Raludotatug Deruxtecan (DS-6000): A Comprehensive Clinical and Scientific Review of a First-in-Class CDH6-Targeted Antibody-Drug Conjugate

I. Executive Summary

Raludotatug deruxtecan (R-DXd), also known by its development code DS-6000, is an investigational, potential first-in-class antibody-drug conjugate (ADC) representing a significant advancement in targeted oncology.[1] It is being jointly developed by Daiichi Sankyo and Merck & Co. (known as MSD outside the United States and Canada) to treat solid tumors that express Cadherin-6 (CDH6), a protein implicated in the progression and poor prognosis of cancers such as ovarian and renal cell carcinoma.[1]

The therapeutic is constructed on Daiichi Sankyo's clinically and commercially successful DXd ADC technology platform. This platform combines a humanized anti-CDH6 IgG1 monoclonal antibody (raludotatug) with a highly potent topoisomerase I inhibitor payload, deruxtecan (DXd), via a stable, tumor-selective, enzymatically cleavable linker.[1] A key feature of this design is a high drug-to-antibody ratio (DAR) of 8, which, combined with the membrane-permeable nature of the DXd payload, facilitates a powerful "bystander effect," enabling the destruction of adjacent tumor cells that may not express the target antigen.[6]

Clinical development is anchored by the first-in-human Phase 1 trial (NCT04707248), which has demonstrated compelling preliminary efficacy signals.[8] In a heavily pretreated cohort of patients with platinum-resistant ovarian cancer, a population with high unmet medical need, raludotatug deruxtecan achieved a confirmed objective response rate (ORR) of 46% and a median duration of response (DoR) of 11.2 months.[10] An even more pronounced ORR of 72.2% was observed in a smaller group of patients with platinum-sensitive ovarian cancer, suggesting potent activity.[12]

Despite this promising efficacy, the program's primary challenge is its safety profile, which is characterized by a significant, dose-dependent risk of treatment-related interstitial lung disease (ILD)/pneumonitis, a known class effect for DXd ADCs.[10] The occurrence of two fatal (Grade 5) ILD events at the 8.0 mg/kg dose level was a pivotal finding that led to the discontinuation of that dose and fundamentally reshaped the drug's development path.[10]

The current clinical strategy reflects a direct response to this benefit-risk challenge. The pivotal REJOICE-Ovarian01 trial (NCT06161025) has been designed as a Phase 2/3 study that incorporates a critical dose-optimization phase to evaluate the safety and efficacy of lower doses (4.8, 5.6, and 6.4 mg/kg) before advancing to a randomized Phase 3 comparison against standard-of-care chemotherapy.[14] The ultimate viability of raludotatug deruxtecan is contingent upon the results of this dose-finding stage. If a therapeutic window can be established that preserves a high degree of clinical efficacy while substantially mitigating the risk of severe or fatal ILD, raludotatug deruxtecan is well-positioned to become a transformative, first-in-class therapy for CDH6-expressing cancers. Conversely, failure to define such a window would present a significant obstacle to regulatory approval and open the door for competing CDH6-targeted agents.

II. Molecular Profile and Mechanism of Action

A. The DXd Antibody-Drug Conjugate Platform: A Foundation of Validated Technology

Raludotatug deruxtecan is an exemplar of Daiichi Sankyo's proprietary DXd ADC technology, a platform that has achieved significant clinical and commercial success.[6] This platform has served as the foundation for multiple approved and late-stage development ADCs, including the highly successful trastuzumab deruxtecan (Enhertu) and the recently approved datopotamab deruxtecan (Datroway).[17] The consistent application of this technology across a portfolio of assets provides a deep reservoir of manufacturing, clinical, and regulatory experience. This established expertise de-risks the technological aspects of drug development, allowing the focus to shift to the unique biology of the novel target—in this case, CDH6—and the precise definition of the therapeutic window for the new conjugate. While this approach provides a known roadmap for development and toxicity management, it also sets a high bar, as the recognized risks of the platform, most notably interstitial lung disease (ILD), must be demonstrably outweighed by substantial clinical efficacy.

The DXd platform is characterized by three core components:

• Payload: The cytotoxic agent is deruxtecan (DXd), a derivative of the camptothecin analogue exatecan.[1] DXd is an exceptionally potent inhibitor of DNA topoisomerase I (TOP1), an enzyme essential for relieving torsional strain during DNA replication and transcription.[6] Scientific literature reports that DXd possesses greater inhibitory potency against TOP1 than SN-38, the active metabolite of irinotecan, which is a payload utilized in other commercially successful ADCs.[6]
• Linker: The antibody and payload are connected through a proprietary, enzymatically cleavable linker based on a tetrapeptide sequence (glycine-glycine-phenylalanine-glycine, or GGFG).[1] This linker is engineered for high stability in the systemic circulation, which is critical for minimizing the premature release of the toxic payload and reducing off-target toxicity. Upon internalization of the ADC into the tumor cell and trafficking to the lysosome, the linker is efficiently cleaved by lysosomal enzymes, such as cathepsins, which are often upregulated in the tumor microenvironment.[1]
• Drug-to-Antibody Ratio (DAR): The DXd conjugation technology consistently yields ADCs with a high and homogenous DAR of approximately 8.[6] This means that each antibody molecule carries a uniform load of eight payload molecules, ensuring a potent and consistent drug product, which is a key advantage over older, more heterogeneous conjugation technologies that can lead to variable pharmacokinetics and efficacy.

B. Raludotatug Deruxtecan (R-DXd; DS-6000): Structure and Design

Raludotatug deruxtecan (CAS Number: 2610074-57-0) is an ADC that integrates the three core components of the DXd platform.[1] It consists of raludotatug, a humanized immunoglobulin G1 (IgG1) monoclonal antibody engineered to target CDH6, which is covalently attached to the deruxtecan (DXd) payload (also referred to as MAAA-1181a) via the GGFG cleavable linker.[1]

C. Cellular Pathway: From Target Binding to Apoptosis

The therapeutic effect of raludotatug deruxtecan is achieved through a precise, multi-step process designed to selectively deliver its cytotoxic payload to cancer cells.[7]

1. Binding: The process begins with the intravenous administration of raludotatug deruxtecan. The antibody moiety, raludotatug, circulates through the bloodstream and specifically recognizes and binds to the CDH6 protein expressed on the surface of tumor cells.[1]
2. Internalization: Following binding, the entire ADC-CDH6 complex is internalized by the cancer cell through endocytosis and is subsequently trafficked to the lysosome, an intracellular organelle rich in degradative enzymes.[2]
3. Payload Release: Inside the acidic and enzyme-rich environment of the lysosome, the tetrapeptide linker is cleaved, liberating the active DXd payload from the antibody.[1]
4. Cytotoxicity: Once freed within the cell, DXd exerts its potent cytotoxic effect. It inhibits TOP1 by binding to and stabilizing the TOP1-DNA cleavage complex. This action prevents the re-ligation of single-strand DNA breaks created by TOP1 during replication, leading to the accumulation of irreversible double-strand DNA breaks when the replication fork collides with the stabilized complex. This extensive DNA damage triggers cell cycle arrest and ultimately induces programmed cell death, or apoptosis.[1]

Preclinical investigations have validated this mechanistic pathway. Treatment of CDH6-expressing cancer cells with raludotatug deruxtecan led to the observed phosphorylation of Chk1, a key marker of the DNA damage response, and the appearance of cleaved caspase-3, a definitive marker of apoptosis execution.[2]

D. The Bystander Effect: A Key Feature for Heterogeneous Tumors

A defining characteristic of the DXd payload, and a key differentiator for the entire platform, is its high cell-membrane permeability.[2] After being released inside a CDH6-positive target cell, the DXd payload is not confined to that cell. It can diffuse across the cell membrane into the surrounding tumor microenvironment and subsequently enter adjacent tumor cells, inducing apoptosis in them as well. This phenomenon is known as the "bystander effect".[2]

The strategic importance of this bystander effect cannot be overstated. A primary challenge in cancer therapy, and a common mechanism of resistance to targeted agents, is tumor heterogeneity. Within a single tumor, the expression of a target antigen like CDH6 can vary significantly from one cell to another. An ADC with a non-permeable payload can only eliminate cells that express the target, leaving a population of antigen-negative cells untouched, which can then proliferate and drive disease recurrence. The bystander effect of DXd directly addresses this challenge. By creating a "kill zone" that extends beyond the initially targeted CDH6-positive cells, raludotatug deruxtecan can eradicate neighboring antigen-negative tumor cells. This capability likely contributes significantly to the high objective response rates observed in clinical trials and suggests that the drug may be effective even in tumors with mixed or moderate levels of CDH6 expression, thereby broadening its potential clinical utility and overcoming a major hurdle for targeted cancer therapies.

III. The Therapeutic Target: Cadherin-6 (CDH6)

A. Biological Function and Expression Profile

The selection of a suitable target antigen is arguably the most critical determinant of an ADC's success. The ideal target is highly expressed on the surface of tumor cells but has minimal or no expression in vital healthy tissues. Cadherin-6 (CDH6) largely fits this profile, making it an attractive target for ADC development.[2]

CDH6, also known as K-cadherin, is a member of the type II classical cadherin family of calcium-dependent transmembrane glycoproteins.[4] These proteins are fundamental mediators of cell-cell adhesion, playing essential roles in embryonic development, tissue morphogenesis, and the maintenance of normal tissue architecture.[5]

• Normal Tissue Expression: In healthy adults, the expression of CDH6 is highly restricted. Its most notable sites of expression are the epithelial cells of the renal tubules in the kidney and the fallopian tubes.[34] Crucially, it is not expressed in the normal ovary, a key point of differentiation for its targeting in ovarian cancer.[36]
• Cancer Tissue Expression: In contrast to its limited expression in normal tissues, CDH6 is frequently and highly overexpressed in several malignancies. It is found in up to 85% of ovarian cancers, particularly those of the high-grade serous subtype, which is the most common and aggressive form of the disease.[2] Significant overexpression is also observed in a majority of renal cell carcinomas (RCC), including both clear cell and papillary subtypes.[2] Furthermore, CDH6 expression has been documented in other cancers, including papillary thyroid cancer, cholangiocarcinoma, and glioma, suggesting a broader potential for CDH6-targeted therapies.[4]

B. CDH6 as a Prognostic Biomarker and Driver of Metastasis

CDH6 is not merely a passive surface marker on cancer cells; it is functionally implicated in tumor progression and aggression. Multiple independent analyses have established a significant correlation between high CDH6 expression and adverse clinical outcomes, including advanced tumor stage and poor patient survival in both ovarian and renal cancers.[4] This makes CDH6 a negative prognostic biomarker.

The biological basis for this prognostic significance lies in its role in promoting metastasis. Research has shown that CDH6 can activate integrin signaling pathways, such as α2β1 and αIIbβ3, which in turn trigger downstream signaling cascades involving kinases like AKT and SRC.[4] These pathways are known to regulate critical cellular processes that drive metastasis, including cell adhesion, migration, and invasion.[4] Silencing CDH6 expression in preclinical models has been shown to result in a significant loss of these pro-metastatic traits.[4]

This functional role elevates CDH6 from being just a "docking site" for an ADC to an active participant in the disease process. This implies that an ADC targeting CDH6, such as raludotatug deruxtecan, may exert a dual anti-tumor effect. The primary effect is the targeted delivery of the cytotoxic DXd payload, leading to direct tumor cell killing. A potential secondary effect could be the disruption of CDH6's pro-metastatic signaling function through antibody binding and internalization. This dual mechanism strengthens the therapeutic rationale for raludotatug deruxtecan, suggesting it could not only eliminate existing tumor cells but also inhibit the very processes that lead to disease dissemination and progression, potentially resulting in more profound and durable clinical responses.

IV. Preclinical Evidence and Pharmacological Profile

A. In Vitro and In Vivo Efficacy

The preclinical development program for raludotatug deruxtecan provided a robust proof-of-concept, validating its potential before advancing to human trials. In vitro studies using a panel of human cancer cell lines confirmed that the cytotoxic activity of the ADC was directly dependent on the level of CDH6 expression on the cell surface, demonstrating target-specific killing.[2]

The most compelling preclinical evidence came from in vivo studies using patient-derived xenograft (PDX) models. In these models, human tumors from patients with ovarian and renal cancer were implanted into immunodeficient mice. Treatment with raludotatug deruxtecan resulted in significant and often complete tumor regression across multiple PDX models, providing strong evidence of its potent anti-tumor activity in a setting that more closely mimics human disease.[2]

B. Pharmacokinetics and Safety in Animal Models

Pharmacokinetic (PK) analyses in mice revealed a predictable, dose-dependent plasma concentration profile, which is essential for determining appropriate dosing schedules for clinical trials.[2]

Crucially, toxicology studies were conducted in non-human primates (cynomolgus monkeys) to assess the safety profile of raludotatug deruxtecan. These studies were reported to show a "favorable" and "acceptable" safety profile, and a highest non-severely toxic dose (HNSTD) of 30 mg/kg was established.[2] This preclinical safety package was deemed sufficient to support the initiation of first-in-human clinical trials.

However, the transition from preclinical models to human subjects revealed a significant translational gap. While the non-human primate studies were described as favorable, they did not predict the severity of the interstitial lung disease (ILD) that was later observed in patients. This discrepancy is a well-recognized challenge in the development of novel therapeutics, particularly ADCs and other immunomodulatory agents. Non-human primate models, while valuable, do not always fully recapitulate complex, human-specific, immune-mediated toxicities like ILD. This underscores the limitations of preclinical toxicology for this class of drugs and reinforces the absolute necessity of meticulous safety monitoring, careful dose escalation, and adaptive trial designs in early-phase human studies. Ultimately, it is the clinical data, not the preclinical data, that defines the true therapeutic window and ultimate viability of an ADC.

V. Clinical Development Program

The clinical development of raludotatug deruxtecan is being pursued through a structured and adaptive program designed to systematically evaluate its safety and efficacy, from initial dose-finding to pivotal registration-enabling studies. The program is anchored by a foundational Phase 1 trial, which has informed the design of subsequent, more definitive trials in key indications.

Table 1: Overview of Key Clinical Trials for Raludotatug Deruxtecan

Trial ID (NCT)	Phase	Title/Acronym	Status	Primary Indication(s)	Key Objectives/Design
NCT04707248	1	A Study of DS-6000a in Subjects With Advanced Renal Cell Carcinoma and Ovarian Tumors	Closed to Accrual	Advanced Renal Cell Carcinoma (RCC), Ovarian Cancer (OVC)	Dose-escalation and expansion to determine Maximum Tolerated Dose (MTD) and Recommended Dose for Expansion (RDE).8
NCT06161025	2/3	REJOICE-Ovarian01	Recruiting	Platinum-Resistant Ovarian, Primary Peritoneal, or Fallopian Tube Cancer	Part A: Dose-optimization of 3 dose levels. Part B: Randomized comparison of selected R-DXd dose vs. investigator's choice chemotherapy.1
NCT06660654	2	REJOICE-PanTumor01	Recruiting	Gynecologic (Endometrial, Cervical, non-HGSOC) and Genitourinary (Urothelial, ccRCC) Cancers	Signal-seeking "basket" trial to evaluate R-DXd in various CDH6-expressing solid tumors.44

A. Foundational Phase 1 Study (NCT04707248): Setting the Stage

The journey of raludotatug deruxtecan into the clinic began with the first-in-human study, NCT04707248. This was a two-part, multicenter, open-label trial that ultimately enrolled 179 patients with advanced renal cell carcinoma (RCC) and ovarian cancer (OVC) for whom standard therapies were no longer effective.[8]

The first part of the study was a dose-escalation phase. This phase followed a standard 3+3 design, where small cohorts of patients were treated with progressively increasing doses of raludotatug deruxtecan, starting at 1.6 mg/kg and escalating up to 9.6 mg/kg.[8] The primary objectives were to assess the safety and tolerability of the drug, identify any dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE).[8]

The second part was a dose-expansion phase. Once a safe and potentially effective dose range was identified, larger cohorts of patients with OVC and RCC were enrolled to receive raludotatug deruxtecan at these selected doses. This phase was designed to gather more robust data on the safety profile and to obtain a preliminary assessment of the drug's anti-tumor activity.[8]

B. Pivotal Phase 2/3 Trial (REJOICE-Ovarian01; NCT06161025): The Path to Approval

Informed by the promising efficacy signals and the critical safety findings from the Phase 1 study, the developers initiated the REJOICE-Ovarian01 trial. This global, randomized, open-label Phase 2/3 study is the cornerstone of the drug's registration strategy and is designed to definitively establish the benefit-risk profile of raludotatug deruxtecan in patients with platinum-resistant, high-grade ovarian, primary peritoneal, or fallopian tube cancer who have received between one and three prior lines of systemic therapy.[1]

The trial's innovative design incorporates two distinct parts:

• Part A (Phase 2 Dose Optimization): This crucial initial phase directly addresses the safety concerns raised in the Phase 1 trial. Approximately 105 patients are being randomized in a 1:1:1 ratio to receive one of three lower doses of raludotatug deruxtecan: 4.8 mg/kg, 5.6 mg/kg, or 6.4 mg/kg, administered intravenously every 21 days.[14] The primary goal of this part is to prospectively evaluate the safety and efficacy (specifically, the objective response rate) of these doses to identify an optimal RDE that balances potent anti-tumor activity with a more manageable safety profile, particularly concerning ILD.[16]
• Part B (Phase 3 Registrational): Once the RDE is selected from Part A, the trial will seamlessly transition into the Phase 3 portion. This part will enroll approximately 450 patients who will be randomized in a 1:1 ratio to receive either raludotatug deruxtecan at the selected RDE or the investigator's choice of standard-of-care single-agent chemotherapy (options include paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan).[14] Randomization will be stratified by key prognostic factors, including the number of prior lines of therapy and tumor CDH6 expression level (high vs. low).[16]

The Phase 3 part is powered for two primary endpoints: ORR and progression-free survival (PFS), both of which will be assessed by a blinded independent central review (BICR) to ensure objectivity.[16]

C. Expansion Study (REJOICE-PanTumor01; NCT06660654): Exploring Broader Potential

To explore the full potential of raludotatug deruxtecan beyond its lead indications, the REJOICE-PanTumor01 study was initiated. This is a Phase 2 "basket" trial, a signal-seeking study designed to efficiently evaluate the activity of a single drug across multiple different cancer types that share a common biomarker—in this case, the potential for CDH6 expression.[44]

The trial is enrolling separate cohorts of patients with various advanced gynecologic and genitourinary tumors, including endometrial cancer, cervical cancer, non-high-grade serous ovarian cancer, urothelial cancer, and clear cell renal cell carcinoma (ccRCC).[44] All patients in this study will receive raludotatug deruxtecan at a dose of 5.6 mg/kg.[45] The primary objective is to assess the ORR in each tumor-specific cohort to identify new areas where the drug may have meaningful clinical benefit and warrant further, more focused development.[45]

The overall clinical strategy for raludotatug deruxtecan is both deliberate and reactive. The Phase 1 trial successfully achieved its goal of identifying a strong efficacy signal but also uncovered a critical, dose-dependent safety liability. In response, the development team has prudently integrated a formal dose-optimization phase directly into the pivotal trial design. This risk-mitigation strategy is intended to prospectively identify the optimal therapeutic index before committing the substantial resources required for a large-scale Phase 3 study. The parallel pan-tumor basket trial represents a standard and effective life-cycle management approach, aiming to maximize the asset's potential value by exploring its activity in additional indications. The entire program's fate now rests on the outcome of REJOICE-Ovarian01 Part A. A successful outcome will validate a specific dose and provide a clear path toward potential regulatory approval, while a failure to identify a dose with a favorable benefit-risk profile would likely lead to the program's termination.

VI. In-Depth Clinical Efficacy Analysis (NCT04707248)

The initial first-in-human Phase 1 trial (NCT04707248) of raludotatug deruxtecan has yielded highly encouraging preliminary efficacy data, particularly in patients with advanced ovarian cancer. These results, presented at major oncology congresses such as the European Society for Medical Oncology (ESMO) and the Society of Gynecologic Oncology (SGO), have established CDH6 as a viable therapeutic target and raludotatug deruxtecan as a potent agent.[9]

Table 2: Efficacy of Raludotatug Deruxtecan in the Phase 1 Trial (NCT04707248)

Patient Cohort	Dose(s) (mg/kg)	N	Confirmed ORR (95% CI)	DCR (%)	Median DoR (months, 95% CI)	Median PFS (months, 95% CI)	Data Source(s)
Ovarian Cancer (Platinum-Resistant, Measurable)	4.8–8.0	50	46% (32–61)	98%	11.2 (3.0–NE)	7.9 (4.4–12.4)	9
Ovarian Cancer (Platinum-Sensitive, Measurable)	4.8–6.4	18	72.2% (46.5–90.3)	88.9%	5.7 (4.2–NE)	8.1 (4.2–NE)	12
Renal Cell Carcinoma	1.6-9.6	-	Early signals of efficacy reported	-	-	-	9
Abbreviations: N, number of patients; ORR, objective response rate; CI, confidence interval; DCR, disease control rate; DoR, duration of response; NE, not estimable; PFS, progression-free survival.

A. Ovarian Cancer Cohort: A Potential Breakthrough in a High Unmet Need Population

The most robust efficacy data to date have emerged from the ovarian cancer cohorts. In a subgroup of 50 patients with measurable, platinum-resistant ovarian cancer who had been heavily pretreated (median of 4 prior lines of therapy), treatment with raludotatug deruxtecan at doses ranging from 4.8 to 8.0 mg/kg produced a confirmed ORR of 46%.[9] This result is highly clinically meaningful, as it substantially exceeds the typical ORRs of 6-13% observed with standard-of-care single-agent chemotherapies in this challenging treatment setting.[48] The responses included one complete response (CR) and 22 partial responses (PRs).[10]

Beyond the response rate, the durability of these responses was particularly noteworthy. The median DoR was 11.2 months, and the median PFS was 7.9 months.[10] This suggests that for the nearly half of patients who respond, the clinical benefit can be sustained for a prolonged period, a significant improvement over existing options. Furthermore, the disease control rate (DCR), which includes patients with stable disease in addition to those with responses, was an impressive 98%, indicating that nearly all patients derived some measure of disease stabilization from the treatment.[10]

In a separate, smaller subgroup analysis of 18 patients with platinum-sensitive ovarian cancer, the efficacy signal was even more striking. This cohort demonstrated a confirmed ORR of 72.2%, comprised entirely of partial responses.[12] While these data are preliminary due to the small sample size, such a high response rate in a pretreated population suggests that raludotatug deruxtecan could be a highly active agent if developed for earlier lines of therapy, provided a safe and tolerable dose can be established.

B. Renal Cell Carcinoma (RCC) Cohort: An Emerging Opportunity

The initial Phase 1 trial was designed to enroll patients with both advanced ovarian cancer and renal cell carcinoma.[8] Early reports from the trial indicated that raludotatug deruxtecan suggested early clinical activity in both tumor types.[9] However, detailed efficacy metrics for the RCC cohort, such as ORR or PFS, have not been publicly disclosed in the available materials. The continued investigation of raludotatug deruxtecan in RCC, specifically the inclusion of a clear cell RCC (ccRCC) cohort in the new REJOICE-PanTumor01 basket trial, strongly implies that the developers observed a sufficient signal of anti-tumor activity in the Phase 1 study to warrant further exploration in this indication.[44]

VII. Comprehensive Safety and Tolerability Assessment

The safety profile of raludotatug deruxtecan is a critical component of its overall clinical profile and has been the primary driver of its development strategy. While generally described as manageable and consistent with the known toxicities of other DXd ADCs, the data from the Phase 1 trial (NCT04707248) revealed a significant, dose-dependent risk of interstitial lung disease (ILD) that has become the program's central challenge.[10]

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

In the safety analysis of patients with ovarian cancer, treatment-emergent adverse events (TEAEs) of any grade were common, occurring in 95% of patients.[13] The most frequently reported TEAEs were primarily gastrointestinal and constitutional, including nausea (58.3%), fatigue (45.0%), and vomiting (33.3%).[9] Hematologic toxicities were also common, including anemia (28.3%) and decreased neutrophil count (25.0%).[13]

Grade 3 or higher TEAEs were reported in 51.7% of patients.[13] The most common severe events were hematologic, with Grade 3 or higher anemia occurring in 18.3% of patients and decreased neutrophil count in 11.7%.[10] These events are generally manageable with supportive care, dose interruptions, or dose reductions.

B. Dose-Limiting Toxicities and Dose Discontinuation

The dose-escalation portion of the Phase 1 trial identified a clear toxicity threshold. Two dose-limiting toxicities (DLTs)—one case of Grade 3 febrile neutropenia and one case of Grade 4 thrombocytopenia—were observed at the 9.6 mg/kg dose level.[9] This finding established that 9.6 mg/kg exceeded the maximum tolerated dose (MTD).

More consequentially, the 8.0 mg/kg dose level was discontinued in October 2022 following the observation of two fatal cases of treatment-related ILD.[10] This severe safety signal was a pivotal event for the program, leading to a strategic pivot to explore lower, potentially safer doses in subsequent clinical development.

C. A Critical Analysis of Interstitial Lung Disease (ILD)

Interstitial lung disease/pneumonitis represents the most significant and life-threatening safety risk associated with raludotatug deruxtecan and is a recognized class-effect toxicity of the DXd ADC platform.[10]

• Fatal Events: The two Grade 5 (fatal) treatment-related ILD events occurred in patients receiving the 8.0 mg/kg dose.[10] This established an unambiguous upper boundary for safe dosing and underscored the potential severity of this adverse event.
• Non-Fatal Events: Importantly, the risk of ILD was not confined to the highest dose levels. Adjudicated cases of treatment-related Grade 2 ILD were also reported in patients receiving lower doses, specifically across the 4.8 mg/kg to 6.4 mg/kg range.[10]

The clinical data for raludotatug deruxtecan present a classic drug development challenge where high efficacy appears to be correlated with significant toxicity. The 8.0 mg/kg dose, while likely a major contributor to the strong efficacy signals observed, proved to be unacceptably toxic due to the fatal ILD cases. The central question for the program's future is whether the lower doses now under investigation in the REJOICE-Ovarian01 trial (4.8, 5.6, and 6.4 mg/kg) can maintain a clinically meaningful and competitive level of anti-tumor activity while reducing the incidence and severity of ILD to a level deemed acceptable by patients, physicians, and regulatory agencies. The observation of Grade 2 ILD even at these lower doses indicates that the risk is not eliminated, but rather potentially mitigated. Therefore, the success of raludotatug deruxtecan is not merely a matter of demonstrating efficacy; it is about establishing a superior benefit-risk profile compared to existing and emerging therapies. The dose-optimization phase of the pivotal trial is explicitly designed to answer this question, and its outcome will be the most critical determinant of the drug's future.

VIII. Therapeutic and Competitive Landscape

A. Standard of Care in Target Indications

Raludotatug deruxtecan is being developed for indications with significant unmet medical needs, particularly platinum-resistant ovarian cancer (PROC).

• Platinum-Resistant Ovarian Cancer: The prognosis for patients with PROC is poor, and the treatment landscape is characterized by therapies with modest efficacy.[48] The current standard of care typically involves single-agent, non-platinum chemotherapy regimens such as paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan.[14] These agents generally yield low objective response rates, often in the range of 6-15%, and short median progression-free survival of only 3-4 months.[48] The addition of the anti-angiogenic agent bevacizumab can improve these outcomes, particularly when combined with weekly paclitaxel, but a substantial need for more effective and durable therapies remains.[48] The recent FDA approval of mirvetuximab soravtansine (Elahere), an ADC targeting folate receptor alpha (FRα), has introduced a new, effective targeted therapy for a biomarker-selected subset of PROC patients and has raised the bar for new agents entering this space.[50]
• Advanced Renal Cell Carcinoma: The treatment paradigm for advanced RCC has been revolutionized by the introduction of immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF) targeted tyrosine kinase inhibitors (TKIs), often used in combination in the first-line setting. However, there remains a need for effective therapies for patients whose disease progresses on these initial treatments.

B. The Emerging CDH6-Targeted Pipeline

While raludotatug deruxtecan is the most clinically advanced CDH6-targeted therapy, it is not without competition. Several other companies are developing ADCs against the same target, creating a race to define the best-in-class agent.

Table 3: Competitive Landscape of CDH6-Targeted ADCs

Drug Name	Developer(s)	Payload	Linker	DAR	Key Indications	Development Phase	Key Clinical Data/Status
Raludotatug deruxtecan (R-DXd)	Daiichi Sankyo / Merck & Co.	DXd (Topo I inhibitor)	Cleavable (GGFG)	8	Ovarian Cancer, Renal Cell Carcinoma	Phase 2/3	Confirmed ORR of 46% in PROC 1
CUSP06	OnCusp Therapeutics / Multitude Therapeutics	Exatecan (Topo I inhibitor)	Cleavable	8	Ovarian Cancer, Solid Tumors	Phase 1b	Confirmed ORR of 36% in HGSOC; FDA Fast Track Designation 37
SIM0505	Simcere Zaiming / NextCure	TOPOi payload	Proprietary	N/A	Solid Tumors	Phase 1 (China); US Phase 1 planned Q3 2025	Preclinical data shows robust anti-tumor activity 53
Abbreviations: ADC, antibody-drug conjugate; DAR, drug-to-antibody ratio; Topo I, topoisomerase I; ORR, objective response rate; PROC, platinum-resistant ovarian cancer; HGSOC, high-grade serous ovarian cancer; FDA, U.S. Food and Drug Administration.

Raludotatug deruxtecan currently holds a significant first-mover advantage, being the only CDH6-directed ADC to have advanced into a pivotal Phase 2/3 trial. However, this lead is challenged by its known safety liability. The emergence of competitors like CUSP06 is particularly notable. CUSP06 employs a very similar ADC construct, featuring an exatecan payload and a high DAR of 8.[51] It has already secured FDA Fast Track Designation for PROC, a regulatory milestone that can expedite development and review, and which may suggest a more favorable early safety profile that garnered regulatory support.[52] While the preliminary ORR of 36% reported for CUSP06 in high-grade serous ovarian cancer is lower than the 46% reported for R-DXd, direct comparisons are difficult due to differences in patient populations, dose levels, and trial designs.[51] Another contender, SIM0505, is in early-stage development but also utilizes a topoisomerase I inhibitor payload and is backed by a partnership between Simcere and NextCure for development outside of China.[53]

This competitive dynamic creates a scenario where the market for CDH6-targeted therapies will likely not be won on efficacy alone. Raludotatug deruxtecan's ILD risk creates a distinct vulnerability and a clear opening for a competitor. An agent that can demonstrate a superior safety profile—specifically, lower rates of severe ILD—while maintaining robust clinical activity could ultimately emerge as the best-in-class therapy, even if it is second or third to market. The benefit-risk balance will be the paramount consideration for clinicians and regulators.

IX. Strategic Analysis and Future Outlook

A. Corporate Strategy: The Merck & Co. Partnership

In October 2023, Daiichi Sankyo entered into a major global development and commercialization agreement with Merck & Co. for three of its DXd ADC candidates, including raludotatug deruxtecan.[1] This collaboration is a powerful endorsement of the asset's potential. The partnership provides not only substantial financial backing to support the extensive and costly clinical trials required for approval but also access to Merck's formidable global expertise in oncology clinical development, regulatory affairs, and commercialization. This strategic alliance significantly enhances the program's probability of technical and regulatory success, assuming the clinical data ultimately support a favorable benefit-risk profile.

B. Regulatory Pathway and Biomarker Strategy

A noteworthy aspect of raludotatug deruxtecan's development is the apparent absence of any expedited regulatory designations from the U.S. Food and Drug Administration (FDA), such as Fast Track or Breakthrough Therapy Designation, based on the available information.[10] This stands in contrast to its direct competitor, CUSP06, which was granted Fast Track Designation for platinum-resistant ovarian cancer.[52]

The lack of such a designation for raludotatug deruxtecan is a telling data point. Expedited programs are granted to drugs that treat serious conditions and demonstrate the potential to address an unmet medical need, based on promising early clinical data. It is plausible that while the efficacy data from the Phase 1 trial were indeed promising, the severe ILD safety signal, including the two patient deaths, may have given regulators pause. The FDA may be exercising caution, preferring to see a more robust characterization of the safety profile at lower, optimized doses before granting a designation that implies an accelerated path to approval. This suggests that the regulatory bar for raludotatug deruxtecan may be higher, and the developers will need to present an exceptionally clean and compelling dataset from the REJOICE-Ovarian01 dose-optimization phase to gain full regulatory support.

The design of the pivotal trial, which includes stratification based on tumor CDH6 expression (high vs. low), indicates that a biomarker strategy is integral to the drug's development.[16] While the potent bystander effect may confer activity in tumors with lower antigen expression, the greatest clinical benefit is anticipated in the CDH6-high population. Defining this patient population precisely will be key to maximizing the drug's benefit-risk ratio and securing regulatory approval.

C. Concluding Assessment

Raludotatug deruxtecan stands as a pioneering, potential first-in-class ADC that has demonstrated a remarkably high ceiling for efficacy in difficult-to-treat cancers with significant unmet medical need. Its mechanism of action is well-rationalized, its DXd platform technology is validated, and its target, CDH6, is biologically relevant and prognostically significant.

However, the program's trajectory has been defined by the dose-dependent ILD toxicity observed in the Phase 1 trial. The future of raludotatug deruxtecan is now entirely dependent on the outcome of the dose-optimization phase of the REJOICE-Ovarian01 study. This phase represents a critical inflection point for the program.

If a dose within the 4.8 mg/kg to 6.4 mg/kg range is proven to be both substantially more effective than standard chemotherapy and to possess a manageable safety profile with a significantly reduced risk of severe ILD, raludotatug deruxtecan is strongly positioned to become a new standard of care for CDH6-expressing malignancies. The backing of Daiichi Sankyo and Merck provides the commercial strength to establish it as a market leader.

Conversely, if the lower doses fail to maintain a compelling efficacy advantage, or if the risk of severe ILD remains unacceptably high, the program faces a high probability of failure. Such an outcome would cede the promising CDH6-targeted therapeutic space to emerging competitors who may be able to achieve a more favorable balance between efficacy and safety. The clinical data generated over the next 12-24 months will be the ultimate arbiter of whether raludotatug deruxtecan fulfills its potential as a breakthrough therapy or becomes a cautionary tale of a potent drug constrained by its own toxicity.

Works cited

1. Raludotatug Deruxtecan | DS-6000a R-DXd » ADC Review, accessed June 24, 2025, https://www.adcreview.com/drugmap/raludotatug-deruxtecan-ds-6000a-r-dxd/
2. (PDF) Raludotatug Deruxtecan, a CDH6-Targeting Antibody–Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models - ResearchGate, accessed June 24, 2025, https://www.researchgate.net/publication/377334363_Raludotatug_Deruxtecan_a_CDH6-Targeting_Antibody-Drug_Conjugate_with_a_DNA_Topoisomerase_I_Inhibitor_DXd_is_Efficacious_in_Human_Ovarian_and_Kidney_Cancer_Models
3. Raludotatug deruxtecan by Daiichi Sankyo for Ovarian Cancer: Likelihood of Approval, accessed June 24, 2025, https://www.pharmaceutical-technology.com/data-insights/raludotatug-deruxtecan-daiichi-sankyo-ovarian-cancer-likelihood-of-approval/
4. Abstract 2850: Characterization of cadherin 6 as a novel therapeutic target in metastatic ovarian carcinoma | Cancer Research, accessed June 24, 2025, https://aacrjournals.org/cancerres/article/79/13_Supplement/2850/634809/Abstract-2850-Characterization-of-cadherin-6-as-a
5. CDH6 as a prognostic indicator and marker for chemotherapy in gliomas - Frontiers, accessed June 24, 2025, https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.949552/full
6. Raludotatug Deruxtecan, a CDH6-Targeting Antibody–Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models - PubMed Central, accessed June 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10911705/
7. Raludotatug Deruxtecan, a CDH6-Targeting Antibody–Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models - AACR Journals, accessed June 24, 2025, https://aacrjournals.org/mct/article/23/3/257/734961/Raludotatug-Deruxtecan-a-CDH6-Targeting-Antibody
8. A Study of DS-6000a in Subjects With Advanced Renal Cell Carcinoma and Ovarian Tumors | ClinicalTrials.gov, accessed June 24, 2025, https://clinicaltrials.gov/study/NCT04707248
9. A Study of DS-6000a in Subjects With Advanced Renal Cell Carcinoma and Ovarian Tumors, accessed June 24, 2025, https://clin.larvol.com/trial-detail/NCT04707248
10. Raludotatug Deruxtecan Continues to Demonstrate Promising Clinical Activity in Patients with Advanced Ovarian Cancer in Early Trial - Daiichi Sankyo, accessed June 24, 2025, https://daiichisankyo.us/press-releases/-/article/raludotatug-deruxtecan-continues-to-demonstrate-promising-clinical-activity-in-patients-with-advanced-ovarian-cancer-in-early-trial
11. Raludotatug Deruxtecan Continues to Demonstrate Promising Clinical Activity in Patients with Advanced Ovarian Cancer in Early Trial - Daiichi Sankyo, accessed June 24, 2025, https://www.daiichisankyo.com/files/news/pressrelease/pdf/202310/20231022_E2.pdf
12. Raludotatug Deruxtecan Shows Activity in Platinum-Sensitive Ovarian Cancer - OncLive, accessed June 24, 2025, https://www.onclive.com/view/raludotatug-deruxtecan-shows-activity-in-platinum-sensitive-ovarian-cancer
13. Raludotatug Deruxtecan Elicits Early Efficacy and Safety in Platinum-Resistant Ovarian Cancer - OncLive, accessed June 24, 2025, https://www.onclive.com/view/raludotatug-deruxtecan-elicits-early-efficacy-and-safety-in-platinum-resistant-ovarian-cancer
14. REJOICE-Ovarian01 Phase 2/3 Trial of Raludotatug Deruxtecan Initiated in Patients With Platinum-Resistant Ovarian Cancer - Merck.com, accessed June 24, 2025, https://www.merck.com/news/rejoice-ovarian01-phase-2-3-trial-of-raludotatug-deruxtecan-initiated-in-patients-with-platinum-resistant-ovarian-cancer/
15. REJOICE-Ovarian01 Phase 2/3 Trial of Raludotatug Deruxtecan Initiated in Patients with Platinum-Resistant Ovarian Cancer - Daiichi Sankyo, accessed June 24, 2025, https://www.daiichisankyo.com/files/news/pressrelease/pdf/202404/20240403_E2.pdf
16. REJOICE-Ovarian01: A phase 2/3 study of raludotatug deruxtecan (R-DXd) in patients with platinum-resistant ovarian cancer (OVC). | Journal of Clinical Oncology - ASCO Publications, accessed June 24, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS5625
17. Raludotatug deruxtecan - Drug Targets, Indications, Patents - Patsnap Synapse, accessed June 24, 2025, https://synapse.patsnap.com/drug/75550c3d5e1443d8a30c52ea1a6dedfe
18. Datopotamab deruxtecan granted breakthrough therapy designation in US for patients with previously treated advanced EGFR-mutated non-small cell lung cancer - AstraZeneca US, accessed June 24, 2025, https://www.astrazeneca-us.com/media/press-releases/2024/datopotamab-deruxtecan-granted-breakthrough-therapy-designation-in-US-for-patients-with-previously-treated-advanced-EGFR-mutated-non-small-cell-lung-cancer.html
19. Datopotamab Deruxtecan Granted Breakthrough Therapy Designation in U.S. for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer - Daiichi Sankyo US, accessed June 24, 2025, https://daiichisankyo.us/press-releases/-/article/datopotamab-deruxtecan-granted-breakthrough-therapy-designation-in-u-s-for-patients-with-previously-treated-advanced-egfr-mutated-non-small-cell-lung-
20. DATROWAY® Approved in the U.S. as First TROP2 Directed Therapy for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer - Daiichi Sankyo US, accessed June 24, 2025, https://daiichisankyo.us/press-releases/-/article/datroway-approved-in-the-u-s-as-first-trop2-directed-therapy-for-patients-with-previously-treated-advanced-egfr-mutated-non-small-cell-lung-cancer
21. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer, accessed June 24, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast
22. Datopotamab Deruxtecan Granted Priority Review in the U.S. for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer - Daiichi Sankyo, accessed June 24, 2025, https://daiichisankyo.us/press-releases/-/article/datopotamab-deruxtecan-granted-priority-review-in-the-u-s-for-patients-with-previously-treated-advanced-egfr-mutated-non-small-cell-lung-cancer
23. Press Release - ENHERTU® Granted Priority Review in the US for Patients with Metastatic HER2 Positive Solid Tumors - Daiichi Sankyo, accessed June 24, 2025, https://www.daiichisankyo.com/files/news/pressrelease/pdf/202401/20240129_E.pdf
24. Datopotamab Deruxtecan Granted Breakthrough Therapy Designation in U.S. for Patients With Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer - Daiichi Sankyo, accessed June 24, 2025, https://www.daiichisankyo.com/files/news/pressrelease/pdf/202412/20241209_E.pdf
25. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer | FDA, accessed June 24, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-hr-positive-her2-low-or-her2
26. FDA Grants Accelerated Approval to Dato-DXd for EGFR+ NSCLC - OncLive, accessed June 24, 2025, https://www.onclive.com/view/fda-grants-accelerated-approval-to-dato-dxd-for-egfr-nsclc
27. Datroway Approved in the U.S. as First TROP2 Directed Therapy for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer - Drugs.com, accessed June 24, 2025, https://www.drugs.com/newdrugs/datroway-approved-u-s-first-trop2-directed-therapy-patients-previously-treated-advanced-egfr-6556.html
28. Most FDA and EMA Oncology Drug Approvals in Q1 2025 Were New Indications for Biologics and Biosimilars - Aptitude Health, accessed June 24, 2025, https://www.aptitudehealth.com/oncology-news/most-fda-and-ema-oncology-drug-approvals-in-q1-2025-were-new-indications-for-biologics-and-biosimilars/
29. ASCO 2025: Real-World Data Support Rechallenging Trastuzumab Deruxtecan After ILD, accessed June 24, 2025, https://www.pharmacytimes.com/view/asco-2025-real-world-data-supports-rechallenging-trastuzumab-deruxtecan-after-ild
30. Definition of raludotatug deruxtecan - NCI Drug Dictionary, accessed June 24, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/raludotatug-deruxtecan
31. A Study of DS-6000a in Subjects With Advanced Renal Cell Carcinoma and Ovarian Tumors, accessed June 24, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-03783
32. Raludotatug Deruxtecan, a CDH6-Targeting Antibody-Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models - PubMed, accessed June 24, 2025, https://pubmed.ncbi.nlm.nih.gov/38205802/
33. aacrjournals.org, accessed June 24, 2025, https://aacrjournals.org/mct/article/23/3/257/734961/Raludotatug-Deruxtecan-a-CDH6-Targeting-Antibody#:~:text=R%2DDXd%20specifically%20binds%20to,cell%20replication%20and%20induces%20apoptosis.
34. Expression of CDH6 in cancer - Summary - The Human Protein Atlas, accessed June 24, 2025, https://www.proteinatlas.org/ENSG00000113361-CDH6/cancer
35. Advancements in CDH6-Targeted Drug Research for Cancer Treatment - Cusabio, accessed June 24, 2025, https://www.cusabio.com/c-21203.html
36. Cadherin-6 type 2, K-cadherin (CDH6) is regulated by mutant p53 in the fallopian tube but is not expressed in the ovarian surface | Oncotarget, accessed June 24, 2025, https://www.oncotarget.com/article/11499/text/
37. First-in-human (FIH) phase 1 study of CUSP06, a cadherin-6 (CDH6)-directed antibody-drug conjugate (ADC), in patients with platinum-refractory/resistant ovarian cancer and other advanced solid tumors. - ASCO Publications, accessed June 24, 2025, https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.3042
38. A phase 1, first-in-human study of CUSP06, a cadherin-6 (CDH6) -directed antibody-drug conjugate, in patients with platinum-refractory/resistant ovarian cancer and other advanced solid tumors. - ASCO Publications, accessed June 24, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS3166
39. DS6000-109 - Institut Curie, accessed June 24, 2025, https://institut-curie.org/clinical-trial/ds6000-109
40. GOG-3096 DS6000-109 (Ovarian, Primary Peritoneal, and Fallopian Tube Cancers) - Clinical Trial - Duke Health, accessed June 24, 2025, https://www.dukehealth.org/clinical-trials/directory/pro00115756
41. DS6000-109 Phase2/3 R-DXd versus Investigator's Choice in Platinum-resistant Ovarian Cancer - NHS Health Research Authority, accessed June 24, 2025, https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/ds6000-109-phase23-r-dxd-versus-investigators-choice-in-platinum-resistant-ovarian-cancer/
42. A Study of Raludotatug Deruxtecan (R-DXd) in Subjects With Platinum-resistant, High-grade Ovarian, Primary Peritoneal, or Fallopian Tube Cancer - ClinicalTrials.Veeva, accessed June 24, 2025, https://ctv.veeva.com/study/a-study-of-raludotatug-deruxtecan-r-dxd-in-subjects-with-platinum-resistant-high-grade-ovarian-p
43. REJOICE-Ovarian01: A phase 2/3 study of raludotatug deruxtecan (R-DXd) in patients with platinum-resistant ovarian cancer (OVC). - ASCO Meeting Program Guide, accessed June 24, 2025, https://meetings.asco.org/abstracts-presentations/238476
44. Raludotatug Deruxtecan for Cancer - Clinical Trials, accessed June 24, 2025, https://www.withpower.com/trial/phase-2-solid-tumors-advanced-solid-tumors-11-2024-0dc51
45. REJOICE-PanTumor01: A phase 2 signal-seeking study of raludotatug deruxtecan (R-DXd) in patients with advanced or metastatic gynecologic or genitourinary tumors. - ASCO Publications, accessed June 24, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS3158
46. Press Release - Daiichi Sankyo Continues to Transform Treatment Landscape for Patients with Cancer with Practice-Changing Data at ASCO, accessed June 24, 2025, https://www.daiichisankyo.com/files/news/pressrelease/pdf/202505/20250522_E2.pdf
47. Trial of DS-6000a Elicits Early Efficacy/Safety Data in RCC and Ovarian Cancer, accessed June 24, 2025, https://www.targetedonc.com/view/trial-of-ds-6000a-elicits-early-efficacy-safety-data-in-rcc-and-ovarian-cancer
48. Overcoming the challenges of drug development in platinum-resistant ovarian cancer - PMC, accessed June 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10616588/
49. Analysis of drug-related interstitial lung disease (ILD) in patients treated with datopotamab deruxtecan (Dato-DXd) - DataSource by Daiichi Sankyo, accessed June 24, 2025, https://datasourcebydaiichisankyo.com/documents/20833/21602/ASCO%202024_Dato-DXd_Sands_Poster_FINAL.pdf
50. ADCs and PARP Inhibitors Are Among 2025's Practice-Changing Agents in Ovarian Cancer, accessed June 24, 2025, https://www.onclive.com/view/adcs-and-parp-inhibitors-are-among-2025-s-practice-changing-agents-in-ovarian-cancer
51. OnCusp Therapeutics Announces Encouraging Initial Phase 1a Results from Ongoing First-in-Human Study Evaluating its CDH6-Directed Antibody-Drug Conjugate, CUSP06, in Platinum-Refractory/Resistant Ovarian Cancer and Other Advanced Solid Tumors at the 2025 ASCO Annual Meeting - PR Newswire, accessed June 24, 2025, https://www.prnewswire.com/news-releases/oncusp-therapeutics-announces-encouraging-initial-phase-1a-results-from-ongoing-first-in-human-study-evaluating-its-cdh6-directed-antibody-drug-conjugate-cusp06-in-platinum-refractoryresistant-ovarian-cancer-and-other-advanced--302470621.html
52. OnCusp Therapeutics Receives FDA Fast Track Designation for CUSP06 for the Treatment of Platinum-Resistant Ovarian Cancer - PR Newswire, accessed June 24, 2025, https://www.prnewswire.com/news-releases/oncusp-therapeutics-receives-fda-fast-track-designation-for-cusp06-for-the-treatment-of-platinum-resistant-ovarian-cancer-302374728.html
53. NextCure and Simcere Zaiming Announce Strategic Partnership for a Novel Antibody-Drug Conjugate Targeting CDH6 - GlobeNewswire, accessed June 24, 2025, https://www.globenewswire.com/news-release/2025/06/16/3099713/0/en/NextCure-and-Simcere-Zaiming-Announce-Strategic-Partnership-for-a-Novel-Antibody-Drug-Conjugate-Targeting-CDH6.html
54. NextCure and Simcere Zaiming Announce Strategic Partnership for a Novel Antibody-Drug Conjugate Targeting CDH6, accessed June 24, 2025, https://ir.nextcure.com/news-releases/news-release-details/nextcure-and-simcere-zaiming-announce-strategic-partnership/
55. NextCure Buys ADC for Up to $745 Million | Cancer Discovery News - AACR Journals, accessed June 24, 2025, https://aacrjournals.org/cdnews/news/2451/NextCure-Buys-ADC-for-Up-to-745-Million
56. FDA Grants Fast Track Designation to CUSP06 for Platinum-Resistant Ovarian Cancer, accessed June 24, 2025, https://www.onclive.com/view/fda-grants-fast-track-designation-to-cusp06-for-platinum-resistant-ovarian-cancer
57. ASCO25: OnCusp reports positive initial Phase Ia data from trial of CUSP06, accessed June 24, 2025, https://www.clinicaltrialsarena.com/news/oncusp-positive-cusp06/
58. OnCusp's CUSP06 Receives FDA Fast Track Designation - Contract Pharma, accessed June 24, 2025, https://www.contractpharma.com/breaking-news/oncusps-cusp06-receives-fda-fast-track-designation/
59. NextCure advances ADC pivot with $745M deal for phase 1 drug - Fierce Biotech, accessed June 24, 2025, https://www.fiercebiotech.com/biotech/nextcure-continues-adc-pivot-745m-deal-simceres-phase-1-drug
60. NextCure And Simcere Zaiming Partner To Develop CDH6-Targeting ADC SIM0505 For Solid Tumors | Nasdaq, accessed June 24, 2025, https://www.nasdaq.com/articles/nextcure-and-simcere-zaiming-partner-develop-cdh6-targeting-adc-sim0505-solid-tumors
61. IDeate-Prostate01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated in Patients with Pretreated Metastatic Castration-Resistant Prostate Cancer - Business Wire, accessed June 24, 2025, https://www.businesswire.com/news/home/20250618458357/en/IDeate-Prostate01-Phase-3-Trial-of-Ifinatamab-Deruxtecan-Initiated-in-Patients-with-Pretreated-Metastatic-Castration-Resistant-Prostate-Cancer
62. IDeate-Prostate01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated in Patients with Pretreated Metastatic Castration-Resistant Prostate Cancer - Merck.com, accessed June 24, 2025, https://www.merck.com/news/ideate-prostate01-phase-3-trial-of-ifinatamab-deruxtecan-initiated-in-patients-with-pretreated-metastatic-castration-resistant-prostate-cancer/
63. Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review | FDA, accessed June 24, 2025, https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapy-accelerated-approval-priority-review
64. Clinical Oncology News & Insights - OncLive, accessed June 24, 2025, https://www.onclive.com/news
65. Press Releases - Media - Daiichi Sankyo, accessed June 24, 2025, https://www.daiichisankyo.com/media/press_release/
66. 46 - YAbS - The Antibody Society, accessed June 24, 2025, https://db.antibodysociety.org/db0/results_cmpny?sort=drug_codes&page=46
67. Pipelines Report 2024: M&A and AI Momentum - Model N, accessed June 24, 2025, https://www.modeln.com/company/news/media-coverage/ma-and-ai-momentum/
68. Merck & Co., Inc. - SEC.gov, accessed June 24, 2025, https://www.sec.gov/Archives/edgar/data/310158/000162828025017867/formars202410-k.pdf
69. Merck & Co., Inc., accessed June 24, 2025, https://www.merck.com/wp-content/uploads/sites/124/2025/02/0001628280-25-007732.pdf
70. Patritumab Deruxtecan Biologics License Application for Patients With Previously Treated Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer Voluntarily Withdrawn - Merck.com, accessed June 24, 2025, https://www.merck.com/news/patritumab-deruxtecan-biologics-license-application-for-patients-with-previously-treated-locally-advanced-or-metastatic-egfr-mutated-non-small-cell-lung-cancer-voluntarily-withdrawn/
71. PRIME: priority medicines - EMA - European Union, accessed June 24, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/research-development/prime-priority-medicines
72. Congresses | Daiichi Sankyo - DataSource by Daiichi Sankyo, accessed June 24, 2025, https://datasourcebydaiichisankyo.com/congresses/-/view/congress/38002/ASCO+GI+2025