Sacituzumab Tirumotecan (Sac-TMT/SKB264) Plus Tagitanlimab (KL-A167) in Patients With Recurrent or Metastatic Esophageal Squamous Cell Carcinoma and Gastric/Gastroesophageal Junction Adenocarcinoma

A Single-Arm, Multicenter Phase II Study of Sacituzumab Tirumotecan (Sac-TMT/SKB264) Combined With Tagitanlimab (KL-A167) as Second-Line Therapy for Recurrent or Metastatic Esophageal Squamous Cell Carcinoma and Gastric/Gastroesophageal Junction Adenocarcinoma

This is a single-arm, multi-center phase II study to evaluate the efficacy and safety of sacituzumab tirumotecan (Sac-TMT/SKB264) combined with tagitanlimab (KL-A167) as 2nd line therapy for recurrent or metastatic esophageal squamous cell carcinoma (ESCC) or gastric/gastroesophageal junction adenocarcinoma (G/GEJA). A total of 75 participants are planned to be enrolled with 10 in the safety lead-in phase and 33 ESCC and 42 G/GEJA in expansion phase, seperately.

Inclusion Criteria:

• Aged ≥18 years at the time of signing the informed consent form;
• Histologically or cytologically confirmed diagnosis of unresectable locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) or gastric/gastroesophageal junction (GEJ) adenocarcinoma;
• Esophageal squamous cell carcinoma (ESCC) and gastric/gastroesophageal junction (GEJ) adenocarcinoma with disease progression following first-line anti-PD-1 combined chemotherapy, and the progression-free survival (PFS) of first-line treatment ≥3 months;
• Radical concurrent chemoradiotherapy, neoadjuvant or adjuvant therapy: disease progression occurring during treatment or within 6 months after treatment discontinuation shall be deemed failure of first-line treatment.

(Note: This also includes patients with advanced or recurrent non-target lesions who experience re-progression after radiotherapy alone. The criteria also apply to patients receiving palliative treatment for local (non-target) lesions for more than 2 weeks.)

• Patients with HER2-positive gastric/gastroesophageal junction adenocarcinoma must have received prior anti-HER2 therapy;

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 within 7 days prior to the first administration of study treatment;

• Expected survival ≥3 months;

• At least one measurable lesion per RECIST v1.1; lesions previously irradiated shall not be selected as target lesions; subjects with only skin lesions or bone lesions are not eligible for enrollment;

• Participants must have recovered from all toxicities related to prior treatments (i.e., improved to Grade 0 or Grade 1, or met the levels specified in the eligibility criteria), except for toxicities not considered a safety risk (e.g., alopecia, vitiligo, and other asymptomatic laboratory abnormalities);

• Adequate organ function defined as follows:

  1. Hematology (no blood transfusion or hematopoietic stimulating agents for correction within 14 days): hemoglobin (Hb) ≥9 g/dL; absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelet count (PLT) ≥100×10⁹/L; neutrophil count (NEUT#) ≥1.5×10⁹/L;

  2. Serum total bilirubin ≤1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≤2.5 × ULN.

     For subjects with liver metastases: ALT and AST ≤5 × ULN, serum bilirubin ≤2 × ULN.

     For subjects with liver and/or bone metastases: ALP ≤5 × ULN; serum albumin ≥30 g/L;

  3. Renal function: creatinine clearance (Ccr) ≥50 mL/min;

  4. Coagulation function: international normalized ratio (INR), activated partial thromboplastin time (APTT) and prothrombin time (PT) ≤1.5 × ULN.

• Female participants of childbearing potential and male subjects with partners of childbearing potential must agree to use effective medical contraceptive measures from the date of signing the informed consent form until 6 months after the last study drug administration (see Appendix 2 for details);

• Participants must voluntarily participate in this study, sign the informed consent form, and demonstrate good treatment compliance and willingness to complete follow-up visits.

Exclusion Criteria:

• Participants diagnosed with other malignant tumors within 3 years prior to study drug administration, except for tumors cured by local therapy (e.g., basal cell carcinoma of the skin, cutaneous squamous cell carcinoma, cervical carcinoma in situ, etc.);

• Participants with known meningeal metastasis, brainstem metastasis, spinal cord metastasis and/or spinal cord compression, or active central nervous system (CNS) metastases without prior local treatment. Participants with previously locally treated brain metastases may be enrolled if they remain clinically stable for at least 4 weeks prior to the first dose and do not require corticosteroids or anticonvulsants for a minimum of 14 days;

• Participants with clinically significant cardiovascular diseases, including:

  1. Severe or uncontrolled cardiac disorders or clinical symptoms requiring treatment within 6 months before the first study dose, including New York Heart Association (NYHA) Class III or IV congestive heart failure, drug-refractory unstable angina, severe arrhythmias requiring pharmacotherapy (excluding atrial fibrillation or paroxysmal supraventricular tachycardia), and myocardial infarction;
  2. Prior history of myocarditis or cardiomyopathy;
  3. QTc interval >480 ms at baseline measurement;

• Participants with severe and/or uncontrolled concomitant diseases, such as decompensated cirrhosis, nephrotic syndrome, poorly controlled hypertension, symptomatic pleural/pericardial effusion or ascites requiring repeated drainage;

• Participants diagnosed with active hepatitis B [hepatitis B surface antigen (HBsAg) positive, with HBV-DNA ≥ 500 IU/mL or above the lower limit of quantification, whichever is higher] or hepatitis C (positive anti-HCV antibody with HCV-RNA above the lower limit of quantification);

• Participants with poorly controlled known human immunodeficiency virus (HIV) infection, including HIV-infected individuals with a history of Kaposi's sarcoma and/or multicentric Castleman's disease;

• Participants with known active tuberculosis;

• Participants with documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or a history of corneal disorders that hinder or delay corneal wound healing;

• Participants who have undergone major surgery (as defined by the investigator) within 30 days before the first study dose or are still recovering from prior surgery;

• Participants with known allergy or hypersensitivity to the study drug or its excipients, or a prior history of severe hypersensitivity reactions to monoclonal antibodies;

• Participants with a history of interstitial lung disease (ILD) or non-infectious pneumonia requiring steroid therapy, current ILD/pneumonia, or suspected ILD/pneumonia that cannot be ruled out by imaging at screening;

• Participants with a history of allogeneic tissue or organ transplantation; Autoimmune diseases requiring systemic therapy within the past 2 years or anticipated immunosuppressive therapy during the study period. Participants with well-controlled type 1 diabetes, euthyroid thyroiditis, hypothyroidism adequately managed via hormone replacement therapy (HRT), or skin disorders not requiring systemic treatment (e.g., vitiligo, psoriasis) are eligible for enrollment;

• Prior treatment with TROP2-targeted agents or any topoisomerase I inhibitors, including antibody-drug conjugates (ADCs);

• Prior administration of any investigational anti-tumor vaccines or any agents targeting T-cell co-stimulatory pathways;

• Vaccination with live vaccines within 30 days before the first study dose, or planned live vaccine administration during the study period;

• Participants requiring strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 2 weeks prior to the first dose and throughout the study period. Concomitant use of strong CYP3A4 inhibitors or inducers is prohibited in this study; representative agents are listed in Appendix 7. All participants shall avoid concomitant use of any known CYP3A4-inducing medications, herbal supplements, and/or relevant foods to the greatest extent possible;

• Receipt of any chemotherapy, radiotherapy, immunotherapy or biotherapy within 4 weeks before the first study dose; receipt of small-molecule tyrosine kinase inhibitors (TKIs), anti-tumor hormonal therapy, systemic immune stimulants (including but not limited to interferon, IL-2), or proprietary Chinese herbal medicines approved for anti-tumor indications within 2 weeks before the first study dose;

• Palliative radiotherapy administered to known metastatic sites within 2 weeks before the first study dose;

• Systemic anti-infective therapy received within 1 week before the first study dose;

• Female participants who are pregnant or breastfeeding;

• Diseases requiring systemic corticosteroid therapy (prednisolone equivalent dose >10 mg/day) or other immunosuppressants within 14 days before the first study dose. Participants receiving intranasal, inhaled, topical cutaneous, local injectable corticosteroids (e.g., intra-articular injection), or corticosteroids for hypersensitivity prophylaxis may be enrolled;

• Any other conditions under which the investigator deems the participant unsuitable for participation in this study.