SHR-A1811 vs Pyrotinib/Capecitabine in Trastuzumab-Resistant HER2+ Advanced Breast Cancer: A Randomized Study

Efficacy and Safety of SHR-A1811 Versus Pyrotinib Plus Capecitabine in Patients With Trastuzumab Primary-Resistant HER2-Positive Advanced Breast Cancer：A Prospective, Multicenter, Open-Label, Randomized, Controlled Study

This is a prospective, multicenter, open-label, randomized, controlled Study. The purpose of this study is to evaluate the efficacy and safety of SHR-A1811 versus pyrotinib plus capecitabine in the treatment of trastuzumab primary-resistant HER2-positive advanced breast cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer; HER2-positive Breast Cancer
• Intervention / Treatment: Drug: SHR-A1811; Drug: Pyrotinib; Drug: Capecitabine; Drug: T-DXd

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hanfang Jiang; Phone Number: +86-010-88196380; Email: hfjiangcn@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years.
2. Histologically or cytologically confirmed HER2-positive advanced breast cancer (IHC 3+, or IHC 2+ with ISH amplification).
3. ECOG performance status 0-2.
4. Estimated life expectancy >12 weeks.
5. At least one measurable lesion per RECIST v1.1 criteria;

6. Patients with trastuzumab primary resistance is defined as follows:

   1. Progression during or within 12 months after treatment in neoadjuvant or adjuvant setting (at least 9 weeks of trastuzumab treatment);
   2. For patients with de novo stage IV disease, progression during or within 3 months after treatment for locally advanced or metastatic disease in the first-line setting (at least 6 weeks of trastuzumab treatment).

7. Adequate organ function as defined by the following laboratory criteria:

   1. Hematologic: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count (PLT) ≥100 × 10⁹/L, hemoglobin (HGB) ≥90 g/L.
   2. Hepatic: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN) (≤5 × ULN in patients with liver metastases); total serum bilirubin (TBIL) ≤1.5 × ULN; serum albumin ≥30 g/L.
   3. Renal: serum creatinine (Cr) ≤1.5 × ULN or calculated creatinine clearance ≥50 mL/min using the Cockcroft-Gault formula.
   4. Coagulation: prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤1.5 × ULN.
   5. Cardiac: left ventricular ejection fraction (LVEF) ≥50%.
8. Women of childbearing potential must have a negative pregnancy test at screening, and subjects of reproductive potential must agree to use effective contraception from study start until 6 months after the last dose of study treatment..
9. Voluntary participation with written informed consent obtained prior to any study-related procedures.

Exclusion Criteria:

1. Prior or current exposure to antibody-drug conjugates (ADCs) containing a topoisomerase I inhibitor, including but not limited to fam-trastuzumab deruxtecan (DS-8201a).
2. Active brain metastases or leptomeningeal metastases (patients with asymptomatic/inactive brain metastases are allowed to be enrolled);
3. Other malignancy diagnosed within 5 years prior to enrollment, excluding cured non-melanoma skin cancer, cervical carcinoma in situ, ductal carcinoma in situ, or stage I grade 1 endometrial cancer;
4. Radiotherapy, any anti-HER2 targeted therapy, or chemotherapy within 4 weeks prior to enrollment; endocrine therapy within 2 weeks prior to enrollment;
5. Positive for human immunodeficiency virus (HIV);
6. Known hypersensitivity to any study drug or its excipients, or to humanized monoclonal antibody products (e.g., trastuzumab, pertuzumab, etc.);
7. Clinically significant cardiovascular disease, such as severe/unstable angina, symptomatic congestive heart failure (NYHA Class ≥II), clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention, myocardial infarction within 6 months prior to first dose, or cerebrovascular accident (including transient ischemic attack).
8. Participants known or suspected to interstitial lung disease.
9. Concurrent participation in any other interventional drug clinical trial.
10. Refusal to comply with protocol-mandated follow-up. Presence of any additional severe physical or psychiatric disorder, or any laboratory abnormality that, in the investigator's judgment, could increase the subject's risk, confound study results, or render the patient unsuitable for enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Treatment Phase 1: SHR-A1811 monotherapy until progression or intolerable adverse events. Treatment Phase 2: Switch to pyrotinib plus capecitabine upon progression from Phase 1, continued until subsequent progression or intolerable adverse events.	Drug: SHR-A1811; 4.8 mg/kg administered as an intravenous infusion on Day 1 of each cycle. 3 weeks a cycle. Continuous medication until study completion, occurrence of intolerable toxicity, disease progression, withdrawal from the study for any reason, or death, whichever occurs first, or until the investigator deems that the patient would no longer benefit from the treatment.; Drug: Pyrotinib; 400 mg, administered orally once daily, continuous medication until study completion, occurrence of intolerable toxicity, disease progression, withdrawal from the study for any reason, or death, whichever occurs first, or until the investigator deems that the patient would no longer benefit from the treatment.; Drug: Capecitabine; 1000mg/m2, administered orally twice daily on Days 1-14, with no administration on Days 15-21, 3 weeks a cycle. Continuous medication until study completion, occurrence of intolerable toxicity, disease progression, withdrawal from the study for any reason, or death, whichever occurs first, or until the investigator deems that the patient would no longer benefit from the treatment.
Active Comparator: Arm 2; Treatment Phase 1: Pyrotinib plus capecitabineuntil progression or intolerable adverse events. Treatment Phase 2: Switch to T-DXd upon progression from Phase 1, continued until subsequent progression or intolerable adverse events.	Drug: Pyrotinib; 400 mg, administered orally once daily, continuous medication until study completion, occurrence of intolerable toxicity, disease progression, withdrawal from the study for any reason, or death, whichever occurs first, or until the investigator deems that the patient would no longer benefit from the treatment.; Drug: Capecitabine; 1000mg/m2, administered orally twice daily on Days 1-14, with no administration on Days 15-21, 3 weeks a cycle. Continuous medication until study completion, occurrence of intolerable toxicity, disease progression, withdrawal from the study for any reason, or death, whichever occurs first, or until the investigator deems that the patient would no longer benefit from the treatment.; Drug: T-DXd; 5.4 mg/kg administered as an intravenous infusion on Day 1 of each cycle. 3 weeks a cycle. Continuous medication until study completion, occurrence of intolerable toxicity, disease progression, withdrawal from the study for any reason, or death, whichever occurs first, or until the investigator deems that the patient would no longer benefit from the treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS during treatment phase 1	progression free survival during treatment phase 1 : time from randomization to the first observation of tumor progression or death from any cause during treatment phase 1.	Start of treatment until 2-year follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total PFS across treatment phase 1 and treatment phase 2	Total progression free survival across treatment phase 1 and treatment phase 2: time from randomization to the second observation of tumor progression or death from any cause across treatment phase 1 and treatment phase 2.	Start of treatment until 3-year follow-up
PFS during treatment phase 2	progression free survival during treatment phase 2 : time from the first observation of tumor progression to the second observation of tumor progression or death from any cause during treatment phase 2.	Start of treatment until 3-year follow-up
ORR during treatment phase 1	Objective response rate during treatment phase 1: proportion of subjects who achieved complete response (CR) or partial response (PR) by primary tumor imaging evaluation during treatment phase 1.	Start of treatment until 2-year follow-up
DCR during treatment phase 1	Disease control rate during treatment phase 1: proportion of subjects who achieved complete response (CR) or partial response (PR) or stable disease (SD) by primary tumor imaging evaluation during treatment phase 1.	Start of treatment until 2-year follow-up
OS	Overall survival: time from randomization to death from any cause.	Start of treatment until 3-year follow-up
Incidence of adverse events		Start of treatment until 3-year follow-up
Severity of adverse events		Start of treatment until 3-year follow-up
Incidence of serious adverse events		Start of treatment until 3-year follow-up
Severity of serious adverse events		Start of treatment until 3-year follow-up

Collaborators and Investigators

• Sponsor: Peking University Cancer Hospital & Institute
• Investigators: Principal Investigator: Hanfang Jiang, Peking University Cancer Hospital & Institute

Study record dates

Study Major Dates

• Study Start (Estimated): March 31, 2026
• Primary Completion (Estimated): January 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: February 11, 2026
• First Submitted That Met QC Criteria: February 11, 2026
• First Posted (Actual): February 18, 2026

Study Record Updates

• Last Update Posted (Actual): February 18, 2026
• Last Update Submitted That Met QC Criteria: February 11, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: HER2-positive breast cancer; SHR-A1811
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Capecitabine; pyrotinib
• Other Study ID Numbers: OBU-BC-II-300

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No