Phase 3 Multicenter Randomized Open-label Study of Ifinatamab Deruxtecan Versus Chemotherapy in Pretreated Advanced Esophageal Squamous Cell Carcinoma

The primary objective of this Phase 3, multicenter, randomized, open-label study is to evaluate the overall survival (**OS**) benefit of **Ifinatamab Deruxtecan (I-DXd)** compared with the investigator’s choice of chemotherapy (**ICC**) in subjects with pretreated advanced or metastatic **Esophageal Squamous Cell Carcinoma (ESCC)**. This objective is clinically relevant as it aims to determine if I-DXd can extend the lifespan of patients with this aggressive cancer type, providing a potential new therapeutic option.

Secondary objectives include:

• To evaluate the progression-free survival (**PFS**) benefit of I-DXd compared with ICC.
• To evaluate the overall response rate (**ORR**) benefit of I-DXd compared with ICC.
• To further evaluate the efficacy of I-DXd compared with ICC.
• To evaluate patient-reported outcomes (**PRO**) endpoints for I-DXd compared with ICC.
• To assess the safety and tolerability of I-DXd.
• To assess the immunogenicity of I-DXd.
• To evaluate B7-H3 protein expression in tumor tissue and its relationship with I-DXd efficacy.
• To characterize the pharmacokinetics (**PK**) of I-DXd in subjects randomized to the I-DXd group.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic profile of I-DXd, including its efficacy, safety, and potential biomarkers of response, which are crucial for optimizing treatment strategies in ESCC.

The clinical trial involves a total of **312 participants** diagnosed with **Esophageal Squamous Cell Carcinoma (ESCC)**. The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants were selected based on specific criteria, including having histologically or cytologically documented unresectable locally advanced or metastatic ESCC, and having experienced disease progression following platinum-based and immune checkpoint inhibitor (ICI) treatment. The trial includes individuals who have undergone a maximum of one prior line of systemic therapy for unresectable advanced or metastatic ESCC. Participants are required to provide adequate baseline tumor samples and must have at least one measurable lesion as determined by computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST v1.1 criteria. Additionally, subjects must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 within seven days prior to the start of the trial. The trial population includes vulnerable groups, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 3**, multicenter, randomized, open-label study designed to evaluate the efficacy and safety of **Ifinatamab deruxtecan** (I-DXd) in patients with pretreated advanced or metastatic **Esophageal Squamous Cell Carcinoma** (ESCC). The primary objective is to assess the overall survival (OS) benefit of I-DXd compared to the investigator's choice of chemotherapy. The trial involves a comparison between I-DXd and standard chemotherapy agents such as **docetaxel**, **irinotecan hydrochloride**, and **paclitaxel**, all administered via intravenous infusion. The study is expected to commence recruitment on July 2, 2025, and conclude by December 28, 2028, with a maximum treatment period of 54 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), documented unresectable locally advanced or metastatic ESCC, and disease progression post platinum-based and immune checkpoint inhibitor (ICI) treatment. Baseline tumor samples and measurable lesions on imaging are required, along with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Following randomization, participants will receive either I-DXd or the investigator's choice of chemotherapy, with follow-up visits scheduled to monitor treatment response and safety.

The primary endpoint is overall survival, defined as the time from randomization to death from any cause. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and disease control rate (DCR), all assessed by blinded independent central review (BICR) per RECIST v1.1 criteria. Additional assessments include patient-reported outcomes (PROs), treatment-emergent adverse events (TEAEs), and pharmacokinetic (PK) parameters. Participants will remain in the study until disease progression, unacceptable toxicity, withdrawal of consent, or study completion, whichever occurs first. Early termination may occur if any of these conditions are met.

The clinical trial involves the administration of **Ifinatamab deruxtecan**, an experimental medication classified as an antibody-drug conjugate (ADC). This investigational product is provided in the form of a **solution for infusion** and is administered via **intravenous use**. The dosing regimen for Ifinatamab deruxtecan is set at a maximum daily dose of 12 mg/kg, with a total maximum dose of 936 mg/kg over a treatment period of up to 54 weeks. The active substance, Ifinatamab deruxtecan, is a protein-based compound developed by Daiichi Sankyo, Inc. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes comparator treatments, which are standard chemotherapy agents. **Docetaxel** is one such comparator, provided as a concentrate for solution for infusion. It is also administered intravenously, with a maximum daily dose of 75 mg/m² and a total maximum dose of 4050 mg/m² over the same 54-week period. Docetaxel is a chemically derived substance and is subject to relabeling and repackaging as part of the trial protocol.

Another comparator used in the study is **Irinotecan hydrochloride**, which functions as a DNA topoisomerase I inhibitor. This medication is also supplied as a concentrate for solution for infusion and administered intravenously. The dosing for Irinotecan hydrochloride is capped at 180 mg/m² per day, with a total maximum dose of 19500 mg/m² over the course of the trial. Similar to Docetaxel, Irinotecan hydrochloride undergoes relabeling and repackaging.

**Paclitaxel** is the third comparator treatment included in the study. It is provided in the same pharmaceutical form as the other comparators and administered intravenously. The dosing schedule for Paclitaxel allows for a maximum daily dose of 175 mg/m², with a total maximum dose of 23400 mg/m² over the 54-week treatment period. As with the other comparator treatments, Paclitaxel is subject to relabeling and repackaging to ensure consistency and compliance with trial requirements.

The efficacy of the investigational drug **Ifinatamab deruxtecan** (I-DXd) will be assessed in a Phase 3, multicenter, randomized, open-label clinical trial involving subjects with pretreated advanced or metastatic esophageal squamous cell carcinoma (ESCC). The primary endpoint for evaluating efficacy is overall survival (OS), defined as the time interval from the date of randomization to the date of death due to any cause. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), and disease control rate (DCR). These will be determined by blinded independent central review (BICR) per RECIST v1.1 criteria.

Patient-reported outcomes (PROs) will be assessed using validated instruments such as the EORTC QLQ-C30 and EORTC OES18, focusing on global health status, quality of life, physical functioning, fatigue, dysphagia, trouble with eating, reflux, and pain. Changes in scores from baseline will be measured for each cycle up to Cycle 4 and Cycle 6. Additionally, the time to deterioration (TTD) from baseline will be calculated using a deterioration score threshold of ≥10 points.

Safety and tolerability will be monitored through the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and adverse events of special interest (AESIs), graded according to the NCI-CTCAE v5.0. This includes monitoring deaths, changes from baseline in vital signs, clinical laboratory results, ECGs, and ECHO/MUGA. Anti-drug antibodies (ADA) will be measured in plasma using a validated assay to determine ADA prevalence and incidence, as well as titer and neutralizing antibodies when ADA is positive.

Additional assessments include B7-H3 protein expression in tumor tissue at baseline, which will be correlated with OS and other efficacy endpoints. Plasma concentrations and pharmacokinetic (PK) parameters such as Cmax, Tmax, AUClast, and AUCtau for I-DXd, total anti-B7-H3 antibody, and DXd will be evaluated in the full PK subset. The trial is estimated to conclude by December 28, 2028, with recruitment starting on July 2, 2025.