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.
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.
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;
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;
Prior history of myocarditis or cardiomyopathy;
Single group
Sacituzumab Tirumotecan + Tagitanlimab
DrugSac-TMT (SKB264): 4mg/kg, IV infusion on Day 1, Q2W A167: 900 mg via IV injection on day 1, Q2W, up to 2 years
Safety Lead-in Phase: Number of Participants Who Experience One or More Dose-Limiting Toxicities (DLTs)
DLTs are defined as any drug-related adverse event (AE) according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) Version 5.0, observed during the DLT evaluation period that results in a change to a given dose or a delay in initiating the next cycle. The percentage of participants who experience at least one DLT will be reported.
Objective Response Rate (ORR)
ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience CR or PR as assessed by investigators will be presented.
Duration of Response (DOR)
For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until PD or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by investigators will be presented.
Progression-Free Survival (PFS)
PFS is defined as the time from enrollment to the first documented progressive disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by investigators will be presented.
Disease Control Rate (DCR)
DCR is defined as the percentage of participants in the analysis population who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions), Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD: No ≥30% decrease in the sum of target lesion diameters, and no ≥20% increase in the sum of target lesion diameters relative to the nadir sum of diameters, with no new lesions identified) per RECIST 1.1.
Overall Survival (OS)
OS is defined as the time from enrollment to the date of death from any cause.
Biomarker exploratory analysis: if there is any correlation between the expression levels of TROP2, HER2, CLDN18.2 and PD-L1 with efficacy
To evaluate the correlation of expression of TROP2, HER2, CLDN18.2 and PD-L1 in formalin-fixed paraffin-embedded (FFPE) tumor samples at baseline with efficacy.
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