Clinical Study of Ifinatamab Deruxtecan (I-DXd, MK-2400 or DS-7300a) and Pembrolizumab (MK-3475) with or without Chemotherapy in Individuals with Esophageal Cancer (KEYMAKER-U06): Substudy 06E

Summary description of the study

This study aims to determine whether the tested drug combinations are safe and effective for the treatment of esophageal squamous cell carcinoma. The study investigates the safety and efficacy of MK-3475 (immunotherapy) with/without conventional chemotherapy in combination with new, experimental substances. Approximately 209 patients are expected to participate in this study worldwide, with about 8 being enrolled in Switzerland. The total duration of the study, from the enrollment of the first patient to the last study-related contact of the last patient, is approximately 6 years. Various treatment approaches for esophageal squamous cell carcinoma are being tested in this study. First, it will be assessed whether the combination of I-DXd and MK-3475 is well tolerated. After this initial phase, additional participants will be randomly assigned to different treatment combinations. Some will receive the standard treatment (Group 1) with MK-3475 and chemotherapy, while others will receive the experimental combination of I-DXd and MK-3475 (Group 2) to compare both treatments. If safety in Group 2 is confirmed, a new combination will be tested in Group 3 and later in Group 4, where it will be combined with additional chemotherapies. Tolerability and side effects will always be monitored. If necessary, new treatment groups may also be opened if a new substance from previous studies shows promising results. The open treatment groups will be communicated to the participant in advance by the study physician, and assignment to an arm will be done randomly by a computer. This study is an so-called "open-label" study. This means that both the participants and the study physician and sponsor know which group the patients have been assigned to and thus also which study medication they are receiving.

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Intervention under investigation

After a thorough eligibility assessment and comprehensive information, the participant will be enrolled in this study and randomly assigned to one of the four currently planned treatments, depending on the open groups. The assignment to the medications is as follows:

• Group 1: MK-3475 in combination with a standard chemotherapy combination called mFOLFOX6

• Group 2: I-DXd in combination with MK-3475

• Group 3: I-DXd in combination with MK-3475 as well as standard chemotherapies (5-FU and Leucovorin/Levoleucovorin)

• Group 4: I-DXd in combination with MK-3475 and standard chemotherapies (5-FU and Oxaliplatin)

The medications used support the body in fighting the tumor. Here are the mechanisms of action of the currently tested medications in this study:

• MK-3475 is an antibody that inhibits the tumor's suppression of the immune system, thereby enhancing the body's own defense.

• I-DXd is an antibody-drug conjugate that consists of an antibody and a chemotherapy agent. The antibody targets a protein on tumor cells, allowing the drug to directly enter these tumor cells while hopefully sparing healthy cells. This aims to reduce the side effects of chemotherapy while effectively combating tumor cells.

• The standard chemotherapies and combinations used in this study are approved therapies for patients with this type of cancer:

o mFOLFOX6 (combination of 5-fluorouracil (5-FU), Leucovorin/Levoleucovorin, and Oxaliplatin)

o 5-fluorouracil (5-FU) and Leucovorin/Levoleucovorin

o 5-fluorouracil (5-FU) and Oxaliplatin

At the beginning of the study, a screening phase of about 28 days will be conducted, during which the study team will assess the eligibility of the participants. Upon successful enrollment in the study, the treatment phase will follow, which is expected to last about 2 years, as long as the participant's cancer does not worsen and the tested medications are well tolerated. During this phase, approximately three visits per month to the study center will be required. The study medications in the mentioned treatment groups will be administered intravenously (IV), through a needle into a vein.

After the treatment phase is completed, the follow-up phase will begin. An initial visit to the study center will occur approximately 30 to 40 days after the completion of the study medications, depending on which treatment group the participant is assigned to. In case of stable disease, follow-up checks will occur approximately every 6 weeks in the first year and then every 9 weeks. After the follow-up is completed, the study physician will contact the participant every 12 weeks (3 months) or more frequently to check on their health status.

During the study appointments, various measures and examinations may be conducted, including: discussion of well-being and current medication, administration of study medication, imaging procedures (CT and/or MRI scans), heart examinations (multiple gated acquisition scan (MUGA), echocardiogram (ECHO), and electrocardiogram (EKG)), eye examinations, collection of blood and urine samples, and assessment of vital signs (pulse, blood pressure, etc.).

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Disease under investigation

This study evaluates the safety and tolerability of I-DXd and MK-3475, with and without chemotherapy, in patients with untreated, advanced, and unresectable/metastatic esophageal cancer (esophageal squamous cell carcinoma). Esophageal cancer, also known as esophageal carcinoma, is a type of cancer that begins in the esophagus. The esophagus is the tube that carries liquid and solid food from the mouth to the stomach. An esophageal carcinoma can also spread to other parts of the body. There are two common types of esophageal carcinomas: • Esophageal adenocarcinoma: usually begins in the lower part of the esophagus at the junction with the stomach. • Esophageal squamous cell carcinoma: usually begins in the upper part or in the middle of the esophagus. Esophageal carcinoma remains a significant health challenge, although a global decline in incidence and mortality rates has been observed. The majority of patients diagnosed with esophageal squamous cell carcinoma receive this diagnosis only at advanced or even metastatic stages, which significantly reduces the chances of cure. First-line therapy with a platinum-based combination chemotherapy has not changed over the years. Recent findings have shown that a combination of chemotherapy and immunotherapy as first-line therapy can significantly improve treatment efficacy. Despite recent advances in the treatment of esophageal cancer, there remains an urgent need for new therapeutic approaches, as many patients become resistant to the latest therapies, and the disease is often diagnosed only at an advanced stage, where therapies may not always be effective.

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Sponsor

MSD Merck Sharp & Dohme AG, Switzerland Merck Sharp & Dohme LLC, USA

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Name of the authorising ethics committee (for multicentre studies, only the lead committee)

Ethics Committee Zurich

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Date of authorisation

08.04.2025

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Results of the trial