First patient dosed in the IDeate-Esophageal01 Phase 3 trial evaluating ifinatamab deruxtecan against standard chemotherapy in patients with advanced esophageal squamous cell carcinoma who progressed after platinum therapy and immunotherapy.
Merck and Daiichi Sankyo have announced the initiation of the IDeate-Esophageal01 Phase 3 trial, evaluating the efficacy and safety of ifinatamab deruxtecan (I-DXd) in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC). The trial will compare this investigational antibody-drug conjugate (ADC) against investigator's choice of chemotherapy in patients whose disease has progressed following treatment with platinum-containing systemic therapy and an immune checkpoint inhibitor.
Ifinatamab deruxtecan is a specifically engineered, potential first-in-class B7-H3 directed DXd antibody drug conjugate discovered by Daiichi Sankyo and being jointly developed with Merck. The companies are advancing this novel therapeutic candidate based on encouraging early clinical data in a disease with limited treatment options.
Addressing a Significant Unmet Need
Esophageal squamous cell carcinoma represents nearly 90% of esophageal cancers globally, with a five-year overall survival rate of only 15% to 20%. The prognosis is particularly poor for patients diagnosed at advanced stages of the disease.
"Patients with metastatic esophageal squamous cell carcinoma continue to experience poor outcomes despite currently available treatments," said Dr. Mark Rutstein, Head of Therapeutic Area Oncology Development at Daiichi Sankyo. "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."
Dr. Marjorie Green, Senior Vice President and Head of Oncology, Global Clinical Development at Merck Research Laboratories, emphasized the challenges of treating this disease: "Advanced esophageal squamous cell carcinoma is a difficult-to-treat disease, and unfortunately overall survival remains low. 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."
Trial Design and Objectives
The IDeate-Esophageal01 trial is a global, multicenter, open-label, randomized Phase 3 study that will evaluate ifinatamab deruxtecan at a dose of 12 mg/kg versus physician's choice of chemotherapy (paclitaxel, docetaxel, or irinotecan hydrochloride). Eligible patients must have advanced or metastatic ESCC with disease progression following treatment with platinum-based chemotherapy and an immune checkpoint inhibitor, with no more than one prior line of systemic therapy in the advanced or metastatic setting.
The primary endpoint of the trial is overall survival, with secondary endpoints including progression-free survival, objective response rate as assessed by blinded independent central review, and safety. The study aims to enroll approximately 510 patients across Asia, Europe, and North America.
The initiation of this pivotal trial follows promising results from the IDeate-PanTumor01 Phase 1/2 trial presented at both the 2022 and 2023 European Society of Medical Oncology (ESMO) meetings, where ifinatamab deruxtecan demonstrated encouraging responses in heavily pretreated patients with ESCC.
Targeting B7-H3: A Novel Approach
B7-H3 is a transmembrane protein belonging to the B7 family of proteins that bind to the CD28 family of receptors, including PD-1. This protein is overexpressed in a wide range of cancer types, including ESCC, and its overexpression has been correlated with poor prognosis, making it a promising therapeutic target.
Currently, there are no B7-H3 directed medicines approved for the treatment of any cancer, positioning ifinatamab deruxtecan as a potential first-in-class therapy. The drug is designed using Daiichi Sankyo's proprietary DXd ADC Technology and comprises a humanized anti-B7-H3 IgG1 monoclonal antibody attached to topoisomerase I inhibitor payloads via tetrapeptide-based cleavable linkers.
Broader Development Program
Beyond esophageal cancer, ifinatamab deruxtecan is being evaluated across multiple tumor types in a comprehensive global development program. This includes:
- IDeate-Lung01: A Phase 2 monotherapy trial in patients with previously treated extensive-stage small cell lung cancer (ES-SCLC)
- IDeate-Lung02: A Phase 3 trial in patients with relapsed SCLC versus investigator's choice of chemotherapy
- IDeate-Lung03: A Phase 1b/2 trial in patients with ES-SCLC in combination with atezolizumab with or without carboplatin as first-line induction or maintenance therapy
- IDeate-PanTumor02: A Phase 2 monotherapy trial in patients with recurrent or metastatic solid tumors
- IDeate-PanTumor01: A Phase 1/2 first-in-human monotherapy trial in patients with advanced solid malignant tumors
The drug has already received orphan drug designation in the EU, Japan, Taiwan, and the United States for the treatment of SCLC, highlighting its potential significance in addressing areas of high unmet medical need.
Strategic Collaboration
The development of ifinatamab deruxtecan is part of a broader strategic collaboration between Daiichi Sankyo and Merck. In October 2023, the companies entered into a global partnership to jointly develop and commercialize three ADCs: patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd), and raludotatug deruxtecan (R-DXd), with Daiichi Sankyo maintaining exclusive rights in Japan and handling manufacturing and supply responsibilities.
This collaboration was expanded in August 2024 to include gocatamig (MK-6070/DS3280), which the companies will jointly develop and commercialize worldwide, except in Japan where Merck maintains exclusive rights.
The IDeate-Esophageal01 trial represents an important advancement in the companies' shared mission to develop innovative therapies for difficult-to-treat cancers and address significant unmet medical needs in oncology.
