GSK-5733584: A Comprehensive Analysis of a Novel B7-H4-Targeted Antibody-Drug Conjugate in Oncology

I. Executive Summary

[GSK-5733584 is an investigational new molecular entity poised to address significant unmet medical needs in advanced solid tumors, particularly within gynecologic oncology. Developed by Hansoh Pharma and licensed by GSK for global development, this agent is an antibody-drug conjugate (ADC) meticulously engineered to target B7-homolog 4 (B7-H4), a transmembrane protein overexpressed on numerous cancers with limited presence in healthy tissues. Its architecture comprises a humanized anti-B7-H4 IgG1 monoclonal antibody, a stable protease-cleavable linker, and a potent topoisomerase-1 inhibitor (TOP1i) payload, rezetecan, with a high drug-to-antibody ratio of 6. This design facilitates the targeted delivery of a cytotoxic agent directly to cancer cells, leading to DNA damage and apoptosis.]

[The clinical development program for GSK-5733584 is robust and strategically focused. Building on promising initial data from a first-in-human Phase 1 study in China (NCT05263479), GSK has launched a global, multiregional Phase 1/2 study, BEHOLD-1 (NCT06431594). This pivotal trial is designed not only to establish a safe and effective dose but also to evaluate clinical activity in dedicated expansion cohorts of heavily pre-treated patients with platinum-resistant ovarian cancer (PROC) and advanced/recurrent endometrial cancer (EC). A subsequent Phase 1/2 study, BEHOLD-2 (NCT06796907), will explore its potential in combination with other anti-cancer therapies.]

[Preliminary data from the initial Phase 1 trial have been encouraging. The agent demonstrated a manageable safety profile, with treatment-emergent adverse events, primarily hematologic, that are consistent with the known effects of its TOP1i payload. Dose-limiting toxicities were observed only at the highest dose level tested. Critically, the study revealed a compelling signal of antitumor activity, with an objective partial response rate of 24.2% in an evaluable, mixed-histology population. The efficacy signal was particularly pronounced in patients with triple-negative breast cancer (TNBC), where response rates exceeded 40% in the potential therapeutic dose range, suggesting broad applicability beyond its initial focus.]

Strategically, GSK-5733584 is positioned to become a cornerstone of GSK's growing oncology franchise. The BEHOLD-1 trial's eligibility criteria specifically target patient populations for whom current standards of care—including platinum chemotherapy, PARP inhibitors, bevacizumab, and immune checkpoint inhibitors—have failed. This precise targeting of a high unmet need could pave the way for an accelerated regulatory pathway. Furthermore, the drug complements GSK's existing assets in gynecologic cancers, Jemperli (dostarlimab) and Zejula[ (niraparib), creating a potential continuum of care. As GSK-5733584 advances, its success will depend on mature data from the BEHOLD studies, its performance relative to other B7-H4-targeted agents in a competitive landscape, and its ability to navigate potential challenges such as payload class cross-resistance.]

II. Molecular Profile and Mechanism of Action

The therapeutic potential of GSK-5733584 is rooted in its sophisticated molecular design, which combines the high specificity of a monoclonal antibody with the potent cytotoxicity of a validated chemotherapy payload. As a new molecular entity, its architecture is a tripartite system, with each component engineered to fulfill a specific role in a multi-step "seek and destroy" mission against cancer cells.[1]

### Component Architecture: A Tripartite System

GSK-5733584 is defined as an immunoconjugate, a class of drugs that physically links distinct functional molecules.[2][ Its structure consists of three core components:]

• Antibody: The targeting moiety is a humanized immunoglobulin G1 (IgG1) monoclonal antibody. This antibody is engineered to bind with high affinity and specificity to B7-homolog 4 (B7-H4), also known as V-set domain-containing T-cell activation inhibitor 1 (VTCN1).[1][ The selection of a humanized IgG1 backbone is a standard and critical choice in ADC design, intended to minimize the risk of immunogenicity in patients and to potentially allow for the engagement of Fc-mediated immune effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC).]
• Payload: The cytotoxic agent is a topoisomerase-1 inhibitor (TOP1i) known as rezetecan (HS-9265).[1][ TOP1i payloads are a clinically validated class of chemotherapeutics that function by interfering with the process of DNA replication and repair. Their high potency makes them ideal for use in ADCs, where only a small number of payload molecules may reach the intracellular target.]
• Linker: The antibody and payload are connected by a stable, protease-cleavable tetrapeptide (GGFG) linker.[3][ The design of the linker is paramount to the safety and efficacy of an ADC. This particular linker is engineered for high stability in systemic circulation, preventing the premature release of the toxic payload that could lead to off-target side effects. Upon internalization of the ADC into the target cancer cell, the linker is designed to be efficiently cleaved by lysosomal proteases, such as cathepsins, which are often present at high concentrations within tumor cells. This ensures that the payload is released specifically at the site of action.]

A defining characteristic of GSK-5733584 is its average drug-to-antibody ratio (DAR) of 6.[3][ The DAR represents the number of payload molecules attached to each antibody. A DAR of 6 is relatively high, reflecting a design choice that prioritizes the delivery of a robust cytotoxic dose to the target cell. This decision to maximize payload delivery accepts the inherent risk of a more pronounced, but predictable, toxicity profile associated with the TOP1i payload class in exchange for potentially greater antitumor efficacy. This approach will directly inform the clinical management of patients, who may require careful monitoring and supportive care, such as growth factor support, to manage expected hematologic side effects.]

### Pharmacodynamics: The "Seek and Destroy" Mechanism

The mechanism of action of GSK-5733584 is a sequential process that leverages the unique properties of each of its components to achieve targeted cell killing.[1]

1. Targeting and Binding: Upon intravenous administration, GSK-5733584 circulates throughout the body. The anti-B7-H4 antibody moiety selectively seeks out and binds to B7-H4 protein expressed on the surface of tumor cells.[1]
2. Internalization: Following binding, the entire ADC-B7-H4 complex is internalized by the tumor cell through endocytosis.[1]
3. Payload Release: Once inside the cell, the complex is trafficked to the lysosome. Within this acidic, enzyme-rich compartment, the protease-cleavable linker is degraded, releasing the active TOP1i payload, rezetecan, into the cytoplasm.[1]
4. Induction of DNA Damage: The freed rezetecan translocates to the nucleus, where it exerts its cytotoxic effect. It binds to the DNA-TOP1 enzyme complex, stabilizing it in a state where a single strand of DNA is cleaved. This action prevents the enzyme from completing its function of re-ligating the DNA strand.[1]
5. Apoptosis: The accumulation of these stabilized "cleavage complexes" poses a major obstacle to the DNA replication machinery during the S-phase of the cell cycle. The collision of replication forks with these complexes leads to the conversion of single-strand breaks into irreversible, lethal double-strand DNA breaks. This extensive DNA damage triggers downstream signaling pathways that activate cell cycle arrest and, ultimately, programmed cell death (apoptosis).[1]

[This targeted delivery mechanism ensures that the potent cytotoxic effect of the TOP1i payload is concentrated specifically within B7-H4-expressing tumor cells, thereby maximizing the therapeutic window and sparing healthy tissues that lack significant B7-H4 expression.]

### The B7-H4 Target: A Compelling Rationale for ADC Development

The selection of B7-H4 as the target antigen is central to the therapeutic hypothesis of GSK-5733584. B7-H4 is a transmembrane protein belonging to the B7 family of immune modulators, which play critical roles in regulating T-cell activation and tolerance.[1]

B7-H4's profile makes it an exceptionally attractive target for ADC development for two primary reasons. First, its expression pattern is highly tumor-selective. It is frequently overexpressed in a wide array of solid tumors—including ovarian, endometrial, triple-negative breast, and cholangiocarcinoma—while its expression in normal, healthy tissues is very limited.[1] This differential expression is the cornerstone of the ADC's intended safety profile, creating a large therapeutic index by directing the cytotoxic payload preferentially to cancer cells.[7] GSK has emphasized that B7-H4 is highly expressed in tumors with significant unmet medical need, as evidenced by poor 5-year survival rates for patients with distant metastatic disease in key indications like endometrial cancer (18%), ovarian cancer (32%), and TNBC (13%).[7]

Second, B7-H4 is not merely a passive docking site for the ADC; it is a functionally active protein that contributes to the cancer's survival. As an immune checkpoint molecule, B7-H4 negatively regulates T-cell immune responses, helping to create an immunosuppressive tumor microenvironment that allows the cancer to evade immune destruction.[1][ This dual identity as both a tumor-associated antigen and a functional immune checkpoint presents a unique therapeutic opportunity. The primary mechanism of GSK-5733584 is the direct killing of tumor cells via payload delivery. However, by targeting and eliminating B7-H4-expressing cells, the ADC may also confer a secondary benefit by reducing a key source of local immunosuppression. This provides a compelling biological rationale for future combination strategies, particularly with other immunotherapies like PD-1 inhibitors. Such a combination could be synergistic, with the ADC killing tumor cells and simultaneously making the tumor microenvironment more permissive to the T-cell-reinvigorating effects of the checkpoint inhibitor. This hypothesis is set to be tested in the BEHOLD-2 clinical trial.]

Table 1: Key Characteristics of GSK-5733584

Characteristic	Description	Source(s)
Alternative Names	GSK5733584, HS-20089	1
Originator/Developer	GSK / Hansoh Pharma	2
Drug Class	Antibody-Drug Conjugate (ADC), Antineoplastic	1
Target Antigen	B7-H4 (VTCN1)	1
Antibody Component	Humanized IgG1 monoclonal antibody	1
Payload Component	Topoisomerase-1 Inhibitor (TOP1i) - Rezetecan (HS-9265)	1
Linker Technology	Protease-cleavable tetrapeptide (GGFG)	3
Drug-to-Antibody Ratio (DAR)	6	3
Mechanism of Action	B7-H4-targeted delivery of a TOP1i payload, inducing DNA damage and apoptosis	1

III. The Clinical Development Program: BEHOLD and Beyond

[The clinical development pathway for GSK-5733584 is a structured, multi-stage program designed to systematically evaluate its safety, pharmacokinetics, and antitumor activity, moving from initial dose-finding to targeted evaluation in specific patient populations and, ultimately, to combination therapies. The program is anchored by the BEHOLD series of studies, which represent the global effort to bring this promising agent to patients.]

### Foundation: First-in-Human Study in China (NCT05263479)

The clinical journey of GSK-5733584 began under its original designation, HS-20089, in a first-in-human Phase 1 study sponsored by its originator, Hansoh Pharma.[3] This foundational trial was conducted in China and enrolled patients with a variety of advanced solid tumors. A key feature of its design was that patients were not pre-selected based on the B7-H4 expression status of their tumors.[3] The primary objectives were to establish the initial safety profile, determine the maximum tolerated dose (MTD), and characterize the pharmacokinetic (PK) properties of the molecule.[5] The study's findings were pivotal; it demonstrated that HS-20089 had an acceptable safety profile and, importantly, showed preliminary signs of antitumor activity.[3] This early evidence of a favorable risk-benefit profile was instrumental in GSK's decision to in-license the asset in October 2023 and commit to a broader, global development program.[8]

### The Global Pillar: BEHOLD-1 Study (NCT06431594)

The centerpiece of the current development strategy is the BEHOLD-1 study, a multiregional, open-label, two-part Phase 1 trial sponsored by GSK.[3] This study, which is actively recruiting participants across North America, Europe, Asia, and Australia, is designed to rigorously validate the early findings and deeply explore the drug's potential in well-defined patient populations.[2]

Part 1a (Dose Escalation):

The first part of the study is a dose-escalation phase with the primary goal of confirming the safety, tolerability, and PK of GSK-5733584 in a non-Chinese patient population and ultimately determining the recommended Phase 2 dose (RP2D).3 It is enrolling approximately 26 to 40 patients with advanced solid tumors who have either failed or are intolerant to established therapies.3 The study employs a "rolling six" dose-escalation design, a common methodology in early-phase oncology trials, to efficiently assess safety at ascending dose levels. The planned intravenous (IV) doses are 2.8, 4.8, 5.8, and 7.2 mg/kg, administered on a once-every-three-weeks (Q3W) schedule.3 The primary endpoint for this phase is the incidence of dose-limiting toxicities (DLTs), which will directly inform the MTD and RP2D.4

Part 1b (Dose Expansion):

Once the RP2D is established, the study will proceed to its second part, a dose-expansion phase. The objective here is to gather more robust data on the clinical activity of GSK-5733584 at two to three selected dose levels in specific cohorts of patients with high unmet medical needs.3 The primary endpoint for this phase shifts from safety to efficacy, specifically the confirmed objective response rate (ORR) as assessed by investigators according to RECIST 1.1 criteria.4 The two initial expansion cohorts are:

• Platinum-Resistant Ovarian Cancer (PROC): This cohort will enroll approximately 90 patients.[3]
• Endometrial Cancer (EC): This cohort will enroll approximately 60 patients.[3]

The eligibility criteria for these cohorts have been crafted with remarkable precision, reflecting a sophisticated development strategy. For the PROC cohort, patients must have progressed on platinum therapy and have already received standard agents like bevacizumab, a PARP inhibitor (if they have a BRCA mutation), and the ADC mirvetuximab soravtansine (if their tumor expresses Folate receptor-α).[10] Similarly, the EC cohort requires patients to have received prior platinum chemotherapy and a PD-(L)1 immune checkpoint inhibitor.[10][ This careful selection targets a "post-everything" patient population for whom there are few or no effective treatment options left. This approach serves two strategic purposes: it addresses a clear and urgent unmet need, which can facilitate a smoother regulatory process, and it aims to elicit a clean efficacy signal by studying the drug in a setting free of confounding treatments. This clearly defines the initial market entry point for GSK-5733584 should it prove successful.]

### The Future: BEHOLD-2 Combination Study (NCT06796907)

Looking ahead, GSK is already laying the groundwork for the next stage of development with the BEHOLD-2 study. This is a Phase 1/2 trial, initiated in March 2025, designed to evaluate the safety and efficacy of GSK-5733584 administered in combination with other anti-cancer therapies for advanced solid tumors.[2] The rationale for this study is to explore potential synergistic effects by pairing the targeted cytotoxicity of GSK-5733584 with agents that have complementary mechanisms of action. Preclinical models and scientific literature have suggested that combining B7-H4-targeted ADCs with therapies like anti-PD-1 antibodies or PARP inhibitors can lead to enhanced tumor regression.[5][ This study is crucial for unlocking the full potential of GSK-5733584 and expanding its use beyond monotherapy.]

The overall clinical strategy demonstrates a clear intent to build a franchise within gynecologic oncology, where GSK already has a strong presence with Jemperli (dostarlimab) in endometrial cancer and Zejula (niraparib) in ovarian cancer.[17][ The BEHOLD-1 trial is enrolling patients who have progressed on the very classes of drugs that GSK markets for first-line and maintenance therapy. This creates a seamless continuum of care within the GSK portfolio, potentially allowing the company to treat a patient across multiple lines of therapy. The BEHOLD-2 combination trial will almost certainly explore combinations with these internal assets, further cementing this franchise strategy and leveraging GSK's deep expertise in this therapeutic area.]

Table 2: Overview of Major Clinical Trials for GSK-5733584

Study Identifier (NCT ID)	Phase	Title/Objective	Population	Status	Sponsor
NCT05263479	Phase 1	First-in-human study of HS-20089 to assess safety, PK, and preliminary activity	Advanced Solid Tumors	Data available	Hansoh Pharma
BEHOLD-1 (NCT06431594)	Phase 1/2	A study to evaluate the safety, tolerability, PK, and clinical activity of GSK5733584	Advanced Solid Tumors, with PROC and EC expansion cohorts	Active - Recruiting	GSK
BEHOLD-2 (NCT06796907)	Phase 1/2	A study of GSK5733584 in combination with other anti-cancer therapies	Advanced Solid Tumors	Active - Recruiting	GSK

Table 3: Key Eligibility Criteria for BEHOLD-1 Dose Expansion Cohorts (PROC & EC)

Criteria	Platinum-Resistant Ovarian Cancer (PROC) Cohort	Endometrial Cancer (EC) Cohort
Histology	High-grade serous/endometrioid ovarian, primary peritoneal, or fallopian tube cancer	Advanced/recurrent endometrial cancer (all epithelial histologies, including carcinosarcoma)
Prior Lines of Therapy	1 to 3 prior systemic lines	1 to 3 prior systemic lines
Required Prior Therapies	- Platinum-based therapy (progression within 6 months) - Prior bevacizumab (if eligible) - Prior PARP inhibitor (if BRCA mutated) - Prior mirvetuximab soravtansine (if FRα-expressing)	- Prior platinum-based therapy - Prior PD-(L)1 inhibitor
Key Exclusions	- Primary platinum refractory disease - Non-epithelial or specific low-grade histologies	- Uterine sarcomas (mesenchymal tumors)
Common Key Exclusions	- Prior B7-H4-targeted therapy - Prior therapy with topoisomerase inhibitors or TOP1i-based ADCs	- Prior B7-H4-targeted therapy - Prior therapy with topoisomerase inhibitors or TOP1i-based ADCs

Sources: [10]

IV. Emerging Clinical Profile: Safety and Efficacy

The initial clinical profile of GSK-5733584 is based on data from the first-in-human Phase 1 dose-escalation study (NCT05263479) conducted in China. These early results, while preliminary, provide the first critical insights into the drug's potential therapeutic window, outlining both its manageable safety risks and its promising antitumor activity.[5]

### Safety and Tolerability Profile

The safety analysis from the Phase 1 trial included 44 patients with advanced solid tumors who received GSK-5733584 at doses ranging from 0.7 mg/kg to 7.2 mg/kg on a Q3W schedule.[5] The overall safety profile was described as acceptable and manageable, with adverse events that were largely consistent with the known toxicities of the topoisomerase-1 inhibitor payload class.[3]

• Dose-Limiting Toxicities (DLTs): DLTs are a key safety endpoint in Phase 1 trials, used to define the maximum tolerated dose (MTD). In this study, DLTs were observed in two patients, both of whom were treated at the highest dose level of 7.2 mg/kg.[5][ While the specific nature of these toxicities was not detailed in the available reports, their occurrence at this dose level is a crucial finding that establishes the upper limit for safe administration and guides the selection of doses for further study in the BEHOLD-1 trial.]
• Treatment-Emergent Adverse Events (TEAEs): The most frequently reported TEAEs (occurring in ≥20% of patients) were predominantly hematologic and gastrointestinal in nature.[5][ The common TEAEs included:]
• Hematologic:[ Leukopenia (low white blood cell count), neutropenia (low neutrophil count), anemia (low red blood cell count), and thrombocytopenia (low platelet count). These myelosuppressive effects are a hallmark of TOP1i agents.]
• Constitutional and Gastrointestinal:[ Nausea, vomiting, fatigue, and anorexia (loss of appetite).]
• Laboratory Abnormalities:[ Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indicating potential transient liver stress, and hyponatremia (low sodium levels).]

[The emergence of DLTs at 7.2 mg/kg, coupled with the strong efficacy signal observed in the 4.8-5.8 mg/kg range (discussed below), suggests that the optimal therapeutic window for GSK-5733584 may be relatively narrow but is now well-defined. This provides a clear path forward for dose selection in the BEHOLD-1 expansion cohorts, which will almost certainly be centered around the 4.8-5.8 mg/kg range. However, it also underscores the critical importance of proactive and careful patient management to mitigate the expected on-target toxicities, as there appears to be limited room to escalate the dose further to overcome any potential drug resistance.]

### Preliminary Antitumor Activity

Efficacy data from the Phase 1 study were reported for 33 response-evaluable patients, providing the first clinical validation of the B7-H4-targeted ADC concept.[5][ The results showed clear evidence of antitumor activity across a range of heavily pre-treated solid tumors.]

• Overall Response: Across the evaluable population, an objective partial response (PR) was achieved in 24.2% of patients (8 out of 33).[5]
• Triple-Negative Breast Cancer (TNBC) Signal: The most compelling efficacy signal emerged from the subgroup of 16 patients with TNBC, a notoriously aggressive and difficult-to-treat cancer.[5]
• [Among all TNBC patients treated across various dose levels, the PR rate was 37.5% (6 out of 16).]
• [When analysis was focused on the 12 TNBC patients treated within the potential therapeutic dose range of 4.8 mg/kg to 5.8 mg/kg, the PR rate was even higher at 41.7% (5 out of 12).]
• Durability of Response: Early data also hinted at the potential for durable clinical benefit. One patient in the lowest dose cohort (0.7 mg/kg) achieved a PR and remained on treatment for over 403 days at the time of the data cutoff, suggesting that responses, when they occur, can be lasting.[8]

[This strong efficacy signal in TNBC is a particularly noteworthy finding. While GSK's immediate global development strategy is focused on leveraging its existing strengths in gynecologic cancers through the BEHOLD-1 PROC and EC cohorts, the asset's most impressive early performance was in breast cancer. This suggests a significant opportunity for future label expansion and indicates that the therapeutic potential of targeting B7-H4 may be very broad. This early signal substantially increases the overall value proposition of GSK-5733584 beyond its initial target indications and raises important strategic questions for GSK regarding the timing and prioritization of a dedicated development program in TNBC.]

Table 4: Summary of Preliminary Safety and Efficacy from Phase 1 (NCT05263479)

Parameter	Finding/Result	Source(s)
Patient Population	N=44 (41 Breast, 2 Ovarian, 1 Endometrial Cancer)	5
Dose Range Studied	0.7 - 7.2 mg/kg IV Q3W	5
Dose-Limiting Toxicities (DLTs)	Observed in 2 patients at the 7.2 mg/kg dose level	5
Common TEAEs (≥20%)	Leukopenia, neutropenia, nausea, anemia, thrombocytopenia, vomiting, fatigue, elevated ALT/AST, anorexia, hyponatremia	5
Response-Evaluable Population	N=33	5
Overall Partial Response (PR) Rate	24.2% (8/33)	5
TNBC Subgroup PR Rate (All Doses)	37.5% (6/16)	5
TNBC Subgroup PR Rate (4.8-5.8 mg/kg)	41.7% (5/12)	5

V. Therapeutic Context and Potential Positioning

[The strategic value of an investigational therapy is defined not only by its intrinsic activity but also by its ability to address unmet needs within the existing and evolving standards of care. GSK-5733584 is being developed to enter two specific, challenging therapeutic landscapes: platinum-resistant ovarian cancer and advanced/recurrent endometrial cancer.]

### Platinum-Resistant Ovarian Cancer (PROC)

Current Landscape and Unmet Need:

Platinum-resistant ovarian cancer, defined by disease progression occurring within six months of completing the last dose of platinum-based chemotherapy, represents a dire clinical scenario with a poor prognosis.21 Although most patients with advanced ovarian cancer initially respond to platinum-based regimens, approximately 85% will eventually experience recurrence, and many will develop platinum resistance.24

The current standard of care for PROC is limited to sequential single-agent, non-platinum chemotherapy, with agents such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), or topotecan.[21] The anti-angiogenic agent bevacizumab may be added to these chemotherapies, which modestly improves progression-free survival (PFS) and response rates.[21] However, the overall efficacy of these regimens is poor, with objective response rates (ORRs) typically in the range of 10-15%, median PFS of less than six months, and median overall survival (OS) of approximately one year.[21][ While newer targeted therapies have emerged, their use is restricted to specific biomarker-defined populations. These include PARP inhibitors for patients with germline or somatic]

BRCA mutations and the ADC mirvetuximab soravtansine for patients whose tumors have high folate receptor-alpha (FRα) expression.[21][ A large proportion of patients with PROC do not have these biomarkers and are left with only poorly effective chemotherapy options, representing a profound unmet medical need.]

Potential Positioning of GSK-5733584:

The BEHOLD-1 clinical trial is strategically designed to position GSK-5733584 directly within this area of high unmet need. The trial's stringent eligibility criteria for the PROC cohort mandate that enrolled patients must have already been treated with and progressed on the most effective modern therapies available, including platinum, bevacizumab, PARP inhibitors (if applicable), and mirvetuximab soravtansine (if applicable).10 This positions GSK-5733584 as a potential new standard of care in the third-line or later setting for a broad, biomarker-unselected PROC population. Success in this heavily pre-treated patient group would represent a major clinical advance.

### Advanced/Recurrent Endometrial Cancer (EC)

Evolving Landscape and Unmet Need:

The treatment paradigm for advanced or recurrent endometrial cancer has undergone a rapid and significant transformation. For decades, the standard first-line treatment was combination chemotherapy with carboplatin and paclitaxel.27 However, recent landmark clinical trials (e.g., RUBY, NRG-GY018) have established a new standard of care: the addition of a PD-1 immune checkpoint inhibitor (dostarlimab or pembrolizumab) to first-line chemotherapy.27 This combination has shown significant benefit, especially for the ~25% of patients whose tumors are mismatch repair-deficient (dMMR), but has also demonstrated improved outcomes for the majority of patients with proficient mismatch repair (pMMR) tumors.27 For patients with pMMR tumors who progress after first-line therapy, the combination of the tyrosine kinase inhibitor lenvatinib with pembrolizumab is an established second-line option.28

This rapid evolution, while beneficial for patients, creates a new and pressing unmet medical need: effective treatments for patients whose disease progresses after[ receiving a modern chemo-immunotherapy regimen. As chemo-IO becomes the universal first-line standard, a large population of patients will emerge for whom there are no clear, effective subsequent therapies.]

Potential Positioning of GSK-5733584:

The design of the BEHOLD-1 EC cohort anticipates this exact clinical scenario. The trial's eligibility criteria specifically require patients to have received prior treatment with both a platinum-based agent and a PD-(L)1 inhibitor.10 This perfectly positions GSK-5733584 to become the next standard of care for patients progressing on the new first-line chemo-IO regimens. By demonstrating efficacy in this emerging post-IO population, GSK-5733584 could fill a critical and growing gap in the endometrial cancer treatment algorithm.

A notable aspect of the development strategy is the use of a retrospective biomarker analysis. The BEHOLD-1 trial requires the collection of tumor tissue for the retrospective measurement of B7-H4 expression by immunohistochemistry (IHC).[10] However, enrollment is not restricted based on B7-H4 status. This "learn-as-you-go" approach is strategically sound. It allows GSK to assess the drug's activity in an all-comers population while simultaneously collecting the data needed to determine if B7-H4 expression correlates with clinical benefit.[4][ If a strong correlation is identified, future pivotal trials could be enriched for patients with high B7-H4 expression to maximize the probability of success. If no such correlation is found, the drug can proceed with a broader, all-comers indication. This de-risks the initial stages of development by not relying on an unvalidated biomarker for patient selection.]

VI. Strategic and Competitive Landscape

[The development of GSK-5733584 is not occurring in a vacuum but is part of a broader corporate strategy at GSK and is situated within a dynamic and competitive therapeutic landscape. Its ultimate success will be determined by its clinical performance, its strategic fit within GSK's portfolio, and its differentiation from competing agents.]

### Corporate Strategy and Asset Origin

GSK-5733584 entered GSK's pipeline through a strategic in-licensing agreement with its originator, Hansoh Pharma, announced in October 2023.[8] Under the terms of the deal, GSK made an upfront payment of $85 million to secure exclusive worldwide rights for the development and commercialization of the asset (then known as HS-20089), excluding mainland China, Hong Kong, Macau, and Taiwan.[8]

This acquisition is a clear manifestation of GSK's stated oncology strategy, which involves "gated investment in ADCs" to unlock opportunities across solid tumors and to bolster its pipeline through targeted business development.[9] GSK leadership has identified GSK-5733584 as a high-potential, early-stage asset and a key future growth driver for the 2027-2031 timeframe. It is viewed as a potential blockbuster therapy, alongside another in-licensed ADC, GSK5764227, which targets B7-H3.[17] The decision to invest in a TOP1i-based ADC, despite it being a well-established payload class, signals a strong conviction in the novelty and potential of the B7-H4 target itself, as well as confidence in the specific molecular engineering of the HS-20089 construct, which GSK believes may confer "best-in-class" potential.[7]

### The Competitive Field of B7-H4-Targeted Agents

GSK-5733584 is a leading candidate but not the only agent targeting B7-H4. The validation of B7-H4 as a promising ADC target has attracted several other pharmaceutical companies, creating an active competitive environment.[5][ Key competitors in clinical development include:]

• Puxitatug Samrotecan (AZD8205): Developed by AstraZeneca, this is also a B7-H4-targeted ADC that utilizes a TOP1i payload.[6] Its similar mechanism of action makes it a direct competitor. Early clinical data have been presented, but a notable observation from an ESMO presentation was the lack of responses among patients who had previously been treated with another TOP1i-based ADC.[30][ This has raised a critical question about potential class-wide cross-resistance among TOP1i payloads.]
• Felmetatug Vedotin (SGN-B7H4V / PF-08046048): Developed by Pfizer/Seagen, this ADC targets B7-H4 but employs a different class of payload: monomethyl auristatin E (MMAE), a potent anti-tubulin agent.[5][ The distinct mechanism of its payload could be a significant differentiating factor, potentially offering an effective treatment option for patients whose tumors are resistant to TOP1i-based therapies.]

[The clinical differentiation among these agents will ultimately hinge on the totality of their efficacy and safety data. Key factors will include their respective ORRs, the durability of responses, and the nature and severity of their unique toxicity profiles, which are often driven by the specific payload and linker technologies used.]

### Future Outlook and Key Catalysts

The development path for GSK-5733584 is clearly defined, with several key catalysts on the horizon. The most immediate and critical milestones are the data readouts from the ongoing BEHOLD-1 study. Initial results from the Part 1a dose-escalation phase will be crucial for confirming the safety profile and RP2D in a global population. Subsequently, the efficacy and safety data from the Part 1b dose-expansion cohorts in PROC and EC will provide the first robust proof-of-concept in these target indications. GSK has stated its intention to use this proof-of-concept data to pursue an accelerated registrational pathway.[17]

In the longer term, the value of GSK-5733584 will be shaped by the results of the BEHOLD-2 combination studies, its potential for label expansion into other B7-H4-expressing tumors like TNBC (where it showed a strong early signal), and its ability to navigate the competitive landscape. A significant strategic challenge will be addressing the question of TOP1i cross-resistance. The BEHOLD-1 trial currently excludes patients who have received prior TOP1i ADCs.[10][ However, as drugs like sacituzumab govitecan and trastuzumab deruxtecan become more entrenched in standard care, a large portion of the future patient population will have had prior exposure to this payload class. Demonstrating efficacy in this post-TOP1i setting, or strategically positioning GSK-5733584]

before[ other TOP1i ADCs in treatment algorithms, will be critical for maximizing its commercial potential.]

Works cited

1. Definition of anti-B7-H4/TOP1i antibody-drug conjugate GSK5733584 - NCI Drug Dictionary, accessed September 16, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-b7-h4-top1i-antibody-drug-conjugate-gsk5733584
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