Becotatugvedotin Plus Pucotenlimab in EGFR-Positive Advanced Gastric/GEJ Adenocarcinoma

Prior treatment

• Receipt of chemotherapy, targeted therapy, immunotherapy, or other anti-cancer therapy within 4 weeks before study treatment initiation, or unresolved treatment-related toxicities \> Grade 1 (except alopecia). Radiotherapy within 4 weeks (or palliative radiotherapy within 2 weeks) before enrollment.
• Untreated or uncontrolled central nervous system (CNS) metastases or leptomeningeal disease. Patients with previously treated brain metastases may be enrolled if clinically stable for at least 4 weeks and receiving no more than prednisone 10 mg/day (or equivalent).
• Current or previous interstitial lung disease (ILD), immune-related pneumonitis, or active pneumonitis requiring systemic corticosteroid treatment.
• History of another active malignancy within the previous 5 years, except adequately treated basal cell carcinoma of the skin, cervical carcinoma in situ, or other malignancies with negligible risk of recurrence.
• Participation in another interventional clinical trial within 4 weeks before enrollment or concurrent participation in another clinical trial involving investigational agents.

Other illness

• HER2-positive disease (IHC 3+ or IHC 2+ with ISH/FISH amplification).
• Active autoimmune disease requiring systemic immunosuppressive therapy, or history of organ transplantation requiring immunosuppressive treatment.
• Uncontrolled active infection, including severe bacterial infection requiring intravenous antibiotics, active tuberculosis, hepatitis B virus (HBV) DNA \>2,000 IU/mL or without appropriate antiviral therapy, untreated hepatitis C virus (HCV) infection with detectable HCV RNA, or uncontrolled human immunodeficiency virus (HIV) infection.
• Active gastrointestinal bleeding, gastrointestinal perforation, bowel obstruction, or gastrointestinal conditions requiring urgent surgical or interventional treatment.
• Known severe hypersensitivity to becotatug vedotin, pucotenlimab, or any of their excipients.
• Any medical, psychiatric, social, or compliance-related condition that, in the opinion of the investigator, would compromise participant safety, interfere with study participation, or affect interpretation of study results.

Lab values

• Prior treatment with any EGFR-targeting antibody-drug conjugate (ADC), including becotatug vedotin (MRG003) or similar EGFR-targeting ADCs. Previous treatment with anti-EGFR monoclonal antibodies (e.g., cetuximab) is permitted.
• Significant cardiovascular or other serious uncontrolled systemic diseases, including myocardial infarction, unstable angina, New York Heart Association (NYHA) class III-IV heart failure, severe arrhythmia, QTc \>470 ms within 6 months before enrollment, or any other condition judged by the investigator to interfere with study participation.

Other

• Baseline Grade ≥2 peripheral neuropathy or clinically significant sensory neuropathy.
• Pregnant or breastfeeding women, or individuals planning pregnancy during the study period.

• Voluntarily provide written informed consent and be willing and able to comply with all study procedures and follow-up requirements.
• Age 18 to 75 years, regardless of sex.
• Histologically or cytologically confirmed unresectable locally advanced, recurrent, or metastatic gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma.
• EGFR-positive tumor confirmed by immunohistochemistry (IHC) performed on archival or newly obtained tumor tissue. EGFR positivity is defined as IHC 1+, 2+, 3+, or 4+, corresponding to membrane staining in ≥1% of tumor cells.
• Disease progression, recurrence, or intolerance following one prior line of systemic therapy for advanced or metastatic disease, including a fluoropyrimidine- and platinum-based regimen with or without a PD-1 inhibitor, and considered eligible for second-line treatment. Patients who relapse within 6 months after completion of neoadjuvant or adjuvant chemotherapy are considered to have failed first-line therapy.
• At least one measurable lesion according to RECIST version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Estimated life expectancy of at least 12 weeks.
• Adequate organ function within 14 days prior to enrollment:
  • Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; Platelet count ≥100 × 10⁹/L; Hemoglobin ≥90 g/L; Total bilirubin ≤1.5 × upper limit of normal (ULN); AST and ALT ≤2.5 × ULN (≤5 × ULN in patients with liver metastases); Serum creatinine ≤1.5 × ULN or creatinine clearance (CrCl) ≥50 mL/min; INR ≤1.5 × ULN, or therapeutic anticoagulation with stable coagulation parameters considered acceptable by the investigator.
• Women of childbearing potential must have a negative pregnancy test before enrollment. Male and female participants of reproductive potential must agree to use effective contraception during study treatment and for at least 6 months after the last dose of study drug.