Sacituzumab Tirumotecan (MK-2870) in Patients With Advanced Small Bowel Adenocarcinoma Refractory or Intolerant to Platinum-Based Combination Therapy

Small bowel adenocarcinoma is a rare cancer with a poor prognosis. For patients with locally advanced or metastatic disease, the usual first treatment is chemotherapy with platinum-based combinations such as FOLFOX or CapeOX. However, once the cancer grows after this treatment or the side effects become too severe, there is no widely accepted standard second-line therapy, and outcomes are generally poor. New treatment options are therefore urgently needed. In a recent translational research study conducted by Fujii, Shoji, et al., immunohistochemical staining for TROP2 was performed in 51 patients with pathologically diagnosed small bowel adenocarcinoma, and TROP2 positivity was confirmed in 43 cases (84.3%). Furthermore, patient-derived organoids were established using tumor tissues obtained from patients with small bowel adenocarcinoma, and the in vitro efficacy of sacituzumab tirumotecan was evaluated. A concentration-dependent growth-inhibitory effect was observed, with significant sensitivity observed in the nanomolar concentration range. Therefore, treatment with sacituzumab tirumotecan targeting TROP2 is expected to improve the prognosis of patients with small bowel adenocarcinoma. The METROPOLIS trial is a multicenter, single-arm, phase II investigator-initiated trial designed to evaluate the efficacy and safety of sacituzumab tirumotecan in patients with locally advanced or metastatic small bowel adenocarcinoma that has progressed during or after, or is intolerant to, platinum-based combination chemotherapy (FOLFOX or CapeOX). Eligible patients are adults (aged 18 years or older) with histologically or cytologically confirmed small bowel adenocarcinoma, a good performance status, adequate organ function, and at least one measurable lesion on a CT scan. Patients who have genomic alterations that make them candidates for previously approved "tumor-agnostic" targeted drugs (for example, high microsatellite instability or high tumor mutational burden) must already have tried and not benefited from, or not tolerated, those treatments. TROP2 positivity is not required for study participation; however, assessment of TROP2 expression is mandatory for exploratory biomarker analyses. Sacituzumab tirumotecan at 4 mg/kg is administered intravenously on Days 1 and 15 of each 28-day cycle and continued until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria are met. Tumor scans with contrast-enhanced CT will be performed every 8 weeks up to week 24 and every 12 weeks thereafter to monitor the response of the sacituzumab tirumotecan. The primary objective is to determine the proportion of patients achieving a tumor response to sacituzumab tirumotecan, as assessed by independent radiologic review. Key secondary objectives include progression-free survival, overall survival, duration of response, and safety profiling. In addition, this study includes a prespecified translational research program. Tumor samples will be examined for TROP2 using immunohistochemistry, and researchers will investigate the relationship between TROP2 and the effects of sacituzumab tirumotecan. Blood and tissue samples will also be collected before treatment, during treatment, and at the time of cancer progression, when possible, for detailed "multi-omics" analyses. These translational studies aim to elucidate why some patients respond whereas others do not, and to identify biomarkers that could inform future treatment strategies for small bowel adenocarcinoma. The METROPOLIS trial has been approved by the Institutional Review Board of the National Cancer Center, Japan, as well as by the ethics committees at participating sites. This trial is conducted with funding and sacituzumab tirumotecan supplied by MERCK SHARP \& DOHME LLC. Enrollment began in January 2027 and is planned to continue through December 2028, with patients followed for at least 12 months after the last participant is enrolled.

Inclusion Criteria: 1. Has a histologically or cytologically confirmed diagnosis of Small bowel Adenocarcinoma. If diagnosed before enrollment, the timing of diagnosis shall not be considered. If this histological diagnosis was performed at the referring institution (i.e., a center not participating in the study), it must be reviewed and verified by a pathologist at the participating study site. 2. Corresponds to any of the following a) to c) 1. It has been determined that R0 resection is not possible due to the combined resection of the invasive lesion in locally advanced small bowel adenocarcinoma. 2. Diagnosed as small bowel adenocarcinoma with distant metastasis, classified as UICC-TNM stage IV. 3. Diagnosed as a postoperative recurrence of small bowel adenocarcinoma. 3. No Active central nervous system (CNS) metastases-including brain metastases, carcinomatous (leptomeningeal) meningitis, or symptomatic spinal metastases that require radiotherapy or surgical intervention. 4. No clinically significant pericardial effusion, pleural effusion, or ascites requiring invasive interventions such as drainage is observed. 5. Age ≥18 years at the time of enrollment. 6. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. At least one target lesion by RECIST version 1.1 identified on contrast-enhanced CT (brain, neck, chest, abdomen, pelvis with ≤5 mm slice thickness) performed within 14 days prior to enrollment (same day of the week within 14 days is acceptable; this applies similarly to other time-based criteria below). 8. Has been previously treated with platinum combinations (FOLFOX or CapeOX therapy) for locally advanced or metastatic small bowel adenocarcinoma and discontinued due to disease progression, recurrence, or toxicities. 9. If a genomic alteration that has a tumor-agnostic indication for solid tumors has been identified, the patient must also be refractory to, intolerant of, or ineligible for the corresponding drug (e.g., pembrolizumab for MSI-High or dMMR, or the combination of dabrafenib and trametinib for BRAF V600E mutations). 10. Archival tumor tissue from either the primary lesion or metastatic lesion is available at the date of enrollment. If archival tumor tissue is not available, consent has been obtained to undergo an additional biopsy to obtain tumor tissue prior to commencement of study drug administration. Assessment of TROP2 expression is mandatory for this study. 11. No prior treatment with Trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugates or antibody-drug conjugates containing anti-topoisomerase I agents. 12. No administration of anticancer therapies (e.g., chemotherapy, targeted therapy, immunotherapy) or other investigational products and radiotherapy (including palliative radiotherapy) for the current malignancy within 14 days prior to enrollment. 13. No major surgery under general anesthesia within 28 days prior to enrollment. 14. Laboratory values within the following criteria based on testing within 14 days prior to enrollment.: 1. Neutrophil count≥1,500/mm3 2. Platelet count≥100,000/mm3 3. Hemoglobin≥9.0 g/dL 4. AST≤75 U/L(In cases of hepatic metastasis, levels up to 150 U/L are acceptable.) 5. ALT≤75U/L(In cases of hepatic metastasis, levels up to 150 U/L are acceptable.) 6. Total bilirubin≤1.5 mg/dL 7. Calculated CrCl≥30mL/min 15. Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1(except for alopecia and vitiligo). Participants with endocrine-related AEs (e.g., hypothyroidism or adrenal insufficiency) who are adequately treated with hormone replacement therapy are eligible. 16. For male patients: Must agree to use acceptable contraception※1,2 and refrain from sperm donation for at least 120 days after the last dose of study drug. For female patients: Must meet one of the following conditions: i) Not of childbearing potential (POCBP) ii) If of childbearing potential: * The patient must not be pregnant, and a pregnancy test (high-sensitivity serum or urine β-hCG test) must confirm a negative result within 14 days prior to enrollment. If a negative result cannot be confirmed by a urine test, a serum pregnancy test is required. * Agrees to use effective contraception ※1,2 from the time of informed consent through at least 210 days after the last dose of study drug. If breastfeeding, agrees to discontinue breastfeeding from the first dose of the study drug through at least 10 days after the last dose. * Uses a contraceptive method that is highly effective (with a failure rate of \