Ifinatamab Deruxtecan (DS-7300): A Comprehensive Review of a Novel B7-H3-Directed Antibody-Drug Conjugate

I. Executive Summary

Ifinatamab deruxtecan (I-DXd), also known by its development codes DS-7300 and DS-7300a, is an investigational antibody-drug conjugate (ADC) emerging as a significant candidate in oncology therapeutics. It is meticulously engineered to target B7-H3 (CD276), a transmembrane protein frequently overexpressed across a wide array of solid tumors and often associated with poor prognosis.[1] The construct of Ifinatamab deruxtecan features a humanized anti-B7-H3 IgG1 monoclonal antibody (MABX-9001a) [4], a cleavable tetrapeptide-based linker, and Daiichi Sankyo’s proprietary topoisomerase I inhibitor payload, DXd.[1] This design leverages Daiichi Sankyo's DXd ADC technology, which has demonstrated success in other approved ADCs.

The development of Ifinatamab deruxtecan is a collaborative effort between Daiichi Sankyo, the originator and manufacturer, and Merck & Co., Inc. (known as MSD outside the U.S. and Canada), who are jointly responsible for its global clinical development and commercialization, with certain regional exceptions.[1] This partnership signifies a substantial commitment to the drug's potential, combining Daiichi Sankyo's specialized ADC platform expertise with Merck's extensive experience in global oncology drug development and marketing. Such collaborations are common in the biopharmaceutical industry to pool resources, share risks, and expedite the journey of promising assets to patients by leveraging complementary strengths in research, manufacturing, clinical execution, and market access.

Ifinatamab deruxtecan is being investigated across a broad spectrum of malignancies. Promising early clinical activity has been observed in indications such as Small Cell Lung Cancer (SCLC), Esophageal Squamous Cell Carcinoma (ESCC), and metastatic Castration-Resistant Prostate Cancer (mCRPC), leading to the initiation of pivotal Phase 3 trials in these settings.[1] Objective response rates (ORRs) in heavily pretreated SCLC patients have been notably high, around 52-55% with the 12 mg/kg dose in early trials.[10] The drug's safety profile is considered manageable, though it includes adverse events common to cytotoxic agents and a particular adverse event of special interest (AESI) associated with DXd payloads: Interstitial Lung Disease (ILD)/pneumonitis, which requires careful monitoring.[13]

Reflecting its potential in areas of high unmet need, Ifinatamab deruxtecan has received Orphan Drug Designation (ODD) for SCLC from regulatory authorities in the United States, European Union, Japan, and Taiwan.[1] The extensive clinical program, encompassing various tumor types and combination strategies, underscores a comprehensive approach to maximize the therapeutic potential of targeting B7-H3.

II. Introduction to Ifinatamab Deruxtecan (DS-7300/I-DXd)

A. Drug Identity and Classification

Ifinatamab deruxtecan is the internationally recognized nonproprietary name for this investigational biopharmaceutical.[4] Throughout its development, it has also been referred to by several code names, most notably DS-7300 and DS-7300a, which are commonly used in scientific literature and clinical trial registries.[1] Other synonyms include I-DXd and variations such as anti-B7-H3/DXd ADC DS-7300a and MABX-9001a, the latter referring to the specific monoclonal antibody component.[4]

The DrugBank accession number for Ifinatamab deruxtecan is DB18212 [5], and its Chemical Abstracts Service (CAS) Number is 2484870-92-8.[24] These unique identifiers are crucial for accurate tracking and information retrieval in chemical and pharmacological databases.

Ifinatamab deruxtecan is classified as a biotechnology product, specifically an Antibody-Drug Conjugate (ADC).[1] ADCs are a class of targeted therapies designed to deliver potent cytotoxic agents directly to cancer cells, thereby minimizing systemic exposure and associated toxicity to healthy tissues. Some sources may also categorize it broadly as an immunomodulator due to its antibody component targeting an immune-related protein (B7-H3) and its potential to induce immunogenic cell death; however, its primary mechanism of action is direct cytotoxicity mediated by the payload.[2]

B. Developers and Strategic Collaborations

Ifinatamab deruxtecan was discovered and initially developed by Daiichi Sankyo, a Japanese pharmaceutical company with a strong focus on oncology and a proprietary DXd ADC technology platform.[1] This platform forms the basis for several of Daiichi Sankyo's ADCs, including Ifinatamab deruxtecan.

In October 2023, Daiichi Sankyo entered into a significant global collaboration with Merck & Co., Inc., Rahway, N.J., USA (known as MSD outside the United States and Canada) to jointly develop and commercialize Ifinatamab deruxtecan, along with two other DXd ADCs: patritumab deruxtecan (HER3-DXd) and raludotatug deruxtecan (R-DXd).[1] Under the terms of this agreement, Daiichi Sankyo and Merck share responsibilities for global development and commercialization. Notably, Daiichi Sankyo retains exclusive rights for Ifinatamab deruxtecan in Japan and is solely responsible for its manufacturing and supply globally.[7]

This type of strategic alliance is common in the pharmaceutical industry, particularly for high-potential oncology assets. It allows the originator company (Daiichi Sankyo), with its specialized platform technology and manufacturing expertise, to partner with a global pharmaceutical leader (Merck), which brings extensive clinical development capabilities, regulatory experience, and broad commercial reach. Such partnerships aim to accelerate and expand the drug's development program, maximize its therapeutic potential across various indications and geographies, and ultimately enhance its market access if approved. The substantial financial commitments often involved in these collaborations also reflect the perceived value and future prospects of the partnered assets. For Ifinatamab deruxtecan, this collaboration provides a robust framework for its comprehensive clinical investigation and potential global launch.

III. Mechanism of Action and Pharmacology

Ifinatamab deruxtecan's mechanism of action is predicated on its sophisticated design as an ADC, integrating specific targeting with potent cell-killing capabilities. This is achieved through Daiichi Sankyo's proprietary DXd ADC technology platform.[1]

A. Antibody-Drug Conjugate (ADC) Construct: The DXd Platform

The I-DXd molecule consists of three key components: a targeting antibody, a cleavable linker, and a cytotoxic payload.

1. Targeting Moiety: Anti-B7-H3 Humanized Monoclonal Antibody (MABX-9001a)

The specificity of Ifinatamab deruxtecan is conferred by its antibody component, a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) designated MABX-9001a.4 This antibody is engineered to bind with high affinity and selectivity to the human B7 homolog 3 protein (B7-H3), also known as CD276.1 By targeting B7-H3, which is overexpressed on the surface of various cancer cells relative to normal tissues, the antibody serves as a delivery vehicle, guiding the ADC to the tumor site.1

2. Linker Technology: Tetrapeptide-Based Cleavable Linker

The MABX-9001a antibody is connected to the cytotoxic payload via an enzymatically cleavable linker.1 This linker is specifically a tetrapeptide-based linker, designed for stability in systemic circulation to prevent premature release of the payload, which could lead to off-target toxicity.1 Upon internalization of the ADC into the target cancer cell and trafficking to the lysosomal compartment, the linker is cleaved by lysosomal enzymes, such as cathepsins, which are typically upregulated in tumor cells.2 While the precise sequence for I-DXd's linker is often generally described as "tetrapeptide-based," Daiichi Sankyo's DXd ADC platform commonly employs a Glycine-Glycine-Phenylalanine-Glycine (GGFG) sequence.38 The United States Adopted Name (USAN) description for Ifinatamab deruxtecan details a thioether linkage with N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]glycylglycyl-L-phenylalanyl-N-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-1-yl]amino]-2-oxoethoxy]methyl]glycinamide, confirming a GGFG motif within the linker structure that connects to the payload.4 This selective cleavage mechanism is critical for ensuring that the cytotoxic payload is released preferentially within the tumor cells.

3. Cytotoxic Payload: Deruxtecan (DXd) – A Topoisomerase I Inhibitor

The cytotoxic component of Ifinatamab deruxtecan is DXd, a highly potent derivative of exatecan (DX-8951), which functions as a DNA topoisomerase I inhibitor.1 The USAN documentation also refers to this payload as MAAA-1181a, a camptothecin derivative.4 Topoisomerase I is an enzyme crucial for relieving torsional stress in DNA during replication and transcription. Inhibition of topoisomerase I by DXd leads to the stabilization of the enzyme-DNA cleavable complex, resulting in DNA single-strand breaks. These breaks, when encountered by the replication machinery, are converted into lethal DNA double-strand breaks, ultimately triggering cell cycle arrest and apoptosis (programmed cell death).2 Ifinatamab deruxtecan has a drug-to-antibody ratio (DAR) of approximately 4, meaning each antibody molecule carries an average of four DXd payload molecules, contributing to its potent antitumor activity.18

The consistent use of the DXd topoisomerase I inhibitor payload and a GGFG-based cleavable linker across several of Daiichi Sankyo's ADCs, including the approved and clinically successful Enhertu® (trastuzumab deruxtecan) and Datopotamab deruxtecan, points to a well-established platform technology. This established platform provides a foundation of knowledge regarding chemistry, manufacturing, and controls (CMC), as well as an understanding of the general pharmacological properties and potential class-specific toxicities, such as ILD/pneumonitis, which can inform the development and monitoring strategies for Ifinatamab deruxtecan.

B. Molecular Target: B7 Homolog 3 Protein (B7-H3/CD276)

1. B7-H3 Expression in Tumors and Prognostic Significance

B7-H3, also known as CD276, is a type I transmembrane protein and a member of the B7 family of immunoregulatory proteins.1 Unlike some other immune checkpoint molecules with restricted expression, B7-H3 is frequently and highly overexpressed on the surface of a wide variety of human solid tumors. These include, but are not limited to, esophageal squamous cell carcinoma (ESCC), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), prostate cancer, breast cancer, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma (HNSCC), colorectal cancer, and hepatocellular carcinoma.1 Immunohistochemical (IHC) studies have confirmed B7-H3 protein expression not only on tumor cells themselves but also on tumor-associated vasculature, endothelium, and fibrous stromal cells within the tumor microenvironment.45

Crucially, the expression of B7-H3 in normal tissues is generally limited or low.[2] This differential expression pattern between tumor and normal tissues is a key attribute that makes B7-H3 an attractive target for cancer therapies like ADCs, as it offers the potential for selective drug delivery to malignant cells while sparing healthy ones. Furthermore, elevated B7-H3 expression has often been correlated with more aggressive tumor biology, increased risk of metastasis, resistance to therapy, and overall poor prognosis in various cancer types.[1]

2. Rationale for Targeting B7-H3 in Oncology

The widespread overexpression of B7-H3 on cancer cells, its association with unfavorable clinical outcomes, and its limited presence in normal tissues provide a strong rationale for its selection as a therapeutic target.1 B7-H3 is implicated in various aspects of cancer progression, including promoting tumor cell proliferation, survival, invasion, and metastasis, as well as contributing to immune evasion by modulating T-cell responses.2 Despite its compelling profile as a target, there are currently no B7-H3-directed medicines approved for the treatment of any cancer.1 This highlights a significant unmet medical need and an opportunity for novel therapies like Ifinatamab deruxtecan to make an impact. Targeting B7-H3 with an ADC aims to leverage its tumor-associated expression for the selective delivery of a potent cytotoxic payload, thereby offering a potentially effective and more targeted treatment approach. The broad expression profile of B7-H3 supports the investigation of I-DXd across a wide range of tumor types, a strategy reflected in its extensive clinical development program. However, early clinical observations have indicated that the level of B7-H3 expression does not always directly correlate with the clinical response to I-DXd.13 This suggests that while B7-H3 expression is essential for initial targeting, other factors such as the efficiency of ADC internalization, intracellular trafficking, payload sensitivity, and characteristics of the tumor microenvironment may also significantly influence therapeutic efficacy. This complexity underscores the need for further research to identify more precise predictive biomarkers for I-DXd.

C. Pharmacodynamics

1. Binding, Internalization, and Intracellular Payload Release

The pharmacodynamic cascade of Ifinatamab deruxtecan begins with the high-affinity binding of its anti-B7-H3 monoclonal antibody component to B7-H3 protein expressed on the surface of tumor cells.2 This specific binding event is crucial for initiating the targeted delivery process. Following binding, the ADC-B7-H3 complex undergoes receptor-mediated endocytosis, a cellular process where the cell membrane invaginates to internalize the bound complex into intracellular vesicles.2 Preclinical studies have demonstrated efficient, target-dependent internalization and payload delivery into tumor cells.6

Once internalized, the ADC is trafficked through the endo-lysosomal pathway. Within the acidic environment of lysosomes, which are rich in proteolytic enzymes, the cleavable tetrapeptide-based linker is enzymatically degraded.[2] This targeted cleavage within the lysosome ensures the release of the active cytotoxic payload, DXd, directly into the cytoplasm of the cancer cell, minimizing its exposure to the systemic circulation and healthy tissues.

2. Inhibition of DNA Topoisomerase I and Induction of DNA Damage

Upon its release into the cancer cell, the DXd payload exerts its cytotoxic effect by inhibiting DNA topoisomerase I.1 Topoisomerase I is a nuclear enzyme essential for relaxing DNA supercoiling during critical cellular processes such as DNA replication, transcription, and repair. DXd intercalates into the DNA and stabilizes the transient covalent complex formed between topoisomerase I and DNA (the cleavable complex), preventing the re-ligation of the DNA strand. This results in the accumulation of DNA single-strand breaks. When the DNA replication machinery encounters these stabilized complexes and single-strand breaks, they are converted into more deleterious DNA double-strand breaks.2 The accumulation of these DNA lesions triggers cellular DNA damage responses, leading to cell cycle arrest, and ultimately, apoptosis (programmed cell death) of the cancer cell.2 Studies with similar ADCs utilizing DXd have shown induction of DNA damage markers like phosphorylated Chk1 and apoptosis markers such as cleaved caspase-3.42

3. Bystander Antitumor Effect

A significant feature of the DXd payload used in Ifinatamab deruxtecan and other Daiichi Sankyo ADCs is its ability to exert a "bystander effect".2 DXd is membrane-permeable, meaning that once it is released within a targeted B7-H3-expressing cancer cell, it can diffuse through the cell membrane and enter adjacent tumor cells.2 These neighboring cells can then be killed by DXd, even if they express low or no B7-H3 on their surface. This bystander killing mechanism is particularly advantageous in tumors that exhibit heterogeneous antigen expression, as it allows the ADC to exert a broader antitumor effect beyond only the cells directly targeted by the antibody. This can potentially overcome some forms of resistance related to antigen loss or heterogeneous expression within the tumor mass, contributing to a more profound and durable therapeutic response.

IV. Clinical Development Program

A. Overview of Clinical Strategy and Investigated Indications

The clinical development of Ifinatamab deruxtecan is characterized by a comprehensive and ambitious strategy, aiming to evaluate its efficacy and safety across a diverse range of solid tumors. The program initiated with first-in-human Phase 1/2 studies designed to assess safety, tolerability, pharmacokinetics, and preliminary antitumor activity, as well as to determine the recommended dose for expansion (RP2D). The IDeate-PanTumor01 study (NCT04145622) served this foundational role, exploring various advanced solid malignancies.[10]

Based on encouraging signals from these early-phase investigations, the program has rapidly advanced to later-stage development. Pivotal Phase 3 trials have been initiated in several key indications where significant unmet medical needs exist and where I-DXd has shown promising activity. These primary focus areas include Small Cell Lung Cancer (SCLC) [1], Esophageal Squamous Cell Carcinoma (ESCC) [1], and metastatic Castration-Resistant Prostate Cancer (mCRPC).[8]

Beyond these lead indications, the IDeate-PanTumor02 study (NCT06330064), a Phase 1b/2 basket trial, is designed to further assess I-DXd's activity in a broader array of tumor types, including endometrial cancer, head and neck squamous cell carcinoma (HNSCC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), urothelial cancer (UC), ovarian cancer (OVC), and triple-negative breast cancer (TNBC).[47]

Furthermore, the clinical strategy also incorporates the evaluation of Ifinatamab deruxtecan in combination regimens. For example, the IDeate-Lung03 trial is investigating I-DXd in combination with atezolizumab, with or without carboplatin, as a first-line induction or maintenance therapy for ES-SCLC.[12] Similarly, the IDeate-Prostate02 umbrella substudy (NCT06863272) is exploring I-DXd in combination with other agents, such as MK-5684 or androgen receptor pathway inhibitors (ARPIs), in mCRPC.[31] This multifaceted approach, encompassing monotherapy across various cancers and combination strategies, aims to fully elucidate the therapeutic potential of Ifinatamab deruxtecan. The aggressive pursuit of multiple Phase 3 trials concurrently in distinct tumor types with high unmet needs reflects the strong confidence the developers have in I-DXd, likely based on compelling early-phase data. This strategy of exploring both monotherapy and combination treatments is typical for promising oncology drugs, seeking to identify optimal therapeutic niches, enhance efficacy, and potentially overcome resistance mechanisms.

B. Key Clinical Trials Overview

The clinical development program for Ifinatamab deruxtecan is extensive, involving multiple trials across different phases and tumor types. A summary of key trials is presented in Table 1.

Table 1: Summary of Key Clinical Trials for Ifinatamab Deruxtecan

Trial ID (NCT Number)	Phase	Official Title (Abbreviated/Purpose)	Status (as of latest snippets)	Conditions Investigated	Key Endpoints (Primary)	Estimated/Actual Enrollment	Sponsor(s)
IDeate-PanTumor01 (NCT04145622)	1/2	Study of I-DXd in Advanced Solid Malignant Tumors	Ongoing, results presented	Advanced solid tumors (SCLC, ESCC, mCRPC, sqNSCLC, EC, HNSCC etc.)	MTD, RP2D, Safety, ORR	~250 (initial reports varied, e.g., N=195, N=70 for specific analyses)	Daiichi Sankyo (early collaboration with Sarah Cannon)
IDeate-Lung01 (NCT05280470)	2	Study of I-DXd in Extensive-Stage SCLC (Dose Optimization & Extension)	Ongoing, interim results presented	Extensive-Stage Small Cell Lung Cancer (ES-SCLC), previously treated	ORR by BICR	~158 (88 in Part 1, ~70 in Part 2)	Daiichi Sankyo / Merck
IDeate-Lung02 (NCT06203210)	3	Study of I-DXd vs TPC in Relapsed SCLC	Recruiting/Open to enrollment	Relapsed Small Cell Lung Cancer (SCLC) (after 1 prior platinum line)	ORR by BICR, Overall Survival (OS)	~540	Daiichi Sankyo / Merck
IDeate-Lung03 (NCT number not consistently provided)	1b/2	Study of I-DXd + Atezolizumab +/- Carboplatin in 1L ES-SCLC	Mentioned as planned/ongoing	Extensive-Stage Small Cell Lung Cancer (ES-SCLC), first-line	Safety, ORR (expected)	Not specified	Daiichi Sankyo / Merck
IDeate-Esophageal01 (NCT06644781)	3	Study of I-DXd vs TPC in Advanced/Metastatic ESCC	Recruiting	Esophageal Squamous Cell Carcinoma (ESCC), pretreated	Overall Survival (OS)	~510	Daiichi Sankyo / Merck
IDeate-Prostate01 (MK-2400-001 / NCT06925737)	3	Study of I-DXd vs Docetaxel in mCRPC	Recruiting	Metastatic Castration-Resistant Prostate Cancer (mCRPC)	Radiographic PFS (rPFS), Overall Survival (OS)	~1440	Merck
IDeate-Prostate02 (MK-2400-01A / NCT06863272)	1/2	Umbrella Substudy of I-DXd Combinations or Monotherapy in mCRPC	Not yet recruiting (planned start June 2025)	Metastatic Castration-Resistant Prostate Cancer (mCRPC)	Safety, RP2D for combos, PSA response	~360	Merck
IDeate-PanTumor02 (NCT06330064)	1b/2	Study of I-DXd in Recurrent/Metastatic Solid Tumors (Basket trial)	Enrollment ongoing	EC, HNSCC, PDAC, CRC, HCC, Esophageal/GEJ Adeno, UC, OVC, TNBC	ORR per investigator, Safety (HCC cohort)	~520	Daiichi Sankyo / Merck

Status, enrollment, and endpoint details are based on the most recent available information from the provided snippets and may be subject to change. TPC = Treatment of Physician's Choice; MTD = Maximum Tolerated Dose; RP2D = Recommended Phase 2 Dose; ORR = Objective Response Rate; BICR = Blinded Independent Central Review; PFS = Progression-Free Survival; OS = Overall Survival; EC = Endometrial Cancer; HNSCC = Head and Neck Squamous Cell Carcinoma; PDAC = Pancreatic Ductal Adenocarcinoma; CRC = Colorectal Cancer; HCC = Hepatocellular Carcinoma; UC = Urothelial Cancer; OVC = Ovarian Cancer; TNBC = Triple-Negative Breast Cancer.

Data Sources for Table 1: 1

This table provides a centralized overview of the clinical development landscape for Ifinatamab deruxtecan, facilitating a quick understanding of the breadth and depth of its investigation.

C. Detailed Review of Significant Clinical Trials:

1. IDeate-PanTumor01 (NCT04145622): Phase 1/2, Advanced Solid Tumors

The IDeate-PanTumor01 study is a first-in-human, open-label, multicenter Phase 1/2 trial designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of Ifinatamab deruxtecan in patients with various advanced solid malignant tumors.7 The study was sponsored by Daiichi Sankyo, with early phases conducted in collaboration with Sarah Cannon Research Institute.10

Part 1 of the study focused on dose escalation, administering I-DXd at doses ranging from 0.8 mg/kg to 16.0 mg/kg intravenously every three weeks (Q3W) to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D).10 Part 2 involved dose expansion cohorts to further assess safety and efficacy in specific tumor types, including SCLC, ESCC, mCRPC, squamous NSCLC (sqNSCLC), endometrial cancer, and HNSCC.10 Patients enrolled were typically heavily pretreated, often having received a median of four or more prior lines of therapy.10

The trial is ongoing, with multiple interim results presented at major oncology conferences such as the World Conference on Lung Cancer (WCLC), the European Society for Medical Oncology (ESMO) Congress, and the ASCO Genitourinary Cancers Symposium.10

Key findings from IDeate-PanTumor01 have been instrumental in shaping the subsequent development of I-DXd. The study demonstrated promising objective response rates (ORRs) across several tumor types. For instance, in patients with SCLC (n=21, receiving ≥6.4 mg/kg), a confirmed ORR of 52.4% was observed, including one complete response (CR) and ten partial responses (PRs). The median duration of response (DOR) in this SCLC cohort was 5.9 months, with a median progression-free survival (PFS) of 5.6 months and a median overall survival (OS) of 12.2 months (data cutoff January 31, 2023, presented at WCLC 2023).10

In patients with mCRPC (n=59, ESMO 2023 data), the confirmed ORR was 25%, with a median DOR of 6.4 months, median PFS of 4.8 months (n=73), and median OS of 13.5 months (n=73).29 For ESCC (n=28, ESMO 2023 data), the confirmed ORR was 21%, median DOR 3.5 months, median PFS 2.8 months, and median OS 7.0 months.29 In sqNSCLC (n=13, ESMO 2023 data), the confirmed ORR was 31% with a median DOR of 4.1 months.29

The safety profile of I-DXd in IDeate-PanTumor01 was reported as generally manageable, with TEAEs consistent with those expected for ADCs employing topoisomerase I inhibitor payloads.13 This foundational trial successfully established initial safety parameters, identified the RP2D (typically 12 mg/kg Q3W for many cohorts), and provided crucial early efficacy signals that justified the advancement of I-DXd into indication-specific Phase 2 and pivotal Phase 3 studies.

2. IDeate-Lung01 (NCT05280470): Phase 2, Extensive-Stage SCLC

Building on the encouraging signals in SCLC from IDeate-PanTumor01, the IDeate-Lung01 trial was initiated. This is a global, multicenter, randomized, open-label, two-part Phase 2 study specifically designed to evaluate the safety and efficacy of Ifinatamab deruxtecan in patients with ES-SCLC.1 The trial is sponsored by Daiichi Sankyo and Merck.

Part 1 of the study, the dose-optimization phase, randomized patients (who had received at least one prior line of platinum-based chemotherapy and a maximum of three prior lines of therapy) to receive I-DXd at either 8 mg/kg Q3W or 12 mg/kg Q3W.11 The primary endpoint for this part was ORR as assessed by BICR. Part 2, the dose-expansion phase, is designed to enroll patients who have received a minimum of two previous lines of systemic therapy, who will receive I-DXd at the selected optimal dose from Part 1 (which was determined to be 12 mg/kg Q3W).12

The trial is ongoing, with interim results from Part 1 presented at conferences including WCLC 2024 and JSMO 2025.11 As of the April 25, 2024 data cutoff for the dose-optimization part (88 patients treated; 46 in the 8 mg/kg arm, 42 in the 12 mg/kg arm):

• The confirmed ORR by BICR was 54.8% (95% CI, 38.7–70.2) in the 12 mg/kg cohort, compared to 26.1% (95% CI, 14.3–41.1) in the 8 mg/kg cohort.[11]
• The median DOR was 4.2 months (95% CI, 3.5–7.0) for the 12 mg/kg dose and 7.9 months (95% CI, 4.1–NE) for the 8 mg/kg dose.[12]
• Median PFS was 5.5 months (95% CI, 4.2–6.7) for 12 mg/kg versus 4.2 months (95% CI, 2.8–5.6) for 8 mg/kg.[12]
• Median OS was 11.8 months (95% CI, 8.9–15.3) for 12 mg/kg versus 9.4 months (95% CI, 7.8–15.9) for 8 mg/kg.[12] Notably, intracranial activity was observed in patients with baseline brain metastases, with a CNS confirmed ORR of 50.0% in the 12 mg/kg group (n=10 with brain target lesions) and 66.7% in the 8 mg/kg group (n=6 with brain target lesions).[16] Based on the totality of data, particularly the substantially higher ORR, the 12 mg/kg Q3W dose was selected as the optimal dose for the extension part of IDeate-Lung01 and for further development in SCLC, including the Phase 3 IDeate-Lung02 trial.[11] The safety profile was manageable, with ILD/pneumonitis reported (see Section VI). The selection of the 12 mg/kg dose, despite some initial numerical advantages in DOR and OS for the 8 mg/kg arm in early data cuts, likely reflects the overall strength of the efficacy signal (particularly ORR) and confidence in managing the toxicity profile at this higher dose as more data matures.

3. IDeate-Lung02 (NCT06203210): Phase 3, Relapsed SCLC

IDeate-Lung02 is a global, multicenter, randomized, open-label Phase 3 trial evaluating Ifinatamab deruxtecan in patients with relapsed SCLC.1 This pivotal study, sponsored by Daiichi Sankyo and Merck, aims to enroll approximately 540 adult patients who have experienced disease progression after only one prior line of platinum-based chemotherapy (with a chemotherapy-free interval of ≥30 days).46

Patients are randomized 1:1 to receive either Ifinatamab deruxtecan (12 mg/kg IV Q3W) or Treatment of Physician's Choice (TPC), which includes topotecan, amrubicin (where approved and available), or lurbinectedin.46 The dual primary endpoints are ORR as assessed by BICR (per RECIST v1.1) and OS.46 Secondary endpoints include investigator-assessed ORR, PFS (by BICR and investigator), DOR, disease control rate (DCR), time to response (TTR), patient-reported outcomes, safety, pharmacokinetics, and immunogenicity.46

Randomization is stratified by chemotherapy-free interval after first-line therapy (<90 days vs. ≥90 days), choice of TPC, prior treatment with PD-(L)1 inhibitors (yes vs. no), and presence/history of asymptomatic brain metastases (yes vs. no).46 Patients with asymptomatic brain metastases are eligible for enrollment.46 Key exclusion criteria include prior treatment with B7-H3 targeted agents or topoisomerase I inhibitors.49

The trial is actively recruiting globally, with the first patient dosed in August 2024.19 IDeate-Lung02 is a critical registration-intent study designed to confirm the efficacy and safety of I-DXd in the second-line setting for SCLC, an area with significant unmet medical need and historically poor outcomes.

4. IDeate-Esophageal01 (NCT06644781): Phase 3, Advanced/Metastatic ESCC

The IDeate-Esophageal01 trial is a global, multicenter, open-label, randomized Phase 3 study evaluating Ifinatamab deruxtecan in patients with unresectable advanced or metastatic ESCC.1 This trial, sponsored by Daiichi Sankyo and Merck, was initiated based on promising efficacy signals for I-DXd in ESCC patients observed in the IDeate-PanTumor01 Phase 1/2 trial.1

The study plans to enroll approximately 510 patients who have experienced disease progression after receiving no more than one prior line of systemic therapy in the advanced or metastatic setting, which must have included platinum-based chemotherapy and an immune checkpoint inhibitor.1 Patients will be randomized to receive either Ifinatamab deruxtecan (12 mg/kg IV Q3W) or TPC, consisting of paclitaxel, docetaxel, or irinotecan hydrochloride.1

The primary endpoint is OS. Secondary endpoints include PFS and ORR (both assessed by BICR), DOR, DCR, and safety.1 Key eligibility criteria include histologically or cytologically documented unresectable locally advanced or metastatic ESCC, age ≥18 years, and adequate tumor tissue for correlative studies.50 Exclusion criteria include prior treatment with B7-H3 targeted agents or topoisomerase I inhibitors, and clinically active CNS metastases.50

The trial is actively recruiting, with the first patient dosed in May 2025.1 This pivotal study aims to establish I-DXd as a new treatment option for patients with pretreated advanced ESCC.

5. IDeate-Prostate01 (MK-2400-001 / NCT06925737): Phase 3, mCRPC

The IDeate-Prostate01 trial is a Phase 3, open-label study designed to evaluate Ifinatamab deruxtecan in patients with mCRPC.8 This Merck-sponsored trial will compare I-DXd monotherapy against docetaxel plus prednisone.8 Eligible patients must have progressed on androgen deprivation therapy (ADT) and have received one or two prior androgen receptor pathway inhibitors (ARPIs), but must not have received prior taxane-based chemotherapy for mCRPC.51

The co-primary endpoints are rPFS and OS.8 The trial aims to enroll approximately 1440 participants.51 The study status is recruiting, with an anticipated start in May 2025 noted in some reports.8 This trial seeks to address the unmet need for effective therapies in later-line mCRPC, building upon the encouraging signals observed for I-DXd in this patient population within the IDeate-PanTumor01 study.

6. IDeate-Prostate02 (MK-2400-01A / NCT06863272): Phase 1/2 Umbrella Substudy, mCRPC

IDeate-Prostate02 is a Phase 1/2, open-label umbrella substudy conducted under the MK-2400-U01 master protocol, sponsored by Merck.8 The primary purpose is to assess the safety and efficacy of Ifinatamab deruxtecan administered either as monotherapy or in combination with other anticancer agents in participants with mCRPC.56 Combination arms may include I-DXd plus MK-5684 or I-DXd plus an ARPI (abiraterone or enzalutamide).56

Key goals include determining safe and tolerable dose levels for the combination regimens and evaluating prostate-specific antigen (PSA) responses.56 The study is planned to enroll approximately 360 participants.31 As of early 2025, the trial was listed as not yet recruiting, with a planned start date around June 2025.8 This study will explore strategies to potentially enhance the activity of I-DXd or overcome resistance mechanisms in mCRPC.

7. IDeate-PanTumor02 (NCT06330064): Phase 1b/2, Recurrent/Metastatic Solid Tumors

IDeate-PanTumor02 is a global, multicenter, open-label, single-arm, parallel-cohort Phase 1b/2 study designed to further evaluate the efficacy and safety of Ifinatamab deruxtecan across a range of recurrent or metastatic solid tumors.34 This basket trial, sponsored by Daiichi Sankyo and Merck, plans to enroll approximately 520 adult patients who have received at least one prior systemic therapy for their specific tumor type and have an ECOG PS of ≤1.47

The study is divided into Stage 1 and Stage 2 for each cohort, with progression to Stage 2 dependent on sufficient safety and efficacy data from Stage 1 (approximately 20 patients per stage per cohort).47 Tumor types being investigated include endometrial cancer (EC), HNSCC, PDAC, CRC, HCC, adenocarcinoma of the esophagus/gastroesophageal junction/stomach, UC, OVC, and TNBC.47

Most cohorts will receive I-DXd at 12 mg/kg Q3W. The HCC cohort includes a safety run-in part with a planned starting dose of 8 mg/kg Q3W, which may be escalated based on tolerability.47 The primary endpoints are ORR per investigator assessment for all cohorts and safety for the HCC safety run-in portion.47 Secondary endpoints include safety, DOR, PFS, OS, DCR, pharmacokinetics, and immunogenicity.47 Enrollment is ongoing.47 This trial aims to rapidly assess I-DXd's activity across a wider spectrum of B7-H3-expressing tumors, potentially identifying new indications for further development.

8. IDeate-Lung03 (NCT number if available): Phase 1b/2, ES-SCLC

The IDeate-Lung03 trial is a Phase 1b/2 study evaluating Ifinatamab deruxtecan in combination with atezolizumab, with or without carboplatin, as a first-line induction or maintenance therapy for patients with ES-SCLC.12 This study explores the potential of moving I-DXd into earlier lines of therapy for SCLC and combining it with standard immunotherapy and chemotherapy regimens. Further details on its status and specific design would require more recent information.

The extensive and strategically designed clinical trial program for Ifinatamab deruxtecan, covering multiple tumor types, lines of therapy, and both monotherapy and combination approaches, underscores the significant investment and belief in its potential as a novel cancer therapeutic. Success in the ongoing pivotal Phase 3 trials could pave the way for regulatory approvals, establishing I-DXd as a first-in-class B7-H3 targeted ADC and offering new hope for patients with difficult-to-treat cancers.

V. Clinical Efficacy

The clinical efficacy of Ifinatamab deruxtecan has been evaluated in various tumor types, primarily through the IDeate-PanTumor01 and IDeate-Lung01 trials, with data presented at major oncology congresses.

A. Efficacy in Small Cell Lung Cancer (SCLC)

SCLC is an aggressive malignancy with limited treatment options, especially in the relapsed/refractory setting. Ifinatamab deruxtecan has demonstrated notable activity in this patient population.

• IDeate-PanTumor01 (Phase 1/2, Dose Escalation): In a cohort of 21 heavily pretreated SCLC patients receiving I-DXd at doses ≥6.4 mg/kg, the confirmed ORR was 52.4% (including 1 CR and 10 PRs). The median DOR was 5.9 months (95% CI: 2.8–7.5), median PFS was 5.6 months (95% CI: 3.9–8.1), and median OS was 12.2 months (95% CI: 6.4–NA), as of the January 31, 2023 data cutoff (presented at WCLC 2023).[10] These results were considered highly promising in a population with a median of 2 prior lines of therapy.
• IDeate-Lung01 (Phase 2, Dose Optimization in ES-SCLC): Interim results as of April 25, 2024, further elucidated the dose-response relationship:
• 12 mg/kg cohort (n=42): Confirmed ORR by BICR was 54.8% (95% CI: 38.7–70.2). Median DOR was 4.2 months (95% CI: 3.5–7.0). Median PFS was 5.5 months (95% CI: 4.2–6.7). Median OS was 11.8 months (95% CI: 8.9–15.3).[11]
• 8 mg/kg cohort (n=46): Confirmed ORR by BICR was 26.1% (95% CI: 14.3–41.1). Median DOR was 7.9 months (95% CI: 4.1–NE). Median PFS was 4.2 months (95% CI: 2.8–5.6). Median OS was 9.4 months (95% CI: 7.8–15.9).[11] The substantially higher ORR with the 12 mg/kg dose led to its selection for further development, despite the DOR and OS appearing numerically longer for the 8 mg/kg dose in this interim analysis, which could be influenced by factors such as patient heterogeneity or differing follow-up maturity at the time of data cut.
• Intracranial Activity: The IDeate-Lung01 study also reported encouraging intracranial activity in patients with baseline brain metastases. In the subset with brain target lesions (n=16), CNS confirmed ORR was 50.0% for the 12 mg/kg group and 66.7% for the 8 mg/kg group.[16]

These consistent efficacy signals in SCLC, particularly the high ORRs in a refractory setting, strongly support the ongoing Phase 3 development (IDeate-Lung02) and highlight I-DXd's potential to address a major unmet need.

B. Efficacy in Esophageal Squamous Cell Carcinoma (ESCC)

In patients with heavily pretreated ESCC, I-DXd has also shown signs of antitumor activity:

• IDeate-PanTumor01 (ESMO 2023 data, n=28): A confirmed ORR of 21% was observed. The median DOR was 3.5 months (95% CI: 2.4–NE), median PFS was 2.8 months (95% CI: 1.6–4.2), and median OS was 7.0 months (95% CI: 4.8–12.2).[29] Earlier presentations from this trial also noted responses in ESCC patients.[1] While more modest than in SCLC, this activity in a difficult-to-treat population was considered sufficient to warrant advancement to the Phase 3 IDeate-Esophageal01 trial.

C. Efficacy in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

I-DXd has demonstrated clinically meaningful activity in late-line mCRPC:

• IDeate-PanTumor01 (ESMO 2023 data, n=59 for ORR/DOR, n=73 for PFS/OS): A confirmed ORR of 25% was reported. The median DOR was 6.4 months (95% CI: 2.8–10.6). Median PFS was 4.8 months (95% CI: 3.9–5.9), and median OS was 13.5 months (95% CI: 10.3–16.6).[29]
• Earlier data from this trial (ASCO-GU 2022, n=29, data cutoff Aug 2021) showed 6 PRs (4 confirmed) and 15 patients with stable disease, along with improvements in PSA levels.[30] These findings support the ongoing Phase 3 trial (IDeate-Prostate01) and the exploration of combination strategies (IDeate-Prostate02).

D. Efficacy in Other Solid Tumors

The broad expression of B7-H3 has prompted investigation of I-DXd in various other solid tumors:

• IDeate-PanTumor01 (ESMO 2023 data): In patients with squamous NSCLC (n=13), a confirmed ORR of 31% and a median DOR of 4.1 months (95% CI: 2.8–NE) were observed.[29] Earlier reports also mentioned responses in endometrial cancer and HNSCC.[10] Across 118 patients with various solid tumors in an earlier analysis of IDeate-PanTumor01, an overall ORR of 32% (33 confirmed responses, equating to 28%) was reported.[10]
• IDeate-PanTumor02 (NCT06330064): This ongoing Phase 1b/2 basket trial is actively enrolling patients to systematically evaluate I-DXd in additional tumor types such as endometrial cancer, HNSCC, PDAC, CRC, HCC, urothelial cancer, ovarian cancer, and TNBC, which will provide more comprehensive data on its activity spectrum.[47]

E. Biomarker Analyses

The role of B7-H3 expression as a predictive biomarker for I-DXd efficacy is still under investigation.

• Initial analyses from the IDeate-PanTumor01 study indicated that while B7-H3 expression was moderate to high in most enrolled patients, there was no clear correlation observed between the level of B7-H3 expression (e.g., by H-score) and ORR, PFS, or OS in the SCLC cohort [13] or generally across other tumor types evaluated.[29] This lack of a straightforward correlation suggests that B7-H3 expression, while necessary for antibody targeting, might not be the sole determinant of response. Other factors, such as the efficiency of ADC internalization, lysosomal processing, intracellular payload concentration, tumor microenvironment characteristics, inherent tumor sensitivity to topoisomerase I inhibitors, or the contribution of the bystander effect, could also play significant roles. Further biomarker research, potentially exploring these alternative factors or more nuanced assessments of B7-H3 (e.g., subcellular localization, isoform expression), is needed to refine patient selection strategies if a predictive biomarker is to be established. The ability of DXd to exert a bystander effect might also contribute to efficacy in tumors with heterogeneous or lower levels of B7-H3 expression, complicating simple biomarker correlations.

The consistent antitumor activity demonstrated by Ifinatamab deruxtecan across multiple, heavily pretreated advanced solid tumors, especially the notable ORRs in SCLC, underpins its extensive ongoing clinical development. The dose-optimization efforts, such as in IDeate-Lung01, are crucial for defining the best therapeutic window, balancing the enhanced efficacy seen at higher doses (e.g., 12 mg/kg) against the potential for increased toxicity.

VI. Safety and Tolerability Profile

The safety and tolerability of Ifinatamab deruxtecan have been evaluated across its clinical development program, primarily in the IDeate-PanTumor01 and IDeate-Lung01 trials. The overall safety profile appears generally manageable and consistent with other ADCs utilizing topoisomerase I inhibitor payloads, particularly those from the DXd platform.[7]

A. Overview of Common Treatment-Emergent Adverse Events (TEAEs)

The most frequently reported TEAEs (any grade) across studies include gastrointestinal and hematologic toxicities, as well as constitutional symptoms.

• Common TEAEs (typically occurring in ≥20% of patients) encompass nausea, fatigue, anemia, vomiting, decreased appetite, infusion-related reactions (IRRs), chills, diarrhea, dehydration, constipation, dyspnea, arthralgia, and hyponatremia.[12]
• For example, in the IDeate-Lung01 SCLC trial (12 mg/kg cohort, data cutoff April 2024), common TEAEs included nausea (50.0%), decreased appetite (42.9%), anemia (35.7%), and decreased neutrophil count/neutropenia (33.3%).[16] In the SCLC cohort of IDeate-PanTumor01 (N=22), nausea (59.1%) and fatigue (50.0%) were predominant.[13]

B. Serious Adverse Events (SAEs) and Grade ≥3 TEAEs

A notable proportion of patients experience Grade ≥3 TEAEs.

• In the IDeate-PanTumor01 SCLC cohort (N=22), 36.4% of patients experienced Grade ≥3 TEAEs.[13]
• In the IDeate-Lung01 SCLC trial (data cutoff April 2024), Grade ≥3 TEAEs occurred in 43.5% of patients in the 8 mg/kg arm and 50.0% in the 12 mg/kg arm.[12]
• In an early analysis of the mCRPC cohort from IDeate-PanTumor01 (n=29, data cutoff Aug 2021), Grade ≥3 TEAEs were reported in 34.5% of patients, with anemia (17.2%) being the most common. No Grade ≥3 treatment-related SAEs were reported in this specific early mCRPC dataset.[30]

C. Adverse Events of Special Interest (AESI)

1. Interstitial Lung Disease (ILD) / Pneumonitis: Incidence, Management

ILD/pneumonitis is a known and serious AESI associated with ADCs containing the DXd payload, such as Enhertu®.43 Careful monitoring for this adverse event is a critical aspect of the Ifinatamab deruxtecan clinical program.

• IDeate-PanTumor01 SCLC cohort (N=22): One event of Grade 2 treatment-related ILD/pneumonitis was reported, as determined by an independent adjudication committee.[13]
• IDeate-Lung01 SCLC trial (data cutoff April 2024): Adjudicated drug-related ILD/pneumonitis was reported in:
• 8 mg/kg cohort: 8.7% (4 out of 46 patients), comprising Grade 2 (n=3) and Grade 5 (n=1) events.[16]
• 12 mg/kg cohort: 11.9% (5 out of 42 patients), comprising Grade 1 (n=1), Grade 2 (n=3), and Grade 3 (n=1) events.[16] The majority of these adjudicated drug-related ILD cases were Grade 1 or 2. The overall incidence was reported as similar between the dose cohorts and consistent with previous reports for I-DXd.[16]
• IDeate-PanTumor01 mCRPC cohort (n=29, early data): No cases of ILD/pneumonitis were reported in this initial analysis.[30]

The occurrence of ILD/pneumonitis, including rare fatal cases, underscores the need for vigilant patient monitoring, prompt investigation of respiratory symptoms, and adherence to established management guidelines, which typically involve withholding or discontinuing the drug and administering corticosteroids based on severity.

D. Dose-Limiting Toxicities (DLTs), Dose Modifications, and Discontinuations

• DLTs: In the dose-escalation part of IDeate-PanTumor01, initial reports covering 70 patients indicated no DLTs observed up to the 16.0 mg/kg dose level.[10]
• Dose Modifications and Discontinuations:
• In the IDeate-PanTumor01 SCLC cohort (N=22), TEAEs led to I-DXd discontinuation in 22.7% of patients (5 patients).[13]
• In the IDeate-Lung01 SCLC trial (data cutoff April 2024), TEAEs leading to treatment discontinuation occurred in 6.5% of patients in the 8 mg/kg arm and 16.7% in the 12 mg/kg arm.[16]
• In the early mCRPC cohort of IDeate-PanTumor01 (n=29), no patients discontinued due to TEAEs, though dose interruptions (21.4%) and reductions (6.9%) occurred.[30]

The safety profile of Ifinatamab deruxtecan shares characteristics with other ADCs in its class, particularly those utilizing the DXd payload. This includes a pattern of gastrointestinal and hematologic toxicities, and the notable risk of ILD/pneumonitis. The observed dose-dependent trend in some TEAEs, with higher rates of Grade ≥3 events and discontinuations at the 12 mg/kg dose compared to 8 mg/kg in the IDeate-Lung01 SCLC trial, highlights the critical balance between maximizing efficacy and maintaining acceptable tolerability. The selection of 12 mg/kg for Phase 3 studies suggests a determination that the efficacy benefits at this dose level are significant and that the associated risks, including ILD/pneumonitis, are considered manageable with appropriate monitoring and intervention strategies.

Table 2: Summary of Common and Serious Treatment-Emergent Adverse Events with Ifinatamab Deruxtecan (Selected Data from SCLC Cohorts)

Adverse Event Category	Any Grade Frequency (%) (IDeate-Lung01, 12mg/kg, n=42)	Grade ≥3 Frequency (%) (IDeate-Lung01, 12mg/kg, n=42)	Notes / Other Cohort Data (IDeate-PanTumor01 SCLC, N=22)
Gastrointestinal
Nausea	50.0	(Grade 3: 4.5% in PanTumor01)	59.1% any grade; 4.5% Grade ≥3
Vomiting	Not specified in 73 summary, but 31.0% in mCRPC 30	Not specified	27.3% any grade; 0% Grade ≥3
Decreased Appetite	42.9	(Grade 3: 4.5% in PanTumor01)	22.7% any grade; 4.5% Grade ≥3
Diarrhea	Not specified in 73 summary, but 27.6% in mCRPC 30	Not specified	13.6% any grade; 0% Grade ≥3
Constipation	Not specified in 73 summary	Not specified	18.2% any grade; 4.5% Grade ≥3
Hematologic
Anemia	35.7	(Most common G≥3 in mCRPC: 17.2% 30)	27.3% any grade; 4.5% Grade ≥3
Neutropenia/Neutrophil Count Dec.	33.3	(Higher in 12mg/kg vs 8mg/kg in Lung01 73)	(Platelet count dec. 13.6% any grade, 0% G≥3 in PanTumor01)
White Blood Cell Count Dec.	21.4	Not specified	Not specified
Constitutional/General
Fatigue	Not specified in 73 summary, but 50.0% in PanTumor01 SCLC	0% (PanTumor01 SCLC)	50.0% any grade; 0% Grade ≥3
Infusion-Related Reactions (IRR)	Not specified in 73 summary, but 34.5% in mCRPC 30	All Gr 1/2 in mCRPC 30	13.6% any grade; 0% Grade ≥3
Pyrexia (Fever)	Not specified in 73 summary	Not specified	18.2% any grade; 0% Grade ≥3
Asthenia	1.4 (12mg/kg) vs 13.0 (8mg/kg) in Lung01 73	Not specified	Not specified
Respiratory
ILD/Pneumonitis (adjudicated drug-related)	11.9% (5/42)	Grade 3: 2.4% (1/42)	PanTumor01 SCLC: 4.5% (1/22) Grade 2. Lung01 8mg/kg: 8.7% (Gr2 n=3, Gr5 n=1) 16
Dyspnea	Not specified in 73 summary	Not specified	13.6% any grade; 0% Grade ≥3
Overall
Any TEAE Grade ≥3	50.0	50.0	36.4%
TEAE leading to Discontinuation	16.7	16.7	22.7%

Note: Frequencies can vary based on patient population, dose, and specific trial. This table presents selected data for illustrative purposes. ILD/Pneumonitis rates are specifically for adjudicated drug-related events.

VII. Regulatory Status and Designations

A. Current Investigational Status Worldwide

Ifinatamab deruxtecan is currently an investigational agent. Its safety and efficacy have not yet been established by regulatory authorities, and it has not received marketing approval for any indication in any country.[1] The drug is under active global clinical development, with numerous Phase 1, 2, and 3 trials ongoing or planned across various regions, including North America, Europe, and Asia, as detailed in Section IV.

B. Orphan Drug Designations (ODD)

Orphan Drug Designation is a status granted by regulatory agencies to drugs intended for the treatment, prevention, or diagnosis of a rare disease or condition. This designation provides pharmaceutical companies with incentives, such as tax credits, user fee waivers, and potential market exclusivity upon approval, to encourage the development of treatments for conditions that affect small patient populations and might otherwise lack commercial viability.

Ifinatamab deruxtecan has received ODD for the treatment of Small Cell Lung Cancer (SCLC) from several major regulatory bodies:

• United States Food and Drug Administration (US FDA): Granted in April 2023.[1]
• European Commission (based on European Medicines Agency (EMA) recommendation): Granted in February 2024.[18]
• Japan (Pharmaceuticals and Medical Devices Agency - PMDA): Orphan drug designation has been granted in Japan for SCLC.[1]
• Taiwan (Food and Drug Administration - TFDA): Orphan drug designation has also been granted in Taiwan for SCLC.[1]

The granting of these ODDs underscores the significant unmet medical need in SCLC, an aggressive and difficult-to-treat cancer, and acknowledges the potential of Ifinatamab deruxtecan to provide a meaningful therapeutic benefit for this patient population. These designations can facilitate aspects of the drug development and review process.

C. Breakthrough Therapy Designations (BTD)

Breakthrough Therapy Designation is a process designed by the US FDA to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). A similar expedited pathway in Europe is the PRIME (PRIority MEdicines) scheme by the EMA.

Based on the currently available research snippets, there is no explicit statement confirming that Ifinatamab deruxtecan itself has received Breakthrough Therapy Designation from the US FDA or a comparable designation like PRIME from the EMA for any indication. Several provided documents mention BTD for a different Daiichi Sankyo ADC, Datopotamab deruxtecan, for specific lung cancer indications.[35] It is important not to conflate the regulatory designations of different products, even from the same developer. The absence of a reported BTD for Ifinatamab deruxtecan to date might reflect various factors, including the stage of data maturation at the time of potential submissions to regulatory agencies, the specific comparative efficacy data available, or strategic decisions by the developers. This is an aspect of its regulatory journey that may evolve as more clinical data become available.

The multiple ODDs for SCLC clearly signal regulatory recognition of I-DXd's potential in a high-need area. This status provides valuable development incentives. The current lack of a specific BTD for I-DXd, based on the provided information, does not diminish its therapeutic potential but indicates that, as of the latest reports, the criteria for such a designation may not have been met or pursued for the available data packages.

VIII. Discussion

Ifinatamab deruxtecan (I-DXd) represents a significant investigational agent in the field of oncology, embodying the advancements in antibody-drug conjugate technology. Its development targets B7-H3, a protein broadly expressed across numerous solid tumors with limited presence in normal tissues, making it a compelling candidate for targeted cancer therapy.[1]

A. Summary of Therapeutic Potential and Unmet Needs Addressed

The therapeutic potential of I-DXd is underscored by the promising clinical activity observed in heavily pretreated patient populations across several difficult-to-treat cancers. In Small Cell Lung Cancer (SCLC), a disease notorious for its aggressive nature and poor prognosis after first-line therapy, I-DXd has demonstrated objective response rates (ORRs) exceeding 50% at the 12 mg/kg dose in early phase trials, along with encouraging duration of response (DOR) and overall survival (OS) data in some cohorts.[10] Similarly, in advanced Esophageal Squamous Cell Carcinoma (ESCC) and metastatic Castration-Resistant Prostate Cancer (mCRPC), conditions with limited effective treatment options in later lines, I-DXd has shown clinically meaningful response rates.[1] These findings are particularly relevant given that there are currently no approved therapies specifically targeting B7-H3.[1] The ability of I-DXd to induce responses in patients who have exhausted standard therapies highlights its potential to address significant unmet medical needs.

The strategic selection of B7-H3 as a target is pivotal. Its widespread expression on tumor cells and association with poor prognosis across diverse malignancies suggest that I-DXd could have broad applicability.[1] Ifinatamab deruxtecan, by leveraging Daiichi Sankyo's DXd ADC platform—known for its potent topoisomerase I inhibitor payload and stable, cleavable linker system—aims to maximize tumor cell killing while managing systemic toxicity. This platform has a precedent of success with other ADCs like Enhertu® and Datopotamab deruxtecan, lending credibility to the technological approach underpinning I-DXd. This established foundation may allow for more informed anticipation and management of certain class-related effects, such as the potential for interstitial lung disease (ILD).

B. Positioning within the B7-H3 Targeted Therapy Landscape

Ifinatamab deruxtecan is positioned as a potential first-in-class B7-H3 directed ADC.[1] While B7-H3 is an attractive target, the landscape of B7-H3-directed therapies is evolving, with other investigational agents, including other ADCs, bispecific antibodies, and CAR T-cells, also in various stages of development.[8] For instance, vobramitamab duocarmazine (MacroGenics, though development was discontinued due to toxicity), GSK5764227 (GSK/Hansoh), and YL201 (MediLink) are other B7-H3 ADCs that have been in clinical trials.[8]

The key differentiating factors for I-DXd within this emerging field will likely be its specific antibody characteristics, the properties of the DXd payload (including its potency and bystander effect), and the overall efficacy and safety profile demonstrated in robust clinical trials. The choice of a topoisomerase I inhibitor payload in I-DXd contrasts with other payloads like DNA alkylating agents (e.g., duocarmycin used in vobramitamab duocarmazine, which faced toxicity issues leading to its discontinuation [8]) or pyrrolobenzodiazepines (PBDs). This difference in payload chemistry can significantly influence both the antitumor activity and the toxicity profile. The extensive clinical program undertaken by Daiichi Sankyo and Merck, targeting multiple tumor types and lines of therapy, aims to firmly establish I-DXd's role and potential advantages.

C. Strengths and Limitations of Available Data

The primary strength of the available data for Ifinatamab deruxtecan lies in the consistent and promising ORRs observed in heavily pretreated patients across several challenging tumor types, particularly SCLC.[10] The initiation of multiple Phase 3 trials based on these early signals indicates a strong belief in its clinical potential. The broad development program itself is a strength, designed to thoroughly evaluate the drug's utility.

However, limitations exist. Much of the detailed efficacy data, especially for indications beyond SCLC, comes from Phase 1/2 studies with relatively small cohort sizes for specific tumor types. While ORR data are encouraging, mature DOR and OS data from larger, randomized controlled trials are essential for definitive conclusions and are still awaited for most indications. The current lack of a clear, predictive biomarker based on B7-H3 expression levels is another limitation [13]; while B7-H3 is the target, its expression level alone does not consistently correlate with response. This complicates precise patient selection and suggests that other biological factors are at play, or that the bystander effect may allow efficacy even in tumors with lower or heterogeneous B7-H3 expression. Identifying robust predictive biomarkers remains an important area for future research. Finally, the risk of ILD/pneumonitis, a known class effect of DXd ADCs, requires careful management and long-term safety monitoring, although current data suggest a manageable profile consistent with the platform.[13]

D. Future Research Directions and Potential Combination Strategies

The future of Ifinatamab deruxtecan hinges on the outcomes of its ongoing and planned Phase 3 trials (IDeate-Lung02 for SCLC, IDeate-Esophageal01 for ESCC, IDeate-Prostate01 for mCRPC).[1] Positive results from these studies would be critical for regulatory approvals.

Beyond monotherapy, a significant avenue for future research lies in combination strategies. The IDeate-Lung03 trial is already exploring I-DXd with atezolizumab +/- carboplatin in first-line ES-SCLC, aiming to improve upon current standards of care.[12] Similarly, the IDeate-Prostate02 study is investigating I-DXd with other targeted agents in mCRPC.[56] These combinations could potentially enhance antitumor activity, overcome resistance mechanisms, or expand the utility of I-DXd to earlier lines of therapy or different patient subgroups.

Further research will also need to focus on:

• Biomarker Development: Identifying more precise predictive biomarkers beyond B7-H3 expression to optimize patient selection. This could involve exploring factors related to ADC internalization, payload sensitivity, tumor microenvironment composition, or co-occurring genomic alterations.
• Mechanisms of Resistance: Understanding how tumors develop resistance to I-DXd will be crucial for developing strategies to overcome it, potentially through rational combination therapies or sequential treatments.
• Long-Term Safety: Continued monitoring in larger patient populations and over longer durations will be necessary to fully characterize the long-term safety profile of I-DXd.

The comprehensive and multi-pronged clinical development strategy, including both monotherapy and combination approaches in various cancers and treatment settings, positions Ifinatamab deruxtecan as a significant asset with the potential to address multiple unmet needs in oncology. The success of this strategy will depend on the outcomes of the pivotal trials and the ability to effectively manage its safety profile.

IX. Conclusion

Ifinatamab deruxtecan (I-DXd / DS-7300) has emerged as a highly promising investigational antibody-drug conjugate, distinguished by its novel targeting of B7-H3 and the utilization of Daiichi Sankyo's clinically validated DXd ADC technology. The extensive global clinical development program, a joint effort by Daiichi Sankyo and Merck & Co., Inc., is rapidly evaluating its potential across a wide spectrum of solid tumors, with notable progress in Small Cell Lung Cancer, Esophageal Squamous Cell Carcinoma, and metastatic Castration-Resistant Prostate Cancer.

Early to mid-stage clinical trial data have consistently demonstrated encouraging antitumor activity, particularly impressive objective response rates in heavily pretreated patient populations for whom existing therapeutic options are often scarce and offer limited benefit. The drug's mechanism, involving targeted delivery of a potent topoisomerase I inhibitor payload (DXd) to B7-H3 expressing cells, coupled with a bystander effect, provides a strong rationale for its efficacy in heterogeneous tumor environments.

The safety profile of Ifinatamab deruxtecan, while including notable toxicities such as gastrointestinal and hematologic adverse events, appears generally manageable. The risk of interstitial lung disease/pneumonitis, a known concern with DXd-based ADCs, requires vigilant monitoring and management but has thus far been reported at rates comparable to other agents in this class. The ongoing Phase 3 trials are critical and will provide more definitive data on the benefit-risk profile of I-DXd in larger, randomized settings.

Regulatory recognition through multiple Orphan Drug Designations for SCLC underscores the potential of Ifinatamab deruxtecan to address significant unmet medical needs. While the precise role of B7-H3 expression level as a predictive biomarker requires further elucidation, the broad activity observed suggests I-DXd could benefit a wide range of patients.

In conclusion, Ifinatamab deruxtecan stands as a significant advancement in the ADC field and a leading candidate in the B7-H3 targeted therapy space. Should the ongoing pivotal trials yield positive results, I-DXd has the potential to become a first-in-class therapeutic agent, offering a new standard of care and improving outcomes for patients battling several challenging and aggressive cancers. Its continued development is keenly watched by the oncology community.

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42 Nakada, T., et al. (2024). Raludotatug Deruxtecan, a CDH6-Targeting Antibody-Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models. Mol Cancer Ther. (Epub ahead of print, related to DXd bystander effect).

43 Enhertu HCP Website. Mechanism of Action | ENHERTU® (fam-trastuzumab deruxtecan-nxki).

44 Feng, Y., et al. (2024). Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability. Cell Rep Med, 5(2), 101395.

3 Yang, S., et al. (2021). B7-H3/CD276: An Emerging Cancer Immunotherapy. Front Immunol, 12, 701006.

82 ADC Review / Journal of Antibody-drug Conjugates. (January 17, 2025). Datopotamab deruxtecan Approved in the USA.

33 Daiichi Sankyo. (January 17, 2025). DATROWAY® Approved in the U.S. for Patients With Previously Treated Metastatic HR Positive, HER2 Negative Breast Cancer.

39 The Antibody Society. YABS1723: Datopotamab deruxtecan.

38 IRIS Biotech GmbH. (September 17, 2024). GGFG Motif for ADC Construction.

40 MedChemExpress. Deruxtecan (MC-GGFG-DXD).

41 MedChemExpress. Deruxtecan analog (Product page for Deruxtecan).

7 Merck & Co., Inc. (Date not specified, likely May 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated in Certain Patients with Pretreated Advanced or Metastatic Esophageal Squamous Cell Carcinoma.7

1 Drugs.com. (May 19, 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated in Certain Patients with Pretreated Advanced or Metastatic Esophageal Squamous Cell Carcinoma.1

11 Oncweekly. (Date not specified, refers to WCLC 2024). I-DXd Demonstrates Efficacy in ES-SCLC: IDeate-Lung01 Trial.

12 Merck & Co., Inc. (September 7, 2024). Ifinatamab Deruxtecan Continues to Demonstrate Promising Objective Response Rates in Patients with Extensive-Stage Small Cell Lung Cancer in IDeate-Lung01 Phase 2 Trial.

48 West Cancer Center. Trial Listing: Daiichi Sankyo DS7300-188 Relapsed Small Cell Lung Cancer (IDeate-Lung02, NCT06203210).

49 Australian New Zealand Clinical Trials Registry (ANZCTR). Trial Review: ACTRN (related to IDeate-Lung02, NCT06203210 eligibility).

56 Veeva Clinical Trials Directory. A Clinical Study of Ifinatamab Deruxtecan-based Treatment Combinations or as Monotherapy to Treat Metastatic Castrate Resistant Prostate Cancer (mCRPC) (MK-2400-01A/IDeate-Prostate02, NCT06863272).

51 Carebox Health. Trial Listing: A Clinical Study of Ifinatamab Deruxtecan (I-DXd) in People With Metastatic Prostate Cancer (MK-2400-001/IDeate-Prostate01, NCT06925737).

57 National Cancer Institute. Clinical Trial Listing: NCI-2025-03341 (MK-2400-01A/IDeate-Prostate02, NCT06863272).

58 MSD Clinical Trials Transparency. Study Overview: MK-2400-01A (IDeate-Prostate02, NCT06863272).

8 OncologyPipeline (ApexOnco). (Date not specified, refers to IDeate-Prostate01 and IDeate-Pantumor01). Merck and Daiichi look for more ifinatamab white space.

10 Larvol Clin. Trial Detail: IDeate-Pantumor 01 / NCT04145622 (General trial info and some results).

45 Shinozaki, E., et al. (2022). B7-H3 expression in tumor cells and tumor-associated macrophages is a favorable prognostic factor for patients with colorectal cancer. Cancer Sci, 113(8), 2849-2860. (Provides IHC context for B7-H3).

81 Zhang, J., et al. (2023). B7-H3-redirected CAR T cells for cancer immunotherapy. J Hematol Oncol, 16(1), 53. (Mentions other B7-H3 ADCs).

60 CareAcross. Trial Listing: A Study of Ifinatamab Deruxtecan in Subjects With Advanced or Metastatic ESCC IDeateEsophageal01 (NCT06644781).

61 Synapse by PatSnap. Disease Overview: Esophageal Squamous Cell Carcinoma (Lists NCT06644781).

52 Targeted Oncology. (March 2024). FDA Fast Tracks PT886 in CLDN18.2+ Pancreatic Cancer (Mentions IDeate-Lung01 NCT05280470, IDeate-Lung02 NCT06203210, IDeate-PanTumor01 NCT04145622, IDeate-PanTumor02 NCT06330064).

53 Targeted Oncology. (October 2023). Motixafortide Shows Benefit to First-Line Pancreatic Cancer Treatment in Phase 2 Trial (Mentions IDeate-Lung01 NCT05280470, IDeate-Lung02 NCT06203210, IDeate-PanTumor01 NCT04145622, IDeate-PanTumor02 NCT06330064).

50 CancerNetwork. (May 19, 2025). Phase 3 IDeate-Esophageal01 Trial Initiated for Unresectable ESCC (NCT06644781).

22 Daiichi Sankyo US. (May 19, 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....

16 Hayashi, H., et al. (JSMO 2025 Presentation). IDeate-Lung01: A Phase 2 trial of ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer (NCT05280470).

62 Veeva Clinical Trials Directory. Ifinatamab Deruxtecan (I-DXd) in Subjects With Pretreated Extensive-Stage Small Cell Lung Cancer (ES-SCLC) (IDeate-Lung01, NCT05280470).

63 Hayashi, H., et al. (JSMO 2025 Poster). IDeate-Lung02: Phase 3 study of ifinatamab deruxtecan (I-DXd) in relapsed small cell lung cancer (NCT06203210).

46 Owonikoko, T. K., et al. (ASCO 2024 Poster, TPS8126). IDeate-Lung02: A phase 3, randomized, open-label study of ifinatamab deruxtecan (I-DXd) vs treatment of physician's choice (TPC) in relapsed small cell lung cancer (SCLC) (NCT06203210).

7 Merck & Co., Inc. (May 19, 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....7

54 Mount Sinai. Clinical Trial Listing: A Study To Evaluate The Efficacy And Safety Of Ifinatamab Deruxtecan (I-DXD) in Subjects With Recurrent/Metastatic Solid Tumors (IDeate-PanTumor02, NCT06330064).

57 National Cancer Institute. Clinical Trial Listing: NCI-2025-03341 (MK-2400-01A/IDeate-Prostate02, NCT06863272).57

31 Trial Medpath. Drug Profile: Ifinatamab deruxtecan (Lists NCT06925737, NCT06863272).

47 ASCO Publications. (2024). Abstract 482024: IDeate-PanTumor02: A phase 1b/2 study to evaluate the efficacy and safety of ifinatamab deruxtecan (I-DXd) in patients (pts) with recurrent or metastatic solid tumors (NCT06330064).

55 National Cancer Institute. Clinical Trial Listing: NCI-2025-00431 (DS7300-203/IDeate-PanTumor02, NCT06330064).

57 National Cancer Institute. Clinical Trial Listing: NCI-2025-03341 (MK-2400-01A/IDeate-Prostate02, NCT06863272).57

64 Larvol Clin. Trial Detail: MK-2400-001 / NCT06925737 (IDeate-Prostate01).

34 Daiichi Sankyo. (May 20, 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....

19 Daiichi Sankyo. (August 1, 2024). IDeate-Lung02 Phase 3 Trial of Ifinatamab Deruxtecan Initiated in Patients with Relapsed Small Cell Lung Cancer.

7 Merck & Co., Inc. (May 19, 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....

21 Merck & Co., Inc. (August 1, 2024). IDeate-Lung02 Phase 3 Trial of Ifinatamab Deruxtecan Initiated in Patients with Relapsed Small Cell Lung Cancer.

10 Larvol Clin. Trial Detail: IDeate-Pantumor 01 / NCT04145622 (Includes WCLC 2023 SCLC results).

17 eCancer. (September 9, 2024). WCLC 2024: Antibody–drug conjugate I-DXd shows clinically meaningful response in patients with extensive-stage small cell lung cancer (IDeate-Lung01).

19 Daiichi Sankyo. (August 1, 2024). IDeate-Lung02 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....19

20 FDA Office of Orphan Products Development. Orphan Drug Designation: Ifinatamab deruxtecan (for SCLC).

78 Daiichi Sankyo US. (January 13, 2025). Datopotamab Deruxtecan Granted Priority Review in the U.S. for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer.

37 BioSpace. (January 13, 2025). Datopotamab Deruxtecan Granted Priority Review in the U.S.....

7 Merck & Co., Inc. (May 19, 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....7

10 Larvol Clin. Trial Detail: IDeate-Pantumor 01 / NCT04145622 (Includes ESMO 2021 data, no DLTs up to 16mg/kg).

57 National Cancer Institute. Clinical Trial Listing: NCI-2025-03341 (MK-2400-01A/IDeate-Prostate02, NCT06863272).57

59 Larvol Clin. Trial Detail: NCT06863272 (IDeate-Prostate02).

47 ASCO Publications. (2024). Abstract 482024: IDeate-PanTumor02... (NCT06330064).47

55 National Cancer Institute. Clinical Trial Listing: NCI-2025-00431 (DS7300-203/IDeate-PanTumor02, NCT06330064).55

65 Dana-Farber Cancer Institute. Trial Listing: IDeate-Prostate01 (NCT06925737).

64 Larvol Clin. Trial Detail: MK-2400-001 / NCT06925737 (IDeate-Prostate01).64

29 Paz-Ares, L., et al. (ESMO Congress 2023). 690P Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with advanced solid tumors: Updated clinical and biomarker results from a phase I/II study (IDeate-PanTumor01, NCT04145622). Ann Oncol, 34(Suppl 2), S481-S482.

13 Johnson, M.L., et al. (WCLC 2023, Abstract OA05.05, as cited in Practicing Clinicians eCase). Ifinatamab Deruxtecan (I-DXd; DS-7300) in Patients with Refractory SCLC: A Subgroup Analysis of a Phase 1/2 Study (IDeate-PanTumor01, NCT04145622).

83 ResearchGate. Publication: 690P Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with advanced solid tumors: Updated clinical and biomarker results from a phase I/II study.29

30 Patel, M.R., et al. (ASCO GU 2022, Abstract 87). DS-7300 (B7-H3 DXd-ADC) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): A subgroup analysis of a phase 1/2 multicenter study (IDeate-PanTumor01, NCT04145622). J Clin Oncol, 40(6_suppl), 87-87.

14 OncoLive. (Date not specified, refers to WCLC 2023). Ifinatamab Deruxtecan Elicits Clinical Activity in SCLC (IDeate-PanTumor01, NCT04145622).

19 Daiichi Sankyo. (August 1, 2024). IDeate-Lung02 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....19

21 Merck & Co., Inc. (August 1, 2024). IDeate-Lung02 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....21

73 Daiichi Sankyo US. (September 7, 2024). Ifinatamab Deruxtecan Continues to Demonstrate Promising Objective Response Rates... IDeate-Lung01 Phase 2 Trial.

35 Daiichi Sankyo. (December 9, 2024). Datopotamab Deruxtecan Granted Breakthrough Therapy Designation in U.S.....

36 Daiichi Sankyo US. (December 9, 2024). Datopotamab Deruxtecan Granted Breakthrough Therapy Designation in U.S.....

76 Withpower.com. Trial Information: Ifinatamab Deruxtecan for Small Cell Lung Cancer (Phase 3, relates to ILD for T-DXd).

15 Daiichi Sankyo. (September 10, 2023). Ifinatamab Deruxtecan Continues to Demonstrate Durable Responses in Patients With Advanced Small Cell Lung Cancer in Early Trial.

77 Pharmaceutical Technology. (Date not specified). Ifinatamab deruxtecan by Daiichi Sankyo for Small-Cell Lung Cancer: Likelihood of Approval.

22 Daiichi Sankyo US. (May 19, 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....22

7 Merck & Co., Inc. (May 19, 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....7

74 Targeted Oncology. (May 19, 2025). First Patient Dosed in Study of I-DXd in Esophageal Cancer.

37 BioSpace. (January 13, 2025). Datopotamab Deruxtecan Granted Priority Review in the U.S.....37

35 Daiichi Sankyo. (December 9, 2024). Datopotamab Deruxtecan Granted Breakthrough Therapy Designation in U.S.....35

23 Orphanet. Orphan Drug: Ifinatamab deruxtecan.

20 FDA Office of Orphan Products Development. Orphan Drug Designation: Ifinatamab deruxtecan (for SCLC).20

19 Daiichi Sankyo. (August 1, 2024). IDeate-Lung02 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....19

21 Merck & Co., Inc. (August 1, 2024). IDeate-Lung02 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....21

75 Targeted Oncology. (May 19, 2025). AI Tool Earns FDA Breakthrough Device Designation in Pancreatic Cancer (Mentions I-DXd trial initiations).

78 Daiichi Sankyo US. (January 13, 2025). Datopotamab Deruxtecan Granted Priority Review in the U.S.....78

79 Business Wire. (December 20, 2024). Datopotamab Deruxtecan Application in the EU for Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer Voluntarily Withdrawn.

80 Daiichi Sankyo. Press Release Archive (General listing).

66 ClinicalTrials.gov. NCT06203210: A Study of Ifinatamab Deruxtecan (I-DXd) Versus Treatment of Physician's Choice (TPC) in Subjects With Relapsed Small Cell Lung Cancer (SCLC) (IDeate-Lung02). (Accessed via search, specific details not in snippet but confirms trial existence).

67 ClinicalTrials.gov. NCT06863272: A Phase 1/2, Open-label Umbrella Substudy of MK-2400-U01 Master Protocol to Evaluate the Safety and Efficacy of Ifinatamab Deruxtecan-based Treatment Combinations or Ifinatamab Deruxtecan Alone in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (IDeate-Prostate02). (Accessed via search, confirms trial existence).

68 ClinicalTrials.gov. NCT04145622: Study of Ifinatamab Deruxtecan (DS-7300a) in Participants With Advanced Solid Malignant Tumors (IDeate-Pantumor01). (Accessed via search, confirms trial existence).

50 CancerNetwork. (May 19, 2025). Phase 3 IDeate-Esophageal01 Trial Initiated for Unresectable ESCC (NCT06644781). (Provides some details for this trial).

16 Hayashi, H., et al. (JSMO 2025 Presentation). IDeate-Lung01: A Phase 2 trial of ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer (NCT05280470). (Provides detailed results for IDeate-Lung01).

63 Hayashi, H., et al. (JSMO 2025 Poster). IDeate-Lung02: Phase 3 study of ifinatamab deruxtecan (I-DXd) in relapsed small cell lung cancer (NCT06203210). (Provides details for this trial).

7 Merck & Co., Inc. (May 19, 2025). IDeate-Esophageal01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated....7

57 National Cancer Institute. Clinical Trial Listing: NCI-2025-03341 (MK-2400-01A/IDeate-Prostate02, NCT06863272).57

47 ASCO Publications. (2024). Abstract 482024: IDeate-PanTumor02... (NCT06330064).47

69 ClinicalTrials.gov. NCT06644781: A Phase 3, Multicenter, Randomized, Open-label Study of Ifinatamab Deruxtecan (I-DXd) in Subjects With Pretreated Advanced or Metastatic Esophageal Squamous Cell Carcinoma (ESCC) (IDeate-Esophageal01). (Accessed via search, confirms trial existence).

70 ClinicalTrials.gov. NCT05280470: Ifinatamab Deruxtecan (I-DXd) in Subjects With Pretreated Extensive-Stage Small Cell Lung Cancer (ES-SCLC) (IDeate-Lung01). (Accessed via search, confirms trial existence).

66 ClinicalTrials.gov. NCT06203210: A Study of Ifinatamab Deruxtecan (I-DXd) Versus Treatment of Physician's Choice (TPC) in Subjects With Relapsed Small Cell Lung Cancer (SCLC) (IDeate-Lung02).66

68 ClinicalTrials.gov. NCT04145622: Study of Ifinatamab Deruxtecan (DS-7300a) in Participants With Advanced Solid Malignant Tumors (IDeate-Pantumor01).68

67 ClinicalTrials.gov. NCT06863272: A Phase 1/2, Open-label Umbrella Substudy... (IDeate-Prostate02).67

71 ClinicalTrials.gov. NCT06330064: A Study to Evaluate the Efficacy and Safety of Ifinatamab Deruxtecan (I-DXd) in Participants With Recurrent or Metastatic Solid Tumors (IDeate-PanTumor02). (Accessed via search, confirms trial existence).

72 ClinicalTrials.gov. NCT06925737: A Clinical Study of Ifinatamab Deruxtecan (I-DXd) in People With Metastatic Prostate Cancer (MK-2400-001/IDeate-Prostate01). (Accessed via search, confirms trial existence).

User Query: Generate a comprehensive report on the medication with the following details: - Name: Ifinatamab deruxtecan - Name (English): Ifinatamab deruxtecan - DrugBank ID: DB18212 - Type: Biotech - CAS Number: 2484870-92-8.# Ifinatamab Deruxtecan (DS-7300): A Comprehensive Review of a Novel B7-H3-Directed Antibody-Drug Conjugate

I. Executive Summary

Ifinatamab deruxtecan (I-DXd), also known by its development codes DS-7300 and DS-7300a, is an investigational antibody-drug conjugate (ADC) emerging as a significant candidate in oncology therapeutics. It is meticulously engineered to target B7-H3 (CD276), a transmembrane protein frequently overexpressed across a wide array of solid tumors and often associated with poor prognosis.[1] The construct of Ifinatamab deruxtecan features a humanized anti-B7-H3 IgG1 monoclonal antibody (MABX-9001a) [4], a cleavable tetrapeptide-based linker, and Daiichi Sankyo’s proprietary topoisomerase I inhibitor payload, DXd.[1] This design leverages Daiichi Sankyo's DXd ADC technology, which has demonstrated success in other approved ADCs.

The development of Ifinatamab deruxtecan is a collaborative effort between Daiichi Sankyo, the originator and manufacturer, and Merck & Co., Inc. (known as MSD outside the U.S. and Canada), who are jointly responsible for its global clinical development and commercialization, with certain regional exceptions.[1] This partnership signifies a substantial commitment to the drug's potential, combining Daiichi Sankyo's specialized ADC platform expertise with Merck's extensive experience in global oncology drug development and marketing. Such collaborations are common in the biopharmaceutical industry to pool resources, share risks, and expedite the journey of promising assets to patients by leveraging complementary strengths in research, manufacturing, clinical execution, and market access.

Ifinatamab deruxtecan is being investigated across a broad spectrum of malignancies. Promising early clinical activity has been observed in indications such as Small Cell Lung Cancer (SCLC), Esophageal Squamous Cell Carcinoma (ESCC), and metastatic Castration-Resistant Prostate Cancer (mCRPC), leading to the initiation of pivotal Phase 3 trials in these settings.[1] Objective response rates (ORRs) in heavily pretreated SCLC patients have been notably high, around 52-55% with the 12 mg/kg dose in early trials.[10] The drug's safety profile is considered manageable, though it includes adverse events common to cytotoxic agents and a particular adverse event of special interest (AESI) associated with DXd payloads: Interstitial Lung Disease (ILD)/pneumonitis, which requires careful monitoring.[13]

Reflecting its potential in areas of high unmet need, Ifinatamab deruxtecan has received Orphan Drug Designation (ODD) for SCLC from regulatory authorities in the United States, European Union, Japan, and Taiwan.[1] The extensive clinical program, encompassing various tumor types and combination strategies, underscores a comprehensive approach to maximize the therapeutic potential of targeting B7-H3.

II. Introduction to Ifinatamab Deruxtecan (DS-7300/I-DXd)

A. Drug Identity and Classification

Ifinatamab deruxtecan is the internationally recognized nonproprietary name for this investigational biopharmaceutical.[4] Throughout its development, it has also been referred to by several code names, most notably DS-7300 and DS-7300a, which are commonly used in scientific literature and clinical trial registries.[1] Other synonyms include I-DXd and variations such as anti-B7-H3/DXd ADC DS-7300a and MABX-9001a, the latter referring to the specific monoclonal antibody component.[4]

The DrugBank accession number for Ifinatamab deruxtecan is DB18212 [9], and its Chemical Abstracts Service (CAS) Number is 2484870-92-8.[24] These unique identifiers are crucial for accurate tracking and information retrieval in chemical and pharmacological databases.

Ifinatamab deruxtecan is classified as a biotechnology product, specifically an Antibody-Drug Conjugate (ADC).[1] ADCs are a class of targeted therapies designed to deliver potent cytotoxic agents directly to cancer cells, thereby minimizing systemic exposure and associated toxicity to healthy tissues. Some sources may also categorize it broadly as an immunomodulator due to its antibody component targeting an immune-related protein (B7-H3) and its potential to induce immunogenic cell death; however, its primary mechanism of action is direct cytotoxicity mediated by the payload.[2]

B. Developers and Strategic Collaborations

Ifinatamab deruxtecan was discovered and initially developed by Daiichi Sankyo, a Japanese pharmaceutical company with a strong focus on oncology and a proprietary DXd ADC technology platform.[1] This platform forms the basis for several of Daiichi Sankyo's ADCs, including Ifinatamab deruxtecan.

In October 2023, Daiichi Sankyo entered into a significant global collaboration with Merck & Co., Inc., Rahway, N.J., USA (known as MSD outside the United States and Canada) to jointly develop and commercialize Ifinatamab deruxtecan, along with two other DXd ADCs: patritumab deruxtecan (HER3-DXd) and raludotatug deruxtecan (R-DXd).[1] Under the terms of this agreement, Daiichi Sankyo and Merck share responsibilities for global development and commercialization. Notably, Daiichi Sankyo retains exclusive rights for Ifinatamab deruxtecan in Japan and is solely responsible for its manufacturing and supply globally.[7]

This type of strategic alliance is common in the pharmaceutical industry, particularly for high-potential oncology assets. It allows the originator company (Daiichi Sankyo), with its specialized platform technology and manufacturing expertise, to partner with a global pharmaceutical leader (Merck), which brings extensive clinical development capabilities, regulatory experience, and broad commercial reach. Such partnerships aim to accelerate and expand the drug's development program, maximize its therapeutic potential across various indications and geographies, and ultimately enhance its market access if approved. The substantial financial commitments often involved in these collaborations also reflect the perceived value and future prospects of the partnered assets. For Ifinatamab deruxtecan, this collaboration provides a robust framework for its comprehensive clinical investigation and potential global launch.

III. Mechanism of Action and Pharmacology

Ifinatamab deruxtecan's mechanism of action is predicated on its sophisticated design as an ADC, integrating specific targeting with potent cell-killing capabilities. This is achieved through Daiichi Sankyo's proprietary DXd ADC technology platform.[1]

A. Antibody-Drug Conjugate (ADC) Construct: The DXd Platform

The I-DXd molecule consists of three key components: a targeting antibody, a cleavable linker, and a cytotoxic payload.

1. Targeting Moiety: Anti-B7-H3 Humanized Monoclonal Antibody (MABX-9001a)

The specificity of Ifinatamab deruxtecan is conferred by its antibody component, a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) designated MABX-9001a.4 This antibody is engineered to bind with high affinity and selectivity to the human B7 homolog 3 protein (B7-H3), also known as CD276.1 By targeting B7-H3, which is overexpressed on the surface of various cancer cells relative to normal tissues, the antibody serves as a delivery vehicle, guiding the ADC to the tumor site.1

2. Linker Technology: Tetrapeptide-Based Cleavable Linker

The MABX-9001a antibody is connected to the cytotoxic payload via an enzymatically cleavable linker.1 This linker is specifically a tetrapeptide-based linker, designed for stability in systemic circulation to prevent premature release of the payload, which could lead to off-target toxicity.1 Upon internalization of the ADC into the target cancer cell and trafficking to the lysosomal compartment, the linker is cleaved by lysosomal enzymes, such as cathepsins, which are typically upregulated in tumor cells.2 While the precise sequence for I-DXd's linker is often generally described as "tetrapeptide-based," Daiichi Sankyo's DXd ADC platform commonly employs a Glycine-Glycine-Phenylalanine-Glycine (GGFG) sequence.38 The United States Adopted Name (USAN) description for Ifinatamab deruxtecan details a thioether linkage with N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]glycylglycyl-L-phenylalanyl-N-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-1-yl]amino]-2-oxoethoxy]methyl]glycinamide, confirming a GGFG motif within the linker structure that connects to the payload.4 This selective cleavage mechanism is critical for ensuring that the cytotoxic payload is released preferentially within the tumor cells.

3. Cytotoxic Payload: Deruxtecan (DXd) – A Topoisomerase I Inhibitor

The cytotoxic component of Ifinatamab deruxtecan is DXd, a highly potent derivative of exatecan (DX-8951), which functions as a DNA topoisomerase I inhibitor.1 The USAN documentation also refers to this payload as MAAA-1181a, a camptothecin derivative.4 Topoisomerase I is an enzyme crucial for relieving torsional stress in DNA during replication and transcription. Inhibition of topoisomerase I by DXd leads to the stabilization of the enzyme-DNA cleavable complex, resulting in DNA single-strand breaks. These breaks, when encountered by the replication machinery, are converted into lethal DNA double-strand breaks, ultimately triggering cell cycle arrest and apoptosis (programmed cell death).2 Ifinatamab deruxtecan has a drug-to-antibody ratio (DAR) of approximately 4, meaning each antibody molecule carries an average of four DXd payload molecules, contributing to its potent antitumor activity.18

The consistent use of the DXd topoisomerase I inhibitor payload and a GGFG-based cleavable linker across several of Daiichi Sankyo's ADCs, including the approved and clinically successful Enhertu® (trastuzumab deruxtecan) and Datopotamab deruxtecan, points to a well-established platform technology. This established platform provides a foundation of knowledge regarding chemistry, manufacturing, and controls (CMC), as well as an understanding of the general pharmacological properties and potential class-specific toxicities, such as ILD/pneumonitis, which can inform the development and monitoring strategies for Ifinatamab deruxtecan.

B. Molecular Target: B7 Homolog 3 Protein (B7-H3/CD276)

1. B7-H3 Expression in Tumors and Prognostic Significance

B7-H3, also known as CD276, is a type I transmembrane protein and a member of the B7 family of immunoregulatory proteins.1 Unlike some other immune checkpoint molecules with restricted expression, B7-H3 is frequently and highly overexpressed on the surface of a wide variety of human solid tumors. These include, but are not limited to, esophageal squamous cell carcinoma (ESCC), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), prostate cancer, breast cancer, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma (HNSCC), colorectal cancer, and hepatocellular carcinoma.1 Immunohistochemical (IHC) studies have confirmed B7-H3 protein expression not only on tumor cells themselves but also on tumor-associated vasculature, endothelium, and fibrous stromal cells within the tumor microenvironment.45

Crucially, the expression of B7-H3 in normal tissues is generally limited or low.[2] This differential expression pattern between tumor and normal tissues is a key attribute that makes B7-H3 an attractive target for cancer therapies like ADCs, as it offers the potential for selective drug delivery to malignant cells while sparing healthy ones. Furthermore, elevated B7-H3 expression has often been correlated with more aggressive tumor biology, increased risk of metastasis, resistance to therapy, and overall poor prognosis in various cancer types.[1]

2. Rationale for Targeting B7-H3 in Oncology

The widespread overexpression of B7-H3 on cancer cells, its association with unfavorable clinical outcomes, and its limited presence in normal tissues provide a strong rationale for its selection as a therapeutic target.1 B7-H3 is implicated in various aspects of cancer progression, including promoting tumor cell proliferation, survival, invasion, and metastasis, as well as contributing to immune evasion by modulating T-cell responses.2 Despite its compelling profile as a target, there are currently no B7-H3-directed medicines approved for the treatment of any cancer.1 This highlights a significant unmet medical need and an opportunity for novel therapies like Ifinatamab deruxtecan to make an impact. Targeting B7-H3 with an ADC aims to leverage its tumor-associated expression for the selective delivery of a potent cytotoxic payload, thereby offering a potentially effective and more targeted treatment approach. The broad expression profile of B7-H3 supports the investigation of I-DXd across a wide range of tumor types, a strategy reflected in its extensive clinical development program. However, early clinical observations have indicated that the level of B7-H3 expression does not always directly correlate with the clinical response to I-DXd.13 This suggests that while B7-H3 expression is essential for initial targeting, other factors such as the efficiency of ADC internalization, intracellular trafficking, payload sensitivity, and characteristics of the tumor microenvironment may also significantly influence therapeutic efficacy. This complexity underscores the need for further research to identify more precise predictive biomarkers for I-DXd.

C. Pharmacodynamics

1. Binding, Internalization, and Intracellular Payload Release

The pharmacodynamic cascade of Ifinatamab deruxtecan begins with the high-affinity binding of its anti-B7-H3 monoclonal antibody component to B7-H3 protein expressed on the surface of tumor cells.2 This specific binding event is crucial for initiating the targeted delivery process. Following binding, the ADC-B7-H3 complex undergoes receptor-mediated endocytosis, a cellular process where the cell membrane invaginates to internalize the bound complex into intracellular vesicles.2 Preclinical studies have demonstrated efficient, target-dependent internalization and payload delivery into tumor cells.6

Once internalized, the ADC is trafficked through the endo-lysosomal pathway. Within the acidic environment of lysosomes, which are rich in proteolytic enzymes, the cleavable tetrapeptide-based linker is enzymatically degraded.[2] This targeted cleavage within the lysosome ensures the release of the active cytotoxic payload, DXd, directly into the cytoplasm of the cancer cell, minimizing its exposure to the systemic circulation and healthy tissues.

2. Inhibition of DNA Topoisomerase I and Induction of DNA Damage

Upon its release into the cancer cell, the DXd payload exerts its cytotoxic effect by inhibiting DNA topoisomerase I.1 Topoisomerase I is a nuclear enzyme essential for relaxing DNA supercoiling during critical cellular processes such as DNA replication, transcription, and repair. DXd intercalates into the DNA and stabilizes the transient covalent complex formed between topoisomerase I and DNA (the cleavable complex), preventing the re-ligation of the DNA strand. This results in the accumulation of DNA single-strand breaks. When the DNA replication machinery encounters these stabilized complexes and single-strand breaks, they are converted into more deleterious DNA double-strand breaks.2 The accumulation of these DNA lesions triggers cellular DNA damage responses, leading to cell cycle arrest, and ultimately, apoptosis (programmed cell death) of the cancer cell.2 Studies with similar ADCs utilizing DXd have shown induction of DNA damage markers like phosphorylated Chk1 and apoptosis markers such as cleaved caspase-3.42

3. Bystander Antitumor Effect

A significant feature of the DXd payload used in Ifinatamab deruxtecan and other Daiichi Sankyo ADCs is its ability to exert a "bystander effect".2 DXd is membrane-permeable, meaning that once it is released within a targeted B7-H3-expressing cancer cell, it can diffuse through the cell membrane and enter adjacent tumor cells.2 These neighboring cells can then be killed by DXd, even if they express low or no B7-H3 on their surface. This bystander killing mechanism is particularly advantageous in tumors that exhibit heterogeneous antigen expression, as it allows the ADC to exert a broader antitumor effect beyond only the cells directly targeted by the antibody. This can potentially overcome some forms of resistance related to antigen loss or heterogeneous expression within the tumor mass, contributing to a more profound and durable therapeutic response.

IV. Clinical Development Program

A. Overview of Clinical Strategy and Investigated Indications

The clinical development of Ifinatamab deruxtecan is characterized by a comprehensive and ambitious strategy, aiming to evaluate its efficacy and safety across a diverse range of solid tumors. The program initiated with first-in-human Phase 1/2 studies designed to assess safety, tolerability, pharmacokinetics, and preliminary antitumor activity, as well as to determine the recommended dose for expansion (RP2D). The IDeate-PanTumor01 study (NCT04145622) served this foundational role, exploring various advanced solid malignancies.[10]

Based on encouraging signals from these early-phase investigations, the program has rapidly advanced to later-stage development. Pivotal Phase 3 trials have been initiated in several key indications where significant unmet medical needs exist and where I-DXd has shown promising activity. These primary focus areas include Small Cell Lung Cancer (SCLC) [1], Esophageal Squamous Cell Carcinoma (ESCC) [1], and metastatic Castration-Resistant Prostate Cancer (mCRPC).[8]

Beyond these lead indications, the IDeate-PanTumor02 study (NCT06330064), a Phase 1b/2 basket trial, is designed to further assess I-DXd's activity in a broader array of tumor types, including endometrial cancer, head and neck squamous cell carcinoma (HNSCC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), urothelial cancer (UC), ovarian cancer (OVC), and triple-negative breast cancer (TNBC).[47]

Furthermore, the clinical strategy also incorporates the evaluation of Ifinatamab deruxtecan in combination regimens. For example, the IDeate-Lung03 trial is investigating I-DXd in combination with atezolizumab, with or without carboplatin, as a first-line induction or maintenance therapy for ES-SCLC.[12] Similarly, the IDeate-Prostate02 umbrella substudy (NCT06863272) is exploring I-DXd in combination with other agents, such as MK-5684 or androgen receptor pathway inhibitors (ARPIs), in mCRPC.[31] This multifaceted approach, encompassing monotherapy across various cancers and combination strategies, aims to fully elucidate the therapeutic potential of Ifinatamab deruxtecan. The aggressive pursuit of multiple Phase 3 trials concurrently in distinct tumor types with high unmet needs reflects the strong confidence the developers have in I-DXd, likely based on compelling early-phase data. This strategy of exploring both monotherapy and combination treatments is typical for promising oncology drugs, seeking to identify optimal therapeutic niches, enhance efficacy, and potentially overcome resistance mechanisms.

B. Key Clinical Trials Overview

The clinical development program for Ifinatamab deruxtecan is extensive, involving multiple trials across different phases and tumor types. A summary of key trials is presented in Table 1.

Table 1: Summary of Key Clinical Trials for Ifinatamab Deruxtecan

Trial ID (NCT Number)	Phase	Official Title (Abbreviated/Purpose)	Status (as of latest snippets)	Conditions Investigated	Key Endpoints (Primary)	Estimated/Actual Enrollment	Sponsor(s)
IDeate-PanTumor01 (NCT04145622)	1/2	Study of I-DXd in Advanced Solid Malignant Tumors	Ongoing, results presented	Advanced solid tumors (SCLC, ESCC, mCRPC, sqNSCLC, EC, HNSCC etc.)	MTD, RP2D, Safety, ORR	~250 (initial reports varied, e.g., N=195, N=70 for specific analyses)	Daiichi Sankyo (early collaboration with Sarah Cannon)
IDeate-Lung01 (NCT05280470)	2	Study of I-DXd in Extensive-Stage SCLC (Dose Optimization & Extension)	Ongoing, interim results presented	Extensive-Stage Small Cell Lung Cancer (ES-SCLC), previously treated	ORR by BICR	~158 (88 in Part 1, ~70 in Part 2)	Daiichi Sankyo / Merck
IDeate-Lung02 (NCT06203210)	3	Study of I-DXd vs TPC in Relapsed SCLC	Recruiting/Open to enrollment	Relapsed Small Cell Lung Cancer (SCLC) (after 1 prior platinum line)	ORR by BICR, Overall Survival (OS)	~540	Daiichi Sankyo / Merck
IDeate-Lung03 (NCT number not consistently provided)	1b/2	Study of I-DXd + Atezolizumab +/- Carboplatin in 1L ES-SCLC	Mentioned as planned/ongoing	Extensive-Stage Small Cell Lung Cancer (ES-SCLC), first-line	Safety, ORR (expected)	Not specified	Daiichi Sankyo / Merck
IDeate-Esophageal01 (NCT06644781)	3	Study of I-DXd vs TPC in Advanced/Metastatic ESCC	Recruiting	Esophageal Squamous Cell Carcinoma (ESCC), pretreated	Overall Survival (OS)	~510	Daiichi Sankyo / Merck
IDeate-Prostate01 (MK-2400-001 / NCT06925737)	3	Study of I-DXd vs Docetaxel in mCRPC	Recruiting	Metastatic Castration-Resistant Prostate Cancer (mCRPC)	Radiographic PFS (rPFS), Overall Survival (OS)	~1440	Merck
IDeate-Prostate02 (MK-2400-01A / NCT06863272)	1/2	Umbrella Substudy of I-DXd Combinations or Monotherapy in mCRPC	Not yet recruiting (planned start June 2025)	Metastatic Castration-Resistant Prostate Cancer (mCRPC)	Safety, RP2D for combos, PSA response	~360	Merck
IDeate-PanTumor02 (NCT06330064)	1b/2	Study of I-DXd in Recurrent/Metastatic Solid Tumors (Basket trial)	Enrollment ongoing	EC, HNSCC, PDAC, CRC, HCC, Esophageal/GEJ Adeno, UC, OVC, TNBC	ORR per investigator, Safety (HCC cohort)	~520	Daiichi Sankyo / Merck

Status, enrollment, and endpoint details are based on the most recent available information from the provided snippets and may be subject to change. TPC = Treatment of Physician's Choice; MTD = Maximum Tolerated Dose; RP2D = Recommended Phase 2 Dose; ORR = Objective Response Rate; BICR = Blinded Independent Central Review; PFS = Progression-Free Survival; OS = Overall Survival; EC = Endometrial Cancer; HNSCC = Head and Neck Squamous Cell Carcinoma; PDAC = Pancreatic Ductal Adenocarcinoma; CRC = Colorectal Cancer; HCC = Hepatocellular Carcinoma; UC = Urothelial Cancer; OVC = Ovarian Cancer; TNBC = Triple-Negative Breast Cancer.

Data Sources for Table 1: 1

This table provides a centralized overview of the clinical development landscape for Ifinatamab deruxtecan, facilitating a quick understanding of the breadth and depth of its investigation.

C. Detailed Review of Significant Clinical Trials:

1. IDeate-PanTumor01 (NCT04145622): Phase 1/2, Advanced Solid Tumors

The IDeate-PanTumor01 study is a first-in-human, open-label, multicenter Phase 1/2 trial designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of Ifinatamab deruxtecan in patients with various advanced solid malignant tumors.7 The study was sponsored by Daiichi Sankyo, with early phases conducted in collaboration with Sarah Cannon Research Institute.10

Part 1 of the study focused on dose escalation, administering I-DXd at doses ranging from 0.8 mg/kg to 16.0 mg/kg intravenously every three weeks (Q3W) to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D).10 Part 2 involved dose expansion cohorts to further assess safety and efficacy in specific tumor types, including SCLC, ESCC, mCRPC, squamous NSCLC (sqNSCLC), endometrial cancer, and HNSCC.10 Patients enrolled were typically heavily pretreated, often having received a median of four or more prior lines of therapy.10

The trial is ongoing, with multiple interim results presented at major oncology conferences such as the World Conference on Lung Cancer (WCLC), the European Society for Medical Oncology (ESMO) Congress, and the ASCO Genitourinary Cancers Symposium.10

Key findings from IDeate-PanTumor01 have been instrumental in shaping the subsequent development of I-DXd. The study demonstrated promising objective response rates (ORRs) across several tumor types. For instance, in patients with SCLC (n=21, receiving ≥6.4 mg/kg), a confirmed ORR of 52.4% was observed, including one complete response (CR) and ten partial responses (PRs). The median duration of response (DOR) in this SCLC cohort was 5.9 months, with a median progression-free survival (PFS) of 5.6 months and a median overall survival (OS) of 12.2 months (data cutoff January 31, 2023, presented at WCLC 2023).10

In patients with mCRPC (n=59, ESMO 2023 data), the confirmed ORR was 25%, with a median DOR of 6.4 months, median PFS of 4.8 months (n=73), and median OS of 13.5 months (n=73).29 For ESCC (n=28, ESMO 2023 data), the confirmed ORR was 21%, median DOR 3.5 months, median PFS 2.8 months, and median OS 7.0 months.29 In sqNSCLC (n=13, ESMO 2023 data), the confirmed ORR was 31% with a median DOR of 4.1 months.29

The safety profile of I-DXd in IDeate-PanTumor01 was reported as generally manageable, with TEAEs consistent with those expected for ADCs employing topoisomerase I inhibitor payloads.13 This foundational trial successfully established initial safety parameters, identified the RP2D (typically 12 mg/kg Q3W for many cohorts), and provided crucial early efficacy signals that justified the advancement of I-DXd into indication-specific Phase 2 and pivotal Phase 3 studies.

2. IDeate-Lung01 (NCT05280470): Phase 2, Extensive-Stage SCLC

Building on the encouraging signals in SCLC from IDeate-PanTumor01, the IDeate-Lung01 trial was initiated. This is a global, multicenter, randomized, open-label, two-part Phase 2 study specifically designed to evaluate the safety and efficacy of Ifinatamab deruxtecan in patients with ES-SCLC.1 The trial is sponsored by Daiichi Sankyo and Merck.

Part 1 of the study, the dose-optimization phase, randomized patients (who had received at least one prior line of platinum-based chemotherapy and a maximum of three prior lines of therapy) to receive I-DXd at either 8 mg/kg Q3W or 12 mg/kg Q3W.11 The primary endpoint for this part was ORR as assessed by BICR. Part 2, the dose-expansion phase, is designed to enroll patients who have received a minimum of two previous lines of systemic therapy, who will receive I-DXd at the selected optimal dose from Part 1 (which was determined to be 12 mg/kg Q3W).12

The trial is ongoing, with interim results from Part 1 presented at conferences including WCLC 2024 and JSMO 2025.11 As of the April 25, 2024 data cutoff for the dose-optimization part (88 patients treated; 46 in the 8 mg/kg arm, 42 in the 12 mg/kg arm):

• The confirmed ORR by BICR was 54.8% (95% CI, 38.7–70.2) in the 12 mg/kg cohort, compared to 26.1% (95% CI, 14.3–41.1) in the 8 mg/kg cohort.[11]
• The median DOR was 4.2 months (95% CI, 3.5–7.0) for the 12 mg/kg dose and 7.9 months (95% CI, 4.1–NE) for the 8 mg/kg dose.[12]
• Median PFS was 5.5 months (95% CI, 4.2–6.7) for 12 mg/kg versus 4.2 months (95% CI, 2.8–5.6) for 8 mg/kg.[12]
• Median OS was 11.8 months (95% CI, 8.9–15.3) for 12 mg/kg versus 9.4 months (95% CI, 7.8–15.9) for 8 mg/kg.[12] Notably, intracranial activity was observed in patients with baseline brain metastases, with a CNS confirmed ORR of 50.0% in the 12 mg/kg group (n=10 with brain target lesions) and 66.7% in the 8 mg/kg group (n=6 with brain target lesions).[16] Based on the totality of data, particularly the substantially higher ORR, the 12 mg/kg Q3W dose was selected as the optimal dose for the extension part of IDeate-Lung01 and for further development in SCLC, including the Phase 3 IDeate-Lung02 trial.[11] The safety profile was manageable, with ILD/pneumonitis reported (see Section VI). The selection of the 12 mg/kg dose, despite some initial numerical advantages in DOR and OS for the 8 mg/kg arm in early data cuts, likely reflects the overall strength of the efficacy signal (particularly ORR) and confidence in managing the toxicity profile at this higher dose as more data matures.

3. IDeate-Lung02 (NCT06203210): Phase 3, Relapsed SCLC

IDeate-Lung02 is a global, multicenter, randomized, open-label Phase 3 trial evaluating Ifinatamab deruxtecan in patients with relapsed SCLC.1 This pivotal study, sponsored by Daiichi Sankyo and Merck, aims to enroll approximately 540 adult patients who have experienced disease progression after only one prior line of platinum-based chemotherapy (with a chemotherapy-free interval of ≥30 days).46

Patients are randomized 1:1 to receive either Ifinatamab deruxtecan (12 mg/kg IV Q3W) or Treatment of Physician's Choice (TPC), which includes topotecan, amrubicin (where approved and available), or lurbinectedin.46 The dual primary endpoints are ORR as assessed by BICR (per RECIST v1.1) and OS.46 Secondary endpoints include investigator-assessed ORR, PFS (by BICR and investigator), DOR, disease control rate (DCR), time to response (TTR), patient-reported outcomes, safety, pharmacokinetics, and immunogenicity.46

Randomization is stratified by chemotherapy-free interval after first-line therapy (<90 days vs. ≥90 days), choice of TPC, prior treatment with PD-(L)1 inhibitors (yes vs. no), and presence/history of asymptomatic brain metastases (yes vs. no).46 Patients with asymptomatic brain metastases are eligible for enrollment.46 Key exclusion criteria include prior treatment with B7-H3 targeted agents or topoisomerase I inhibitors.49

The trial is actively recruiting globally, with the first patient dosed in August 2024.19 IDeate-Lung02 is a critical registration-intent study designed to confirm the efficacy and safety of I-DXd in the second-line setting for SCLC, an area with significant unmet medical need and historically poor outcomes.

4. IDeate-Esophageal01 (NCT06644781): Phase 3, Advanced/Metastatic ESCC

The IDeate-Esophageal01 trial is a global, multicenter, open-label, randomized Phase 3 study evaluating Ifinatamab deruxtecan in patients with unresectable advanced or metastatic ESCC.1 This trial, sponsored by Daiichi Sankyo and Merck, was initiated based on promising efficacy signals for I-DXd in ESCC patients observed in the IDeate-PanTumor01 Phase 1/2 trial.1

The study plans to enroll approximately 510 patients who have experienced disease progression after receiving no more than one prior line of systemic therapy in the advanced or metastatic setting, which must have included platinum-based chemotherapy and an immune checkpoint inhibitor.1 Patients will be randomized to receive either Ifinatamab deruxtecan (12 mg/kg IV Q3W) or TPC, consisting of paclitaxel, docetaxel, or irinotecan hydrochloride.1

The primary endpoint is OS. Secondary endpoints include PFS and ORR (both assessed by BICR), DOR, DCR, and safety.1 Key eligibility criteria include histologically or cytologically documented unresectable locally advanced or metastatic ESCC, age ≥18 years, and adequate tumor tissue for correlative studies.50 Exclusion criteria include prior treatment with B7-H3 targeted agents or topoisomerase I inhibitors, and clinically active CNS metastases.50

The trial is actively recruiting, with the first patient dosed in May 2025.1 This pivotal study aims to establish I-DXd as a new treatment option for patients with pretreated advanced

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