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

A Single-Arm, Open-Label, Phase II Study of Becotatugvedotin Combined With Pucotenlimab in Patients With EGFR-Positive Advanced/Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Who Have Failed Standard First-Line Therapy

Advanced gastric cancer (AGC) and gastroesophageal junction (GEJ) adenocarcinoma remain associated with poor prognosis after failure of first-line systemic therapy. Although immune checkpoint inhibitor-based chemoimmunotherapy has become the standard first-line treatment for HER2-negative advanced disease, most patients eventually experience disease progression. Current second-line treatment options provide limited clinical benefit, highlighting the need for novel therapeutic strategies.

Epidermal growth factor receptor (EGFR) is overexpressed in approximately 20-30% of gastric cancers and is associated with aggressive tumor biology and poor prognosis. Previous studies evaluating anti-EGFR monoclonal antibodies or tyrosine kinase inhibitors in unselected gastric cancer populations failed to demonstrate survival benefit, largely because of the lack of biomarker-based patient selection and the limited efficacy of conventional EGFR-targeted agents. Becotatug vedotin (MRG003), an EGFR-directed antibody-drug conjugate (ADC) carrying monomethyl auristatin E (MMAE), exerts potent cytotoxic activity through EGFR-mediated internalization and intracellular payload release. In addition, MMAE-containing ADCs may induce immunogenic cell death and remodel the tumor immune microenvironment, providing a strong biological rationale for combination with programmed cell death protein-1 (PD-1) blockade. Pucotenlimab is a humanized anti-PD-1 monoclonal antibody with demonstrated antitumor activity and favorable safety in multiple solid tumors.

This is a prospective, single-center, open-label, single-arm phase II investigator-initiated trial designed to evaluate the efficacy and safety of becotatug vedotin in combination with pucotenlimab as second-line treatment in patients with EGFR-positive unresectable locally advanced, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma who have progressed after standard first-line therapy. Approximately 28 patients will be enrolled. Participants will receive becotatug vedotin (2.0 mg/kg, intravenous infusion, every 3 weeks) plus pucotenlimab (200 mg, intravenous infusion, every 3 weeks) until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision.

The primary endpoint is objective response rate (ORR) assessed according to RECIST version 1.1. Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DoR), time to response (TTR), and safety. Exploratory analyses will evaluate the association between treatment outcomes and biomarkers including EGFR expression, PD-L1 expression, tumor mutational burden, microsatellite instability/mismatch repair status, and immune-related biomarkers, aiming to identify patients most likely to benefit from this combination therapy.

Inclusion Criteria:

1. Voluntarily provide written informed consent and be willing and able to comply with all study procedures and follow-up requirements.

2. Age 18 to 75 years, regardless of sex.

3. Histologically or cytologically confirmed unresectable locally advanced, recurrent, or metastatic gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma.

4. 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.

5. 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.

6. At least one measurable lesion according to RECIST version 1.1.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

8. Estimated life expectancy of at least 12 weeks.

9. 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.

10. 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.

Exclusion Criteria:

1. 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.
2. 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.
3. HER2-positive disease (IHC 3+ or IHC 2+ with ISH/FISH amplification).
4. 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).
5. Current or previous interstitial lung disease (ILD), immune-related pneumonitis, or active pneumonitis requiring systemic corticosteroid treatment.
6. Active autoimmune disease requiring systemic immunosuppressive therapy, or history of organ transplantation requiring immunosuppressive treatment.
7. 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.
8. 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.
9. Baseline Grade ≥2 peripheral neuropathy or clinically significant sensory neuropathy.
10. Active gastrointestinal bleeding, gastrointestinal perforation, bowel obstruction, or gastrointestinal conditions requiring urgent surgical or interventional treatment.
11. 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.
12. Pregnant or breastfeeding women, or individuals planning pregnancy during the study period.
13. Known severe hypersensitivity to becotatug vedotin, pucotenlimab, or any of their excipients.
14. 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.
15. Participation in another interventional clinical trial within 4 weeks before enrollment or concurrent participation in another clinical trial involving investigational agents.