substudy 06c: a study of sacituzumab tirumotecan (mk-2870) with pembrolizumab (mk-3475) and chemotherapy in participants with first-line locally advanced unresectable/metastatic gastroesophageal adenocarcinoma (mk-3475-06c/keymaker-u06)

Conditions: Gastroesophageal Junction; Gastroesophageal Adenocarcinoma; Esophageal Neoplasms; Esophageal Cancer

Summary: this is a phase 1/2, multicenter, open-label umbrella platform study that will evaluate the safety and tolerability of sacituzumab tirumotecan with pembrolizumab and fluoropyrimidine chemotherapy for the first-line (1l) treatment of participants with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (her2)-negative gastric, gastroesophageal junction, or esophageal adenocarcinoma. this substudy will have two phases: a safety lead-in phase and an efficacy phase. the safety lead-in phase will be used to evaluate the safety and tolerability, and to establish a recommended phase 2 dose (rp2d) for sacituzumab tirumotecan in combination with chemotherapy and immunotherapy. there is no formal hypothesis in this study.

the master protocol is mk-3475-u06.

Eligibility criteria:
inclusion criteria: the main inclusion criteria include but are not limited to the following: * has histologically and/or cytologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic 1l gastroesophageal adenocarcinoma * has gastroesophageal adenocarcinoma that is known to be human epidermal growth factor receptor 2 (her2)/neu-positive are excluded. her2 status is not required if her2/neu testing is not mandatory per local standard of care (soc) * is not expected to require tumor resection during the treatment course * has not had prior systemic therapy administered in the recurrent or metastatic setting * has provided an archival tumor tissue sample or most recently obtained core, or incisional, or excisional biopsy for a tumor lesion * participants who have adverse events (aes) due to previous anticancer therapies must have recovered to \<grade 1 or baseline. participants with endocrine-related aes who are adequately treated with hormone replacement therapy are eligible * has adequate organ function * has measurable disease per response evaluation criteria in solid tumors version 1.1 (recist 1.1) as determined by the local site investigator/radiology assessment and verified by blind independent review committee (bicr) * has eastern cooperative oncology group (ecog) performance status of 0 or 1 assessed within 3 days before allocation/randomization. * has a life expectancy of at least 6 months * who are hepatitis b surface antigen (hbsag) positive are eligible if they have received hepatitis b virus (hbv) antiviral therapy for at least 4 weeks, and have undetectable hbv viral load prior to randomization. * who has history of hepatitis c virus (hcv) infection are eligible if hcv viral load is undetectable at screening. * human immunodeficiency virus (hiv)-infected participants must have well-controlled hiv on antiretroviral therapy (art) exclusion criteria: the main exclusion criteria include but are not limited to the following: * has squamous cell or undifferentiated gastroesophageal cancer. * has had previous therapy for locally advanced unresectable or metastatic gastric/gej/esophageal adenocarcinoma * has experienced weight loss \>20% over 3 months before the first dose of study intervention * has a history of documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing * has grade \>2 peripheral neuropathy * has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease * has uncontrolled, significant cardiovascular disease or cerebrovascular disease within 6 months preceding study intervention * has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment * hiv-infected participants with a history of kaposi's sarcoma and/or multicentric castleman's disease * has received prior treatment with a trophoblast antigen 2 (trop2)-targeted antibody-drug conjugate (adc) * has received prior treatment with a topoisomerase i inhibitor-based adc and/or a topoisomerase i inhibitor-based chemotherapy * has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention * has received prior therapy with an anti-programmed cell death protein 1 (pd-1), anti-programmed cell death-ligand 1 (pd-l1), anti-programmed cell death-ligand 2 (pd-l2) agent or with an agent directed to another stimulatory or co-inhibitory t-cell receptor (tcr) * has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation related toxicities, requiring corticosteroids * has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention * has received a strong inducer/inhibitor of cyp3a4 that cannot be discontinued * has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration * has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention * has known additional malignancy that is progressing or has required active treatment within the past 3 years * has known active central nervous system (cns) metastases and/or carcinomatous meningitis * has severe hypersensitivity (≥grade 3) to pembrolizumab, sacituzumab tirumotecan, or other biologic therapy, chemotherapy (ie, oxaliplatin, fluorouracil, capecitabine), leucovorin, levoleucovorin, or any of their excipients * has active autoimmune disease that has required systemic treatment in the past 2 years * has history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease * has an active infection requiring systemic therapy * has concurrent active hepatitis b (defined as hepatitis b surface antigen \[hbsag\] positive and/or detectable hbv dna) and hepatitis c virus (defined as anti-hepatitis c virus \[hcv\] ab positive and detectable hcv ribonucleic acid \[rna\] infection * has gi obstruction, poor oral intake, or difficulty in taking oral medication * has poorly controlled diarrhea * has had a major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention * has history of allogeneic tissue/solid organ transplant * have not adequately recovered from major surgery or have ongoing surgical complications

Keywords: programmed cell death-1 (pd1, pd-1) programmed cell death 1 ligand 1(pdl1, pd-l1) programmed cell death 1 ligand 2 (pdl2, pd-l2)