A Study of Becotatug Vedotin (MRG003) Combined With Epirubicin as Neoadjuvant Therapy for EGFR-Positive, Unresectable Recurrent Sinonasal Adenoid Cystic Carcinoma

This is a prospective, multicenter, single-arm, open-label phase II clinical study. Patients with histologically confirmed recurrent sinonasal adenoid cystic carcinoma (SNACC) that is deemed unresectable by a multidisciplinary team (MDT) and positive for EGFR expression (IHC) are eligible.

Intervention:

• MRG003 (Becotatug vedotin): 2.0 mg/kg IV on day 1 of each 21-day cycle.
• Epirubicin: 75 mg/m² IV on day 1 of each 21-day cycle.
• Total of 3 neoadjuvant cycles.

Primary Outcome Measure: Objective response rate (ORR) according to RECIST v1.1, assessed 21 days (±7 days) after the third cycle.

Secondary Outcome Measures:

• Safety and tolerability (CTCAE v5.0)
• Surgical conversion rate (proportion of patients achieving R0/R1 resection after neoadjuvant therapy)
• R0 resection rate and pathological response rate (major pathological response ≤10% viable tumor cells; pathological complete response 0%)
• Disease control rate (DCR), progression-free survival (PFS), and overall survival (OS)

Sample Size: 40 evaluable patients. Assuming a historical ORR of 10% with single-agent epirubicin, the study is designed to detect an improvement to 35% with the combination (one-sided exact binomial test, α=0.05, power 80%). The sample size also ensures sufficient power for key secondary endpoints and supports the translational sub-study (≥28 successful organoid models).

Translational Research Component: Pre-treatment tumor biopsies will be used to establish patient-derived organoids (PDOs). Organoids will be characterized (H&E, immunofluorescence, STR genotyping) and tested ex vivo for sensitivity to MRG003, epirubicin, and their combination. Associations between organoid drug sensitivity and clinical response (ORR, tumor shrinkage, PFS) will be explored.

Statistical Analysis: Primary analysis will be performed on the full analysis set (all treated patients). ORR and other binary endpoints will be reported with exact 95% confidence intervals (Clopper-Pearson method). PFS and OS will be estimated using Kaplan-Meier method. Translational data will be analyzed using Spearman rank correlation, Chi-square or Fisher's exact tests, and exploratory Cox regression.

Study Duration: Approximately 48 months, including 24 months enrollment, 3-6 months treatment/short-term follow-up per patient, and 24 months long-term survival follow-up after last patient enrollment.

Data Monitoring: An independent Data Safety Monitoring Board (DSMB) will conduct interim safety review after 20 patients are enrolled.

Inclusion criteria

Age ≥ 18 years, male or female. Histopathologically confirmed sinonasal adenoid cystic carcinoma (SNACC) with measurable recurrent disease located in the sinonasal/skull base region, irrespective of the presence of regional lymph node or distant metastases.

EGFR expression positive by immunohistochemistry (IHC) performed at a central laboratory.

Multidisciplinary team (MDT) assessment at baseline confirms that the tumor is not amenable to radical (R0) surgical resection.

At least one measurable lesion in the skull base/sinonasal region according to RECIST v1.1 (longest diameter ≥ 10 mm).

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate bone marrow, hepatic, renal, and cardiac function as defined by protocol-specified laboratory parameters.

Willing to provide written informed consent (including consent for clinical treatment and biospecimen research) and able to comply with study procedures.

Exclusion criteria

Prior treatment with any antibody-drug conjugate (ADC) that contains monomethyl auristatin E (MMAE) as the payload.

Prior systemic chemotherapy containing epirubicin or any other anthracycline within 6 months before study enrollment.

Active uncontrolled infection, or active autoimmune disease requiring systemic therapy.

Symptomatic or urgent (e.g., requiring radiotherapy or surgery) central nervous system (CNS) metastases.

Known severe hypersensitivity to any component of the study drugs. Pregnant or breastfeeding women, or men/women planning to become pregnant within 6 months after the last dose of study treatment.

Any medical or psychosocial condition that, in the investigator's judgment, may interfere with study participation, increase patient risk, or confound data interpretation.