A Single-arm, Exploratory, Phase II Clinical Study of the Efficacy and Safety of Trastuzumab (T-DXd) in Combination With Pyrotinib in Patients Progressed After T-DXd Treatment for Advanced HER2-positive Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- The objective response rate（ORR） was evaluated according to the RECIST v1.1 standard
研究概览
简要总结
This is a single-arm, exploratory, phase II study evaluating the efficacy and safety of trastuzumab deruxtecan (T-DXd) in combination with pyrotinib in patients with HER2-positive advanced breast cancer whose disease has progressed after prior treatment with T-DXd.T-DXd is the established standard second-line therapy for HER2-positive advanced breast cancer. However, acquired resistance inevitably develops, and there is currently no approved standard treatment for patients progressing after T-DXd. Real-world studies report an objective response rate (ORR) of approximately 14.5% and a median progression-free survival of only 3 to 4 months in this setting, representing a major unmet medical need.Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor that potently inhibits HER1, HER2 and HER4 kinase activity and blocks downstream PI3K/AKT and MAPK signaling. Preclinical and clinical data (including the HER2CLIMB-02 and TROPHY studies) support the synergistic potential of combining an anti-HER2 antibody-drug conjugate with a tyrosine kinase inhibitor.Participants receive T-DXd 5.4 mg/kg intravenously on Day 1 of each 21-day cycle plus pyrotinib 320 mg orally once daily, continuously, until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria. Tumor response is assessed using RECIST v1.1.The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Approximately 28 participants will be enrolled.
详细描述
HER2-positive breast cancer accounts for approximately 15-20% of all breast cancers and is characterized by high aggressiveness and a propensity for relapse and metastasis. The CLEOPATRA study established taxane plus trastuzumab and pertuzumab as the international first-line standard. For patients failing first-line therapy, trastuzumab deruxtecan (T-DXd, DS-8201) has become the globally accepted second-line standard. T-DXd is a next-generation HER2-directed antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody, a cleavable tetrapeptide linker, and a topoisomerase I inhibitor payload (DXd), with a drug-to-antibody ratio of approximately 8. Its bystander effect enables activity against neighboring tumor cells with low or absent HER2 expression. In DESTINY-Breast03, T-DXd prolonged median progression-free survival from 6.8 months (T-DM1) to 28.8 months, reducing the risk of progression or death by 67%. Both the Chinese CSCO guidelines and major international guidelines recommend T-DXd as the highest-level second-line option.On August 12, 2026, based on the results of the DESTINY-Breast09 Phase III clinical trial, the indication of T-DXd for the first-line treatment of adult patients with unresectable or metastatic HER2-positive breast cancer was approved in China.Nevertheless, resistance to T-DXd is inevitable, and the population progressing after T-DXd continues to grow. No approved standard therapy and no high-level evidence exist for this setting. Across regimens including other ADCs, chemotherapy, HER2 monoclonal antibodies or TKIs, the ORR after T-DXd progression is approximately 14.5% with a median PFS of only 3-4 months. Real-world data show a median rwPFS of 4.7 months with tucatinib plus trastuzumab plus capecitabine and 2.6 months with sacituzumab govitecan. New clinical evidence is therefore urgently needed.
RATIONALE Mechanisms of T-DXd resistance are multifactorial and include reduced HER2 expression or altered HER2 binding, increased drug efflux (e.g., ABCC1 overexpression) and secondary genomic alterations (ERBB2, NFE2L2, KEAP1, TOP1). We hypothesize that combining T-DXd with pyrotinib may produce synergistic antitumor activity through: (1) complementary mechanisms providing vertical dual blockade of HER2 signaling (extracellular antibody-mediated payload delivery plus intracellular kinase inhibition); (2) suppression of bypass pathway activation such as PI3K/AKT, thereby reversing or circumventing resistance; (3) enhanced ADC cytotoxicity induced by TKI-mediated alteration of intracellular signaling and cell-cycle distribution; and (4) clinical precedent from the TROPHY study, in which T-DXd plus pyrotinib showed a favorable safety profile with the recommended pyrotinib dose established at 320 mg.
STUDY DESIGN This is an investigator-initiated, open-label, single-arm, exploratory phase II study conducted at Fujian Cancer Hospital. Approximately 28 evaluable participants will be enrolled. A Simon's minimax two-stage design is used, with a null hypothesis ORR of 14.5%, an alternative hypothesis ORR of 35%, a one-sided alpha of 0.05 and power of at least 80%. In stage 1, 15 participants will be evaluated; if 2 or fewer responses are observed the study will be stopped for futility, otherwise an additional 13 participants will be enrolled to a total of 28. If more than 7 responses are observed among the 28 participants, the regimen will be considered worthy of further investigation.
INTERVENTION
- Trastuzumab deruxtecan (T-DXd): 5.4 mg/kg intravenous infusion, Day 1 of each 21-day cycle. First infusion over at least 90 minutes; if tolerated, subsequent infusions may be shortened to approximately 30 minutes. Permitted dose reductions: 4.4 mg/kg and 3.2 mg/kg.
- Pyrotinib: 320 mg orally once daily, continuously, administered with or immediately after a meal. Permitted dose reduction: 240 mg once daily.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Voluntarily signed written informed consent; age ≥ 18 years; either sex.
- •Histologically or cytologically confirmed unresectable locally advanced or metastatic breast cancer.
- •HER2-positive status confirmed by a central laboratory or the institutional pathology department according to the current ASCO/CAP guidelines, defined as immunohistochemistry (IHC) 3+ or in situ hybridization (ISH) positive.
- •Prior treatment with T-DXd in the second-line or later setting, with radiologically documented disease progression during or after T-DXd therapy according to RECIST v1.
- •At least one measurable lesion according to RECIST v1.
- •Patients with brain metastases are eligible if the metastases are untreated and do not require immediate local therapy, or if previously treated with local therapy (e.g., radiotherapy, surgery) with a washout period of at least 4 weeks.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Life expectancy of at least 3 months.
- •Adequate organ function as defined below, without transfusion or hematopoietic growth factor support within 14 days prior to the first dose:
- •a. Absolute neutrophil count ≥ 1.5 × 10^9/L; b. Platelet count ≥ 100 × 10^9/L; c. Hemoglobin ≥ 80 g/L; d. Total bilirubin ≤ 1.5 × ULN; e. ALT and AST ≤ 2.5 × ULN within 7 days prior to the first dose (≤ 5 × ULN in patients with hepatic metastases); f. Serum creatinine ≤ 1.25 × ULN and creatinine clearance ≥ 60 mL/min.
- •Women of childbearing potential must agree to use highly effective contraception during the study and for 7 months after the last dose; men must agree to use highly effective contraception during the study and for 4 months after the last dose. Serum or urine pregnancy test must be negative within 7 days before enrollment.
排除标准
- •History of severe hypersensitivity to the study drugs (T-DXd, pyrotinib) or to any of their excipients.
- •Patients with brain metastases meeting any of the following: clinically significant central nervous system symptoms requiring continuous corticosteroid or anticonvulsant therapy to control symptoms; brain metastases assessed as requiring immediate local therapy; poorly controlled (more than 1 week) generalized or complex partial seizures.
- •History of clinically significant pulmonary disease, including but not limited to: any history of interstitial lung disease (ILD) or pneumonitis requiring steroid treatment; current active ILD/pneumonitis, or suspected ILD/pneumonitis on screening imaging that cannot be excluded.
- •Clinically significant cardiovascular disease, including but not limited to: acute myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack within 6 months prior to screening; clinically uncontrolled hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg); New York Heart Association (NYHA) class III or higher heart failure; QTc prolongation with QTcF > 470 ms using Fridericia's correction.
- •Severe or uncontrolled systemic disease that, in the investigator's judgment, would compromise protocol compliance or safety assessment, such as active infection or poorly controlled diabetes mellitus.
- •Known human immunodeficiency virus (HIV) infection, or untreated active hepatitis B (HBsAg positive with HBV DNA > 500 IU/mL) or hepatitis C (HCV antibody positive with HCV RNA above the lower limit of quantification).
- •Major surgery or significant unhealed trauma within 4 weeks prior to the first dose of study treatment.
- •Chemotherapy, other targeted therapy, or immunotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of study treatment.
- •Participation in another interventional clinical study within 4 weeks, or within 5 half-lives of the investigational product (whichever is shorter), prior to the first dose of study treatment.
- •Chronic diarrhea, malabsorption syndrome, or other gastrointestinal disorder that may affect the absorption of orally administered medication.
研究组 & 干预措施
T-DXd plus Pyrotinib
Trastuzumab Deruxtecan (T-DXd): Intravenous infusion at 5.4 mg/kg on Day 1 of each 21-day cycle. The first infusion is administered over not less than 90 minutes; if well tolerated, subsequent infusions may be shortened to approximately 30 minutes. Protocol-defined dose reduction levels are 4.4 mg/kg (first reduction) and 3.2 mg/kg (second reduction); further reduction requires treatment discontinuation.
Pyrotinib:Oral tablet, 320 mg once daily on a continuous schedule, taken with or immediately after a meal. A single dose reduction to 240 mg once daily is permitted for toxicity management; multiple interruptions and dose adjustments are allowed.
干预措施: Trastuzumab Deruxtecan (T-DXd) (Drug)
T-DXd plus Pyrotinib
Trastuzumab Deruxtecan (T-DXd): Intravenous infusion at 5.4 mg/kg on Day 1 of each 21-day cycle. The first infusion is administered over not less than 90 minutes; if well tolerated, subsequent infusions may be shortened to approximately 30 minutes. Protocol-defined dose reduction levels are 4.4 mg/kg (first reduction) and 3.2 mg/kg (second reduction); further reduction requires treatment discontinuation.
Pyrotinib:Oral tablet, 320 mg once daily on a continuous schedule, taken with or immediately after a meal. A single dose reduction to 240 mg once daily is permitted for toxicity management; multiple interruptions and dose adjustments are allowed.
干预措施: Pyrotinib (Drug)
结局指标
主要结局
The objective response rate（ORR） was evaluated according to the RECIST v1.1 standard
时间窗: 3 years
次要结局
- The Disease Control Rate (DCR) was evaluated according to the RECIST v1.1 standard(3 years)
- progression-free survival (PFS)(3 years)
- Overall Survival (OS)(3 years)
- The safety was according to the classification standard of drug AE in NCI-CTCAE 5.0(3 years)
研究者
Fan Wu
Chief Physician
Fujian Cancer Hospital