Neoadjuvant Gemcitabine Plus Trastuzumab Rezetecan in HER2-positive UTUC

Condition(s) studied

Investigational drug(s) / intervention(s)

Trastuzumab Rezetecan: Gemcitabine 1000 mg/m² is given via intravenous infusion, followed by intravenous administration of trastuzumab rezetecan 4.8 mg/kg 3 hours thereafter. The treatment consists of 4 cycles in total with a 21-day cycle interval. Patients without pathological complete response (pCR) will receive 2 cycles of adjuvant therapy

Gemcitabine: Gemcitabine 1000 mg/m² is given via intravenous infusion, followed by intravenous administration of trastuzumab rezetecan 4.8 mg/kg 3 hours thereafter. The treatment consists of 4 cycles in total with a 21-day cycle interval. Patients without pathological complete response will receive 2 cycles of adjuvant therapy

Radical nephroureterectomy: After completing four cycles of neoadjuvant therapy, patients undergo radical nephroureterectomy (RNU). The surgical resection typically includes: 1\) The affected kidney (including the perirenal fat capsule); 2) The entire ureter from the renal pelvis to the intramural segment; 3) A bladder cuff around the ureteral orifice; 4) In addition, ipsilateral regional lymph node dissection (e.g., hilar, para-aortic, and paracaval nodes) may be performed depending on tumor stage and clinical indication.

Study summary

Upper tract urothelial carcinoma (UTUC) carries a poor prognosis, with conventional GC (gemcitabine plus cisplatin) regimens achieving only a 19% pathological complete response (pCR) rate in the neoadjuvant setting. Antibody-drug conjugates (ADCs) have shown promising results in advanced urothelial carcinoma, Meanwhile the clinical application of traditional cisplatin-based chemotherapy is associated with significant limitations. Therefore, exploring the efficacy and safety of Trastuzumab Rezetecan (an anti-HER2 ADC) combined with gemcitabine in UTUC is of considerable importance.

This trial will enroll patients with HER2 2-3+ UTUC. After pathological diagnosis, patients will receive intravenous infusions of gemcitabine and Trastuzumab Rezetecan. The treatment regimen consists of a 21-day cycle: 4 cycles of neoadjuvant therapy, followed by 2 cycles of adjuvant therapy for patients who do not achieve pCR (total of 6 cycles). For patients with suboptimal pathological downstaging after surgery (≥ypT3 or ypN+), combination with immune checkpoint inhibitors (ICIs) is recommended.

During the neoadjuvant period, adverse events will be closely monitored. Regular imaging and follow-up assessments will be performed, and events such as disease recurrence, progression, and their corresponding time points will be documented.

The primary endpoint is pCR rate. Secondary endpoints include adverse events during the neoadjuvant period, event-free survival (EFS), overall survival (OS).

Eligibility

Primary outcome measure(s)

• Pathological Complete Response (pCR) — Within 1 week after completion of radical nephroureterectomy
  Defined as the absence of residual viable tumor cells (ypT0N0) in RNU specimens. Assessed post surgery. Method: A central pathology review committee performs review of slides from all eligible patients. Two senior uropathologists (associate professor level or above) read independently; consensus is final, otherwise a third senior pathologist adjudicates blindly. ypT and ypN are recorded.

Trial sites (10)

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