earlier treatment lines and broader patient populations, it is expected to more profoundly reshape the diagnostic and treatment landscape for HER2-positive colorectal cancer. An increasing number of patients stand to benefit from this era of precision oncology transformation.
Conclusion
From lung cancer and breast cancer to colorectal cancer, China's original next-generation HER2 ADC trastuzumab rezetecan continues to break new ground. The success of HORIZON-CRC01 and the subsequent NMPA approval represent not only good news for cancer patients but also a shining moment for Chinese research and original drugs. As trastuzumab rezetecan moves toward earlier treatment lines and broader populations, it will contribute more deeply to reshaping the landscape of precision oncology and to realizing the goals of the Healthy China 2030 strategic plan.
About the Principal Investigator
Prof. Li Jin (李进)
President, China Pharmaceutical University Affiliated Shanghai GOBROAD Cancer Hospital
Lifetime Professor, Tongji University Affiliated Shanghai East Hospital
Clinic Schedule: Every Monday All Day, Thursday Morning, Saturday Morning
Specialization: Prof. Li focuses on digestive system malignancies, with expertise in molecular targeted therapy, immunotherapy, investigational new drug clinical trials, and multidisciplinary team discussions for complex solid tumors, particularly gastrointestinal cancers.
Academic appointments: President, Asian Federation of Medical Oncology (FACO); Chairman, CSCO Colorectal Cancer Expert Committee; Director-General, National Health Commission Center for Capacity Building and Continuing Education; Chairman, Beijing CSCO Clinical Oncology Research Foundation; Vice-Chairman, Chinese Medical Continuing Education Association Abdominal Oncology Committee; Chairman, Shanghai Waigaoqiao Cell and Gene Therapy Industry Alliance; Deputy Editor-in-Chief, Cancer Science.
References
- NMPA Drug Approval Document Delivery Information, August 6, 2026. Official Link
- 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. Abstract #3505.
- Li Z, Song Z, Hong W, et al. SHR-A1811 (antibody-drug conjugate) in advanced HER2-mutant non-small cell lung cancer: a multicenter, open-label, phase 1/2 study. Signal Transduction and Targeted Therapy, 2024, 9(1): 182.
- Zhang T, You L, Xu J, et al. Abstract LB031: SHR-A1811, a novel anti-HER2 ADC with superior bystander effect, optimal DAR and favorable safety profiles. Cancer Research, 2023, 83(8_Supplement): LB031-LB031.
- CSCO Colorectal Cancer Diagnosis and Treatment Guidelines (2026 Edition).
- Xu T, Shen L, Li J, et al. SHR-A1811 plus chemotherapy and BP102 as 1L therapy for HER2-expressing mCRC: Data from a phase Ib/II study. 2026 ASCO. Abstract #3569.
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