A Study of JSKN003 Versus Trastuzumab in Combination With Pertuzumab and Docetaxel as First-Line Treatment for HER2-Positive Recurrent or Metastatic Breast Cancer

A Randomized, Controlled, Open-Label, Multicenter, Phase II Clinical Study Evaluating the Efficacy and Safety of JSKN003 Versus Trastuzumab in Combination With Pertuzumab and Docetaxel as First-Line Treatment for Participants With HER2-Positive Recurrent or Metastatic Breast Cancer

This study is a randomized, controlled, open-label, multicenter, phase II superiority clinical trial. The planned study population consists of participants with HER2-positive recurrent or metastatic breast cancer who have not previously received systemic therapy for advanced disease (participants who have undergone one prior endocrine treatment regimen are eligible for enrollment). The study aims to compare the efficacy and safety of JSKN003 versus trastuzumab combined with pertuzumab and docetaxel as first-line treatment for participants with HER2-positive recurrent or metastatic breast cancer.

Approximately 60 participants will be enrolled in this study and randomly assigned in a 2:1 ratio to receive either JSKN003 (experimental group) or trastuzumab combined with pertuzumab and docetaxel (control group). Randomization will be stratified by hormone receptor status (both estrogen receptor and progesterone receptor negative vs. estrogen receptor and/or progesterone receptor positive).

Hormone receptor-positive participants in the experimental group may receive concomitant endocrine therapy after completing six cycles of treatment. Participants who are intolerant to JSKN003 may continue treatment with its parental antibody, KN026. Hormone receptor-positive participants in the control group may receive concomitant endocrine therapy after discontinuation of docetaxel treatment. All participants will receive the study treatment as planned until disease progression, unacceptable toxicity, withdrawal of informed consent, loss to follow-up, or death, whichever occurs first.

Inclusion Criteria:

• 1Voluntary participation in this study and signing of the informed consent form (ICF).

• Age ≥ 18 years.

• Histologically and/or cytologically confirmed recurrent or metastatic breast cancer.

• HER2-positive tumor status confirmed by the central laboratory (Positive definition: IHC 3+, or IHC 2+ with positive ISH).

• No prior systemic chemotherapy and/or HER2-targeted therapy for recurrent or metastatic disease. Participants who have received one prior endocrine therapy regimen are eligible. Participants who experienced recurrence more than 12 months after completing (neo)adjuvant HER2-targeted therapy may be considered for enrollment.

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

• Presence of at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

• Adequate organ and bone marrow function (without transfusion or use of hematopoietic growth factors for correction within 14 days prior to testing):

  1. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, Platelet count ≥ 100 × 10⁹/L, Hemoglobin ≥ 90 g/L.
  2. Hepatic function: Total bilirubin (TBIL) ≤ 1.0 × upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases); alkaline phosphatase (ALP) ≤ 2.5 × ULN.
  3. Renal function: Creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula).
  4. Coagulation function: International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN. For participants receiving anticoagulant therapy, the investigator must deem both INR and APTT to be within a safe and effective therapeutic range.
  5. Left ventricular ejection fraction (LVEF) > 50%.

• Life expectancy ≥ 3 months.

• For female participants of childbearing potential, a negative serum pregnancy test result must be obtained within 7 days prior to randomization. Participants of childbearing potential or those with partners of childbearing potential must agree to use reliable and effective methods of contraception during the study treatment period and for at least 7 months after the last dose of study treatment.

Exclusion Criteria:

• Contraindications to trastuzumab, pertuzumab, and docetaxel, or deemed by the investigator as unsuitable for treatment with JSKN003.

• Prior treatment with antibody-drug conjugates containing a topoisomerase I inhibitor (e.g., DS-8201, SHR-A1811, TQB-2102, etc.).

• Toxicities from prior anti-tumor therapy have not recovered to ≤ Grade 1 per CTCAE 6.0 (except for toxicities judged by the investigator to pose no safety risk, such as alopecia, peripheral neuropathy, or isolated laboratory abnormalities, which must have resolved to ≤ Grade 2).

• During prior anti-HER2 therapy, left ventricular ejection fraction (LVEF) decreased to <50%, symptomatic congestive heart failure occurred, or toxicity leading to permanent treatment discontinuation was experienced.

• Known hypersensitivity and/or contraindications to corticosteroids (including but not limited to active peptic ulcer disease, severe hypertension, severe hypokalemia, glaucoma, etc.).

• Use of strong CYP3A4 inhibitors within 14 days prior to randomization.

• History of hypersensitivity to any component of the investigational drug(s) or any known excipient.

• Spinal cord compression or clinically active central nervous system (CNS) metastases, defined as untreated or symptomatic, or requiring corticosteroids or anticonvulsants to manage related symptoms. Participants are eligible if they have been clinically stable for >4 weeks after treatment for brain metastases without requiring corticosteroids or anticonvulsants and have recovered from acute toxicities of radiotherapy. Whole-brain radiotherapy or stereotactic radiosurgery must have been completed at least 2 weeks prior to study enrollment.

• Active malignancy within 3 years prior to randomization, except for the breast cancer under investigation in this trial and any locally curable tumors that have undergone definitive treatment (e.g., resected basal cell or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, early-stage thyroid cancer, etc.).

• Uncontrolled or significant cardiovascular or cerebrovascular diseases, including but not limited to:

  1. New York Heart Association (NYHA) Class II or higher congestive heart failure, unstable angina, myocardial infarction, or arrhythmia causing hemodynamic instability within 6 months prior to randomization;
  2. Primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy);
  3. History of clinically significant QT interval prolongation, or QTcF (calculated using Fridericia's formula) >480 ms during screening;
  4. Arterial/venous thrombotic events within 6 months prior to randomization, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
  5. Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg).

• History of (non-infectious) interstitial lung disease (ILD)/non-infectious pneumonitis requiring steroid treatment, current ILD/non-infectious pneumonitis, or suspected ILD/non-infectious pneumonitis that cannot be ruled out by imaging during screening.

• Clinically significant pulmonary-specific comorbidities, including but not limited to any underlying pulmonary disease within 3 months prior to study enrollment, (e.g., pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, moderate to large pleural effusion, etc.).

• Prior pneumonectomy.

• Any documented autoimmune, connective tissue, or inflammatory disease (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.).

• History of immunodeficiency, such as congenital immunodeficiency disease, organ transplantation, etc..

• Uncontrolled active infection or disease, including but not limited to:

  1. Active HBV or HCV infection. Participants who are HBsAg positive and/or HCV antibody positive during screening must undergo HBV DNA and/or HCV RNA testing. Only participants with HBV DNA below the upper limit of normal and/or negative HCV RNA are eligible;
  2. HIV infection or history of AIDS;
  3. Known active tuberculosis;
  4. Active syphilis. Participants with positive TP-Ab during screening must undergo TRUST or RPR testing; participants positive for both are excluded;
  5. Other active infections or systemic use of anti-infective drugs for more than 1 week continuously within 28 days prior to randomization.

• History of partial or complete intestinal obstruction, inflammatory bowel disease, chronic diarrhea, or gastrointestinal bleeding within 6 months prior to randomization.

• Concurrent participation in another clinical study (except for non-interventional studies or the follow-up phase of an interventional study) or less than 4 weeks from the end of the previous clinical study (last dose) at the time of randomization.

• Anti-tumor therapy including radiotherapy, targeted therapy, immunotherapy, and other investigational drugs within 28 days prior to randomization, or use of traditional Chinese medicine with anti-tumor indications within 14 days prior to randomization.

• Uncontrolled serous cavity effusions (e.g., pleural effusion, ascites, pericardial effusion) requiring frequent drainage or medical intervention within 14 days prior to randomization, or requiring additional intervention within 2 weeks post-intervention (excluding cytological examination of effusion).

• Major surgical procedures (e.g., abdominal, thoracic surgery; excluding minor procedures such as diagnostic puncture, infusion port placement, or biliary stent placement) within 28 days prior to randomization, or anticipated need for major surgery during the study period.

• Women who are breastfeeding.

• Any other condition that may interfere with the participant's ability to undergo study procedures, is not in the participant's best interest to participate, or may affect study outcomes: e.g., history of psychiatric disorders, drug or substance abuse, or any other clinically significant disease or condition.