Daiichi Sankyo and Merck Launch Phase 3 IDeate-Esophageal01 Trial of Ifinatamab Deruxtecan in Advanced Esophageal Squamous Cell Carcinoma
Daiichi Sankyo and Merck have officially initiated dosing in their pivotal Phase 3 clinical trial, named IDeate-Esophageal01, marking a significant step forward in the development of innovative therapies for advanced esophageal squamous cell carcinoma (ESCC). The trial is designed to evaluate the safety and efficacy of the investigational antibody-drug conjugate (ADC), ifinatamab deruxtecan (I-DXd), in comparison with the investigator’s choice of chemotherapy in patients with unresectable advanced or metastatic ESCC who have experienced disease progression following prior treatment with a platinum-containing chemotherapy regimen and an immune checkpoint inhibitor.
This launch signals a potentially critical advancement in treatment for a population with high unmet medical needs. ESCC is a particularly aggressive form of esophageal cancer and accounts for approximately 90% of all esophageal cancer cases globally. The disease often presents in its later stages and is associated with a grim prognosis—five-year overall survival rates remain dismally low at approximately 15% to 20%. For those with unresectable or metastatic disease who have already undergone standard first-line therapies, therapeutic options are extremely limited, and the outlook is especially bleak.
A New Hope: Ifinatamab Deruxtecan
Ifinatamab deruxtecan is a next-generation antibody-drug conjugate specifically engineered to target B7-H3, a protein broadly expressed in many solid tumors, including ESCC. It is a potential first-in-class therapy that leverages Daiichi Sankyo’s proprietary DXd ADC technology and represents an effort to improve upon existing treatment paradigms by offering more tumor-specific cytotoxic delivery while limiting damage to healthy tissues.
The drug was discovered by Daiichi Sankyo and is being co-developed with Merck & Co., Inc., known as MSD outside the United States and Canada. The two companies are collaborating on the global clinical development of ifinatamab deruxtecan as part of their broader strategic oncology partnership. This collaboration aims to bring forward a series of novel ADCs that combine Daiichi Sankyo’s targeted delivery technology with Merck’s oncology development expertise.
The Phase 3 IDeate-Esophageal01 Trial
The IDeate-Esophageal01 study is a randomized, open-label, multicenter Phase 3 trial that will enroll patients diagnosed with unresectable advanced or metastatic ESCC who have progressed on or after a platinum-containing chemotherapy and an immune checkpoint inhibitor. These patients represent a particularly vulnerable subgroup who have already exhausted frontline treatment options and have few remaining effective therapies.
Participants in the study will be randomized to receive either ifinatamab deruxtecan or the investigator’s choice of chemotherapy. The study will evaluate key endpoints such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety outcomes. Biomarker analyses will also be conducted to explore the potential for B7-H3 expression as a predictive marker of response.
The initiation of this Phase 3 trial builds upon promising early results observed in the IDeate-PanTumor01 Phase 1/2 trial, which evaluated ifinatamab deruxtecan across multiple tumor types. At both the 2022 and 2023 meetings of the European Society for Medical Oncology (ESMO), data were presented showing encouraging anti-tumor activity in heavily pretreated patients with ESCC, fueling optimism for further clinical development.
Expert Insights
Dr. Mark Rutstein, Head of Oncology Therapeutic Area Development at Daiichi Sankyo, emphasized the urgent need for more effective treatment strategies for ESCC patients who fail first-line therapy.
“Patients with metastatic esophageal squamous cell carcinoma continue to experience poor outcomes despite currently available treatments,” said Dr. Rutstein. “The encouraging clinical activity seen in our early-phase signal-finding trial supports further evaluation of ifinatamab deruxtecan as a potential treatment strategy for these patients.”
His sentiment was echoed by Dr. Marjorie Green, Senior Vice President and Head of Oncology Global Clinical Development at Merck Research Laboratories. Dr. Green highlighted the collaboration’s strategic importance and the unmet need in ESCC.
“Advanced esophageal squamous cell carcinoma is a difficult-to-treat disease, and unfortunately overall survival remains low,” said Dr. Green. “The initiation of the pivotal Phase 3 IDeate-Esophageal01 clinical trial demonstrates our shared commitment with Daiichi Sankyo to further expand our clinical development program evaluating this potentially first-in-class ADC across multiple solid tumors where there are unmet needs for new treatment options.”
The Clinical Landscape of ESCC
Esophageal squamous cell carcinoma remains one of the most lethal malignancies worldwide. It is particularly prevalent in parts of Asia, sub-Saharan Africa, and certain regions of South America, where it represents a significant public health burden. The disease is frequently diagnosed at a late stage, as early symptoms such as difficulty swallowing and weight loss often go unrecognized.
In recent years, the treatment landscape for metastatic ESCC has modestly improved, particularly with the introduction of immune checkpoint inhibitors targeting PD-1/PD-L1 pathways. However, while these immunotherapies have shown some survival benefit in the first-line setting, a majority of patients eventually progress, leaving clinicians with few effective second-line options.
Standard second-line treatments typically include cytotoxic chemotherapy agents such as paclitaxel, irinotecan, or docetaxel, which are often associated with modest efficacy and significant toxicity. The lack of targeted therapies has contributed to the poor prognosis in this setting, underscoring the need for more precise and effective treatment modalities.
Targeting B7-H3: A Promising Therapeutic Strategy
Ifinatamab deruxtecan’s mechanism of action centers around targeting B7-H3, a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed in various cancers and has been associated with poor prognosis, increased tumor aggressiveness, and immune evasion. Its limited expression in normal tissues makes it an attractive target for ADC-based approaches.
By linking a humanized monoclonal antibody that specifically binds B7-H3 with a potent topoisomerase I inhibitor payload via a cleavable linker, ifinatamab deruxtecan delivers its cytotoxic agent directly to the tumor site. This targeted approach is designed to minimize systemic toxicity and enhance therapeutic efficacy.
Preclinical studies have demonstrated the agent’s potential to induce apoptosis in B7-H3-positive tumor cells, and early-phase clinical data have further validated its activity, particularly in heavily pretreated solid tumors. The ongoing IDeate-Esophageal01 trial represents the first large-scale test of its efficacy and safety in a pivotal trial setting specific to ESCC.
With the launch of IDeate-Esophageal01, Daiichi Sankyo and Merck aim to address a critical gap in the treatment of advanced ESCC. Should the trial confirm the promising data seen in earlier studies, ifinatamab deruxtecan could become a much-needed therapeutic option for patients who have exhausted standard treatment avenues.
Beyond ESCC, the development of ifinatamab deruxtecan may have implications for other B7-H3-expressing solid tumors. The broader IDeate clinical program is evaluating the drug’s potential across a variety of malignancies, further positioning it as a key asset in the evolving oncology pipelines of both companies.
This collaborative effort underscores a growing trend in oncology research—partnerships between pharmaceutical companies aimed at accelerating the development of novel therapies. As Daiichi Sankyo and Merck push forward with their joint ADC programs, patients suffering from hard-to-treat cancers may soon benefit from the next generation of precision medicines.
For now, the industry and clinical community will watch closely as the IDeate-Esophageal01 trial progresses, with the hope that it will usher in a new era of treatment for advanced ESCC and set a precedent for future ADC therapies in other challenging cancer types.
