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

<Background and Rationale> Small bowel adenocarcinoma is a rare gastrointestinal malignancy that accounts for fewer than 3% of all gastrointestinal cancers and is associated with poor prognosis. Most patients are diagnosed at an advanced stage because lesions in the distal duodenum, jejunum, and ileum are difficult to detect endoscopically, and symptoms such as anemia, obstruction, or bleeding often appear only after the disease has progressed. For patients with locally advanced or metastatic small bowel adenocarcinoma, fluoropyrimidine plus oxaliplatin regimens such as FOLFOX and CapeOX are widely used as first-line systemic therapy. Prospective studies have reported objective response rates of approximately 40-50% and median overall survival of about 13-20 months with these platinum-based combinations. However, there is no established standard of care beyond first-line treatment, and outcomes after failure of platinum-based chemotherapy are dismal, with small retrospective series suggesting modest activity of regimens such as irinotecan-based chemotherapy or taxanes and very low response rates in routine practice. In the absence of targetable alterations qualifying for tumor-agnostic approved therapies, best supportive care remains the default recommendation for many patients after failure of first-line therapy.

Sacituzumab tirumotecan is an antibody-drug conjugate (ADC) consisting of 1) a TROP2-targeting monoclonal antibody (sacituzumab); 2) a cytotoxic payload in the class of topoisomerase 1 inhibitors (tirumotecan); and 3) a novel, irreversible but hydrolyzable linker that joins the monoclonal antibody and the cytotoxic drug payload.

Sacituzumab tirumotecan selectively targets TROP2 on the surface of tumor cells. Following the internalization of the complex through the endosomal-lysosomal pathway, the cytotoxic drug payload (tirumotecan) is released inside the tumor cell, leading to cell cycle arrest in the S or G2/M phase and eventually tumor cell apoptosis. In addition, sacituzumab tirumotecan triggers antibody-dependent cell-mediated cytotoxicity and bystander activity to kill tumor cells but shows no complement-dependent cytotoxicity. Normal tissues express relatively low levels of TROP2 compared with some cancers; therefore, sacituzumab tirumotecan may provide a targeted therapy that could possibly improve efficacy and tolerability.

Immunohistochemical staining for TROP2 was performed on 51 patients with small bowel adenocarcinoma diagnosed pathologically at the National Cancer Center Hospital, Japan, from July 2010 to July 2023, and TROP2 positivity was confirmed in 43 out of 51 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.

<Study Objectives> This investigator-initiated phase II clinical trial aims to evaluate the efficacy and safety of sacituzumab tirumotecan monotherapy in patients with locally advanced or metastatic small bowel adenocarcinoma refractory to or intolerant of platinum-based combination therapy (FOLFOX or CapeOX).

The primary endpoint of this study is the objective response rate (ORR) as assessed by the independent imaging review committee. Secondary endpoints include objective response rate ORR as assessed by the investigator (site assessment), progression-free survival, overall survival, disease control rate, the incidence of adverse events, adverse reactions, and serious adverse events/adverse reactions, as well as measures of treatment feasibility, including dose intensity and relative dose intensity, and efficacy outcomes such as duration of response and time to response.

<Study Design> The METROPOLIS trial is a multicenter, single-arm, phase II investigator-initiated trial.

<Study Treatment> All participants receive sacituzumab tirumotecan at a dose of 4 mg/kg, administered as an intravenous infusion on Day 1 and Day 15 of each 28-day cycle.

Treatment is initiated within 7 days of registration and is continued until one or more of the following occur:

• Radiographic or clinical disease progression
• Unacceptable toxicity
• Withdrawal of consent
• Investigator or Steering Committee decision based on participant safety or protocol-defined criteria

<Efficacy Assessments> Tumor scans with contrast-enhanced CT (brain,neck, chest, abdomen, and pelvis) will be performed every 8 weeks up to week 24 and every 12 weeks thereafter to evaluate the response of the sacituzumab tirumotecan. Tumor response and disease progression are evaluated according to RECIST version 1.1.

<Endpoints>

Primary Endpoint:

Objective Response Rate (ORR) as assessed by the Independent Imaging Review Committee.

Secondary Endpoints:

Objective Response Rate (ORR) as assessed by the investigator (site assessment).

Progression-Free Survival (PFS) Overall Survival (OS) Disease Control Rate (DCR) Incidence and severity of adverse events and adverse drug reactions (CTCAE v5.0) Dose intensity (DI),Relative dose intensity (RDI) Duration of Response(DoR), Time to Response

<Study Oversight and Funding> National Cancer Center Hospital, Japan, is the coordinating sponsor and is responsible for overall trial coordination, data management, monitoring, and analysis.

Merck Sharp & Dohme LLC provides the investigational product and research funding for the study.

<Prespecified translational research program> A prespecified translational research program is embedded in the trial. Archival tumor tissue or a pretreatment biopsy is required for enrollment whenever feasible. Tumor TROP2 expression will be evaluated centrally by immunohistochemistry, and exploratory analyses will investigate the association between TROP2 expression levels and clinical outcomes with sacituzumab tirumotecan. Additionally, blood and tissue biospecimens will be collected at baseline, during treatment, and at disease progression, where possible, for multi-omics analyses. These studies aim to elucidate the mechanisms of sensitivity and resistance, identify predictive and prognostic biomarkers, and generate hypotheses for subsequent biomarker-driven trials in small bowel adenocarcinoma.

Inclusion criteria

• 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.

• Corresponds to any of the following a) to c)

• 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.
• Diagnosed as small bowel adenocarcinoma with distant metastasis, classified as UICC-TNM stage IV.
• Diagnosed as a postoperative recurrence of small bowel adenocarcinoma.
• No Active central nervous system (CNS) metastases-including brain metastases, carcinomatous (leptomeningeal) meningitis, or symptomatic spinal metastases that require radiotherapy or surgical intervention.
• No clinically significant pericardial effusion, pleural effusion, or ascites requiring invasive interventions such as drainage is observed.
• Age ≥18 years at the time of enrollment.
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• 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).
• 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.
• 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).
• 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.
• No prior treatment with Trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugates or antibody-drug conjugates containing anti-topoisomerase I agents.
• 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.
• No major surgery under general anesthesia within 28 days prior to enrollment.
• Laboratory values within the following criteria based on testing within 14 days prior to enrollment.:

• Neutrophil count≥1,500/mm3
• Platelet count≥100,000/mm3
• Hemoglobin≥9.0 g/dL
• AST≤75 U/L(In cases of hepatic metastasis, levels up to 150 U/L are acceptable.)
• ALT≤75U/L(In cases of hepatic metastasis, levels up to 150 U/L are acceptable.)
• Total bilirubin≤1.5 mg/dL
• Calculated CrCl≥30mL/min
• 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.
• 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 <1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate the study intervention after the last dose of study intervention. The patient agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction.
• The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs include condoms, pessaries or diaphragms, oral contraceptives, and intrauterine devices.
• Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.

• 1. The patient must not be currently pregnant and, when engaging in penile-vaginal intercourse with a partner who is capable of becoming pregnant, must use a condom (male or female type). In addition, because condoms may break or leak, the partner must also use an additional effective contraceptive method.
• 2．If the patient is confirmed to be azoospermia-either due to vasectomy or secondary to a medical condition-based on medical records, physical examination, or medical history as documented by site personnel verified by the investigator, additional contraception is not required.
• Written informed consent obtained from the patient.

Exclusion criteria

• Has a known additional malignancy that is progressing or has required active treatment. However, the following i) to iv) are not excluded.

i) Completely resected the following cancers: basal cell carcinoma; stage I squamous cell carcinoma; carcinoma in situ; intramucosal carcinoma; non-muscle-invasive bladder cancer.

ii) Gastrointestinal cancers curatively resected by endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR).

ⅲ) Localized prostate cancer treated with curative intent and showing no evidence of progression, or low-risk or very low-risk localized prostate cancer (by standard guidelines) either treated with definitive intent or untreated in active surveillance with stable disease.

iv) Other cancers with no recurrence observed within past three years.

• Patients with active gastrointestinal ulcers.
• Has a history of pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease ,or has suspected ILD or pneumonitis that cannot be ruled out by standard diagnostic assessments at Screening.
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea).
• Has a current and past history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF interval to≥480 ms, prior treatment history with cardiotoxic agents and/or other serious cardiovascular and cerebrovascular diseases within 6 months before enrollment.
• Severe hypersensitivity (Grades ≥3) to study intervention, any of their excipients, and/or to another biologic therapy.
• Is currently receiving a strong inducer/inhibitor of CYP3A4 that cannot be discontinued for the duration of treatment with study intervention. The required washout period before starting study intervention is 2 weeks.

Note: A list of strong inducers/inhibitors of CYP3A4 can be found at the following website:https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems

• Is currently participating in another therapeutic clinical trial. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anti-cancer therapy is prohibited.
• Has an active infection requiring systemic therapy.
• Positive for HBs antigen, or negative for HBs antigen but positive for either HBs antibody or HBc antibody and positive for HBV DNA quantification. Patients are eligible if they have received antiviral therapy for hepatitis B for at least 4weeks and have HBV DNA is below the lower limit of quantification at the time of enrollment.
• Positive for HIV, Positive for HCV RNA, or, if HCV RNA is negative, has not completed curative antiviral therapy at least 28 days prior to enrollment. HCV RNA testing is required only for patients who test positive for HCV antibodies.
• Has a history or current evidence of any condition due to a concurrent psychiatric disorder or psychiatric symptoms that interfere with activities of daily living and interfere with the individual's participation.
• Received a live or live-attenuated vaccine within 30 days before enrollment. Administration of killed vaccines are allowed.