Trastuzumab rezetecan for HER2-positive advanced solid tumors resistant to standard treatments

Trastuzumab Rezetecan in Advanced Solid Tumors Refractory to Standard Therapies: A Multicenter, Single-Arm, Phase II Study With Multiple Cohorts

This treatment gives trastuzumab rezetecan every three weeks to see if it helps adults with HER2-positive advanced solid tumors — including extramammary Paget's disease, rare tumors like urachal cancer, and urothelial carcinoma — that have stopped responding to standard treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 90 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fudan University (Academic / other)
• Drugs / interventions: enfortumab, disitamab, Trastuzumab
• Locations: 1 site (Shanghai, Shanghai Municipality)
• Trial ID: NCT07309770 on ClinicalTrials.gov

What this trial studies

This single-center, multi-cohort phase II trial enrolled 90 adults with HER2-positive advanced solid tumors into three cohorts of 30 patients each (extramammary Paget's disease, rare solid tumors, and urothelial carcinoma) after prior standard therapy failure. All participants received trastuzumab rezetecan (SHR-A1811) 4.8 mg/kg every three weeks and were followed until progression, withdrawal, loss to follow-up, or death. Tumor response was measured radiologically every six weeks during treatment, safety was reviewed 30 days after the last dose, and survival follow-up occurred every three months thereafter. Eligibility required histologic confirmation of disease, HER2 expression (IHC ≥1+), ECOG 0–2, and at least one measurable lesion per RECIST v1.1.

Who should consider this trial

Good fit: Adults (≥18) with histologically confirmed HER2-positive (IHC ≥1+) unresectable locally advanced or metastatic extramammary Paget's disease, certain rare solid tumors (e.g., urachal cancer), or urothelial carcinoma who have progressed on standard therapies and have ECOG 0–2 and at least one measurable lesion are ideal candidates.

Not a fit: Patients without HER2 expression (IHC 0), those who can still receive effective standard treatments, or those with performance status worse than ECOG 2 are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this treatment could offer a new targeted option that shrinks tumors and potentially extends survival for patients with HER2-positive advanced cancers who have no standard therapies left.

How similar studies have performed: Other HER2-targeting antibody–drug conjugates have shown activity across multiple HER2-expressing cancers, so the approach has precedent, although SHR-A1811 itself is a newer agent with more limited published data.

Eligibility criteria

Inclusion Criteria:

Voluntarily sign a written informed consent form.

Age ≥ 18 years.

Diagnosed with the corresponding advanced tumor confirmed by histology and/or cytology, combined with imaging or ultrasound assessment, and pathologically confirmed as HER2-positive (i.e., HER2 ≥ 1+ by immunohistochemistry \[IHC\]).

Cohort 1 only: Histologically confirmed extramammary Paget's disease (EMPD) with unresectable locally advanced or metastatic disease.

Cohort 2 only: Histologically confirmed locally advanced or metastatic rare solid tumor (e.g., sarcoma, urachal cancer) refractory to standard treatment or for whom no standard treatment is available.

Cohort 3 only: Histologically confirmed locally advanced or metastatic urothelial carcinoma with disease progression following first-line treatment with a PD-1/PD-L1 inhibitor combined with enfortumab vedotin or disitamab vedotin.

ECOG Performance Status: 0 to 2.

At least one measurable lesion (according to RECIST v1.1 criteria: non-nodal lesions with longest diameter ≥10 mm on CT scan, nodal lesions with short axis ≥15 mm on CT scan).

Hematological function:

Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L

Platelet count (PLT) ≥ 70 × 10⁹/L

Hemoglobin (HGB) ≥ 80 g/L

Hepatic function:

Serum total bilirubin (TBIL) ≤ 1.5 × Upper Limit of Normal (ULN)

Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if liver metastases are present)

Serum albumin ≥ 28 g/L

Renal function:

Serum creatinine (Cr) ≤ 1.5 × ULN or Creatinine clearance ≥ 50 mL/min (calculated using the standard Cockcroft-Gault formula)

Coagulation function:

International Normalized Ratio (INR) ≤ 1.5 and/or Prothrombin Time (PT) ≤ 1.5 × ULN

Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN

Estimated life expectancy ≥ 3 months.

Use of medically approved contraception during the treatment period and for at least 120 days after the end of the study; sperm donation or cryopreservation for fertilization purposes is not allowed during this period.

Ability to comply with the study visit schedule and other protocol requirements.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from participation in this study:

Presence of any severe and/or uncontrolled disease, including:

Poorly controlled hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg); poorly controlled diabetes (fasting blood glucose \[FBG\] \> 10 mmol/L).

≥ Grade 2 myocardial ischemia, myocardial infarction, arrhythmia (QTcF ≥ 470 ms), or ≥ Grade 2 congestive heart failure (New York Heart Association \[NYHA\] classification).

Active or uncontrolled severe infection (≥ CTCAE Grade 2 infection) requiring systemic antibacterial, antifungal, or antiviral treatment, including tuberculosis infection.

History of active tuberculosis.

Uncontrolled ascites, pericardial effusion, or pleural effusion requiring repeated drainage.

Active hepatitis (liver enzyme levels not meeting inclusion criteria; for Hepatitis B: HBV DNA ≥ 2000 IU/ml or ≥ 10⁴ copies/ml; for Hepatitis C: HCV RNA ≥ 2000 IU/ml or ≥ 10⁴ copies/ml; carriers with chronic hepatitis B virus \[HBV DNA \< 10⁴ IU/ml\] may be enrolled if they receive concomitant antiviral therapy during the trial).

History of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency diseases.

Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

Known presence of brain metastases, leptomeningeal metastasis, spinal cord compression, or spinal metastasis.

Within 6 months prior to the first dose: history of esophageal/gastric varices, severe ulcer, unhealed wound, gastrointestinal perforation, abdominal fistula, intestinal obstruction, intra-abdominal abscess, acute gastrointestinal bleeding; extensive intestinal resection (partial colectomy or extensive small bowel resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.

Presence of non-healing or poorly healed wounds, active ulcers.

Toxicity from previous antineoplastic therapy that has not resolved to ≤ Grade 1 per NCI CTCAE v5.0 (except for alopecia).

Major surgical treatment, open biopsy, or significant traumatic injury within 28 days prior to the start of study treatment; or presence of long-term unhealed wounds or fractures.

History of severe hypersensitivity reaction to monoclonal antibodies; known allergy to the active components or excipients of the study drug(s).

Participation in another clinical trial within 4 weeks prior to the start of the study.

Administration of a live vaccine within 30 days prior to the first dose, or planned administration during the study.

History of severe allergy.

Bleeding tendency, coagulopathy, or undergoing thrombolytic therapy.

History of drug abuse or inability to discontinue use, or history of psychiatric disorders.

History of clear neurological or psychiatric disorders, such as dementia, epilepsy, or susceptibility to seizures.

Any condition that, in the investigator's judgment, seriously endangers subject safety, affects subject completion of the study (e.g., severe diabetes, thyroid disease, psychosis), may compromise subject safety or the ability to provide informed consent (including abnormal laboratory findings), or involves psychological, familial, sociological, or geographical conditions that may preclude compliance with the study protocol and follow-up plan.

Any other reason deemed by the investigator to make the subject unsuitable for participation in this clinical trial.

Where this trial is running

Shanghai, Shanghai Municipality

• Fudan University Shanghai Cancer Center — Shanghai, Shanghai Municipality, China (Recruiting)

Study contacts

• Study coordinator: Sheng Zhang

Conditions Urachal Cancer; Advanced Solid Tumor Cancer; Antibody-drug Conjugates; Antibody-Drug Conjugates; Rare tumor; Extra-mammary Paget disease; Urachal cancer; Trastuzumab Rezetecan