A Decision Brief on CLDN18.2 in Gastric/GEJ Cancer

Executive Summary

This brief provides a comprehensive analysis to guide a “Go / No-Go” decision on initiating an R&D program targeting Claudin 18.2 (CLDN18.2) for gastric and gastro-oesophageal junction (GEJ) adenocarcinoma. Our analysis covers the scientific, clinical, competitive, regulatory, and commercial landscapes, concluding with a strategic recommendation based on a five-year outlook (2025–2030).

The Opportunity: CLDN18.2 has been unequivocally validated as a therapeutic target by the recent global approvals and successful launch of Astellas’s monoclonal antibody (mAb), zolbetuximab (Vyloy™). The target is expressed in a significant subset (~30-40%) of the ~968,000 annual new cases of gastric cancer worldwide, a market with high unmet need and projected to grow to nearly $48 billion by 2035 27, 50. Zolbetuximab’s rapid uptake and blockbuster sales projections (≥$1 billion peak consensus) confirm a substantial commercial appetite for effective CLDN18.2-directed therapies 21.

The Challenge: The competitive landscape is formidable and rapidly evolving. Astellas holds a significant first-mover advantage with zolbetuximab, which has established a robust efficacy and safety benchmark in the first-line setting. The pipeline is densely populated with over 60 programs, including late-stage monoclonal antibodies, multiple Phase II/III antibody-drug conjugates (ADCs), and a burgeoning number of CAR-T and bispecific antibody programs, particularly in China and the US 19. Furthermore, the intellectual property (IP) landscape is a complex “thicket” of composition-of-matter and functional claims that requires careful navigation 36, 38, 41.

Key Findings:

Scientific Validation is Unambiguous: CLDN18.2’s tumor-specific expression makes it an ideal target. Zolbetuximab’s pivotal SPOTLIGHT and GLOW trials demonstrated statistically significant and clinically meaningful improvements in Progression-Free Survival (PFS) and Overall Survival (OS) when added to standard chemotherapy 9, 10.

The mAb Window is Closed: Developing a “me-too” monoclonal antibody to compete with zolbetuximab is strategically untenable. The market is primed for next-generation therapies that can offer differentiation.

ADCs Represent the Most Viable “Fast-Follower” Strategy: ADCs are the most mature next-generation modality, with multiple assets in mid-to-late-stage development (e.g., LaNova’s LM-302, Innovent’s IBI-343) showing promising activity in later lines of therapy 12, 19. This modality offers clear avenues for differentiation through novel antibodies, advanced linker-payload technologies, and a potentially superior therapeutic index.

CAR-T and Bispecifics are High-Risk, High-Reward: CAR-T therapies like CARsgen’s satricabtagene autoleucel (CT041) have shown impressive early responses but face significant hurdles, including on-target/off-tumor gastric toxicity, complex manufacturing logistics, and high costs 15, 20. Bispecifics are at an earlier stage of development and represent a longer-term opportunity.

A “Green-Field” Build is Not Feasible: The capital investment, timelines, and specialized expertise required to build manufacturing capabilities for advanced biologics—especially ADCs or cell therapies—from the ground up are prohibitive. A “buy” or “partner” strategy is the only realistic path to enter this competitive field in a timely manner.

Strategic Recommendation: Conditional GO

We recommend a Conditional GO to initiate a CLDN18.2 program, with the explicit strategy of in-licensing or co-developing a differentiated, potentially best-in-class Antibody-Drug Conjugate (ADC).

This approach balances the significant market opportunity with the intense competitive pressures. It avoids a futile head-to-head battle with an established mAb and instead positions our company as a “fast follower” with a next-generation asset. The focus should be on identifying a preclinical or early clinical-stage ADC with a clear differentiation strategy, such as a novel epitope, a superior safety profile, or activity in zolbetuximab-resistant settings.

High-Priority Next Actions:

Initiate Partner Outreach (0-3 Months): Immediately begin targeted business development outreach to a pre-vetted shortlist of companies with promising early-stage CLDN18.2 ADC assets.

Commission FTO Analysis (0-3 Months): Engage legal counsel to conduct a deep-dive Freedom-to-Operate (FTO) analysis on 2-3 lead candidate assets identified through initial screening.

Establish Diligence Teams (3-6 Months): Form cross-functional due diligence teams to rigorously evaluate the scientific, technical, and commercial potential of shortlisted partnership opportunities.

Secure Asset (6-12 Months): Execute a licensing, co-development, or acquisition agreement to secure rights to the chosen asset and formally launch the internal development program.

1.0 Scientific & Clinical Landscape

1.1 Biology and Prevalence of CLDN18.2 in Gastric/GEJ Cancer

Claudin 18.2 (CLDN18.2) is an isoform of a tight junction protein, which in healthy tissue is exclusively expressed in the gastric mucosa and sequestered within the gastric pits, inaccessible to circulating antibodies. During malignant transformation in gastric and GEJ cancers, the disruption of cellular polarity exposes the extracellular loops of CLDN18.2 on the tumor cell surface. This tumor-specific presentation makes it an exceptional target for cancer therapies like monoclonal antibodies, which can induce antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) 1. The prevalence of CLDN18.2 expression in G/GEJ adenocarcinoma is consistently reported in the range of 25-40%, though definitions of positivity vary across studies. The pivotal trials for zolbetuximab, SPOTLIGHT and GLOW, used a stringent cutoff of ≥75% of tumor cells showing moderate-to-strong staining, which identified 38.4% of screened patients as eligible 4.

Table 1: Prevalence of CLDN18.2 Expression in G/GEJ Adenocarcinoma

Study	Patient Cohort (n)	CLDN18.2+ Definition	Prevalence	Key Findings
Shitara et al., 2024 (SPOTLIGHT/GLOW Screening) 4	3,783 (Global)	≥75% cells with moderate-strong staining	38.4%	Similar rates in gastric vs. GEJ; most prevalent in diffuse-type histology.
Zhang et al., 2025 (China) 2	937 (Resected)	≥2+ intensity in ≥5% of cells	25.8%	Enriched in EBV-positive tumors; no association with PD-L1 or HER2.
Martínez-Ciarpaglini et al., 2025 (Spain) 3	270 (Biopsies)	≥2+ or 3+ in ≥75% of cells	33%	Inverse correlation with signet-ring content; worse PFS in intestinal-type advanced tumors.
Ahn et al., 2025 (Korea) 5	1,538 (TMA)	≥50% / ≥75% cutoffs	34.7% / 24.4%	Significant overlap with FGFR2b overexpression (60% of FGFR2b+ were also CLDN18.2+).

The data confirm that CLDN18.2 is a prevalent biomarker across geographies, particularly in diffuse-type and EBV-positive cancers. Its expression appears largely independent of other key biomarkers like HER2 and PD-L1, defining a distinct and substantial patient segment. The VENTANA CLDN18 (43-14A) RxDx IHC assay has been established as a reliable and reproducible companion diagnostic 8.

1.2 Critical Appraisal of Pivotal and Ongoing Trials

Monoclonal Antibodies: The Zolbetuximab Benchmark Astellas’s zolbetuximab is the first-in-class and only approved CLDN18.2-targeted therapy. Its approval was based on two global Phase III trials in the first-line (1L) setting for patients with CLDN18.2-positive, HER2-negative advanced G/GEJ adenocarcinoma.

Table 2: Pivotal Phase III Trials for Zolbetuximab

Trial	Regimen	n	Primary Endpoint	Median PFS (HR)	Median OS (HR)	Key Safety Signals
SPOTLIGHT (NCT03504397) 9, 20	Zolbetuximab + mFOLFOX6 vs. Placebo + mFOLFOX6	565	PFS	11.0 vs. 8.9 months (HR ~0.73)	18.2 vs. 15.6 months (HR 0.78)	Nausea (76%), Vomiting (67%)
GLOW (NCT03653507) 1020	Zolbetuximab + CAPOX vs. Placebo + CAPOX	507	PFS	8.2 vs. 6.8 months (HR 0.69)	14.4 vs. 12.2 months (HR 0.77)	Nausea, Vomiting

These trials successfully met their primary endpoints, establishing a new standard of care. The survival benefit is statistically significant and clinically meaningful, setting a high efficacy bar for any new entrant. The primary toxicities are on-target gastrointestinal effects (nausea, vomiting), which are generally manageable but notable 10.

Antibody-Drug Conjugates (ADCs): The Leading “Fast-Follower” Modality

ADCs aim to improve upon the efficacy of naked mAbs by delivering a potent cytotoxic payload directly to the tumor. Several are in development, with promising data in later-line settings. Tecotabart Vedotin (LM-302): In a Phase 1/2 trial for heavily pretreated (≥2 prior lines) CLDN18.2+ patients, this ADC demonstrated an Objective Response Rate (ORR) of 32.7% and a median PFS of 4.9 months. Toxicities were manageable and related to the MMAE payload 12. A Phase III trial is underway. IBI-343 (Innovent): This ADC is also in Phase III development in China and Japan 19. SKB-315 (Kelun-Biotech/Merck): An early-stage ADC that is part of a major partnership, highlighting significant industry interest 19. ADCs show clear activity in patients who have progressed on other therapies, suggesting they could be positioned in second-line or later, or potentially move into the first-line setting if they demonstrate a superior risk/benefit profile to zolbetuximab. Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: High-Risk, High-Reward CAR-T therapy represents a potentially curative approach but comes with substantial challenges. Satricabtagene Autoleucel (CT041/TAC01-CLDN18.2): This is the most advanced CLDN18.2 CAR-T. Phase I/II data in heavily pretreated patients showed a promising Disease Control Rate (DCR) of 67%, with two durable partial responses (PRs) in patients with high CLDN18.2 expression. However, safety signals included Cytokine Release Syndrome (CRS) and on-target/off-tumor toxicities like gastritis and gastric hemorrhage, though these were reported as manageable 15,20. The primary hurdle for CAR-T is mitigating the on-target toxicity to healthy gastric tissue while preserving anti-tumor efficacy. The complex and costly “vein-to-vein” manufacturing and logistics further complicate its path to broad adoption in solid tumors 75. Bispecific Antibodies: An Emerging Frontier Bispecifics, such as T-cell engagers (e.g., Amgen’s AMG-910) or dual-checkpoint inhibitors (e.g., QureBio’s Q-1802), are in early-stage development. PM-1032 showed an early ORR of 20% in a Phase I/II trial 20. This modality is less mature than ADCs but offers another avenue for differentiation by engaging multiple biological pathways simultaneously.

2.0 Competitive Intelligence

The CLDN18.2 space is highly competitive, with Astellas’s zolbetuximab as the established leader and a deep pipeline of followers across all major modalities and geographies.

2.1 Pipeline Mapping by Modality

China is a major hub of CLDN18.2 development, with over 45 programs, followed by the US with over 20 19.

Table 3: Overview of the CLDN18.2 Competitive Pipeline

Modality	Key Players & Assets (Phase)	Strategic Implication
Monoclonal Antibody (mAb)	Astellas (Zolbetuximab - Approved), AstraZeneca (AZD-0901 - Ph III), FutureGen (FG-M108 - Ph III), Jiangsu Aosaikang (ASKB-589 - Ph III) 19	The 1L mAb market is becoming saturated. Competing here requires significant differentiation or a focus on niche populations.
Antibody-Drug Conjugate (ADC)	LaNova/BMS (LM-302 - Ph III), Innovent (IBI-343 - Ph III), AstraZeneca (AZD-0901 - Ph II/III), Sotio (SOT-102 - Ph II), Kelun/Merck (SKB-315 - Ph I) 19	This is the most dynamic and competitive “fast-follower” space. Multiple late-stage assets are poised to challenge zolbetuximab, likely in 2L+ first.
CAR-T Cell Therapy	CARsgen (Satricabtagene autoleucel - Ph II), Legend Biotech (LB-1908 - Ph I), Multiple Chinese biotechs (Ph I) 19	CARsgen is the clear leader. This is a high-risk area with potential for disruptive efficacy but significant safety and manufacturing hurdles.
Bispecific Antibody	Amgen (AMG-910 - Ph I), Astellas (ASP-2138 - Ph I), I-Mab (Givastomig - Ph I), QureBio (Q-1802 - Ph II) 19	An emerging field with diverse mechanisms (CD3, 4-1BB, PD-L1). Currently less mature than ADCs, offering a longer-term opportunity.

2.2 Profiles of Key Competitors

Astellas Pharma: The undisputed market leader. Having acquired zolbetuximab’s originator (Ganymed) for up to $1.3 billion, Astellas has successfully navigated global regulatory approvals and is building a franchise, recently licensing a preclinical ADC from Evopoint for up to $1.34 billion 21, 23. AstraZeneca: A formidable competitor with a strong oncology portfolio and ADC expertise. Their asset, AZD-0901, is in late-stage development as both a mAb and an ADC 19. Innovent Biologics: A leading Chinese biotech with a Phase III ADC (IBI-343) and a major strategic partnership with Takeda for global development, highlighting the value of these next-generation assets 45, 46. CARsgen Therapeutics: The frontrunner in the CAR-T space with satricabtagene autoleucel (CT041), which has shown promising early data and is advancing in global trials 19.

2.3 Patent Thickets and Freedom-to-Operate (FTO)

The CLDN18.2 IP landscape is crowded and presents a significant FTO challenge. Key considerations include: Composition-of-Matter Claims: The space is dominated by patents claiming specific antibody sequences (HCDR/LCDR sets). Any new mAb or the antibody portion of an ADC/CAR-T/Bispecific must be designed to avoid infringing on these claims, which generally expire in the late-2030s to early-2040s 38, 39, 40. Epitope Claims: Early patents, such as those from Ganymed (now BioNTech/Astellas), include functional claims covering antibodies that bind to the same epitope as zolbetuximab. A new antibody must demonstrate it binds to a distinct epitope 37. Linker-Payload IP: For ADCs, there is a second layer of IP around the linker chemistry and cytotoxic payload. For example, patents from Kelun-Biotech and Ganymed cover specific linker-payload combinations (e.g., vc-MMAE) for CLDN18.2-targeting ADCs 37, 41. Developing a proprietary linker or using a novel payload is a key FTO strategy. Strategic Mitigation: A successful FTO strategy requires developing a novel antibody with unique CDR sequences targeting a non-overlapping epitope. For ADCs, employing proprietary linker-payload technology is crucial. Given the density of the landscape, in-licensing an asset with an established and clear IP position is a major de-risking step.

3.0 Regulatory & Reimbursement Outlook

Zolbetuximab’s successful global regulatory journey has paved the way for future CLDN18.2-targeted therapies.

Table 4: Global Regulatory and Reimbursement Status of Zolbetuximab (as of Nov 2025)

Region / Agency	Regulatory Status	Reimbursement / HTA Status
United States (FDA)	Approved Oct 2024 for 1L CLDN18.2+, HER2- G/GEJ cancer 11.	Billable under J-code J1326. No ICER review has been conducted to date.
European Union (EMA)	Approved Sep 2024 for 1L CLDN18.2+, HER2- G/GEJ cancer 32.	National pricing negotiations are ongoing in other EU states 35.
Japan (MHLW/PMDA)	Approved Mar 2024 (first in the world) 33.	Listed on the National Health Insurance (NHI) drug price list, ensuring broad access.
China (NMPA)	Approved Jun 2025 34.	Awaiting inclusion in the National Reimbursement Drug List (NRDL); provincial tendering is the near-term access path.

The key takeaway is that regulators globally have accepted the clinical benefit of targeting CLDN18.2. Payers and HTA bodies, have also recognized its value, albeit with pressure on pricing. This established pathway significantly de-risks the regulatory and market access strategy for a well-differentiated follow-on product.

4.0 Market & Commercial Assessment

4.1 Epidemiology and Addressable Market

Gastric cancer is the fifth most common malignancy globally, with an estimated 968,350 new cases in 2022. The highest incidence rates are in Eastern Asia (China, Japan), Eastern Europe, and parts of South America 50, 51. The majority of patients (>65%) are diagnosed with advanced or metastatic disease, where the prognosis is poor 51. Addressable Patient Population: With a CLDN18.2 prevalence of ~38% in the 1L advanced G/GEJ setting, the initial addressable market for a targeted therapy is substantial. Market Size: The global market for G/GEJ adenocarcinoma therapeutics was valued at $9.1 billion in 2025 and is forecast to grow at a remarkable 18% CAGR to $47.7 billion by 2035 27. This growth is driven by the introduction of novel targeted therapies and immunotherapies.

4.2 Revenue Potential and Pricing Analogues

Zolbetuximab’s commercial performance provides a strong positive signal: Early Sales: Astellas reported ¥12.2 billion (~$80 million) in its first full fiscal year post-launch in Japan, an “exceptional start” 21. Peak Sales Forecast: Analyst consensus projects peak annual sales of ≥$1 billion, with some models suggesting Japan alone could contribute nearly $900 million by 2030 21, 22. Pricing for a new CLDN18.2 therapy will be benchmarked against other advanced oncology biologics.

Table 5: Pricing Benchmarks for Oncology Modalities

Modality	Typical Annual Cost (US)	Relevance to CLDN18.2 Strategy
Naked mAbs (e.g., trastuzumab)	$70,000 – $120,000	Zolbetuximab is likely priced in the upper end of this range.
Antibody-Drug Conjugates (e.g., Enhertu)	$150,000 – $200,000+	Sets the pricing expectation for a next-generation CLDN18.2 ADC, offering a significant premium over a mAb if differentiation is proven 28.
CAR-T Cell Therapies (e.g., Yescarta)	$400,000 – $500,000 (WAC)	Represents the ceiling for therapies with curative potential, but less relevant for solid tumors until durable responses are more common 29.

4.3 Key Unmet Medical Needs

Despite recent advances, significant unmet needs remain: Poor Survival in Later Lines: Median OS in the real world remains poor (12-15 months), and effective options after first-line therapy are limited 58. This creates a clear opportunity for therapies like ADCs that have shown activity in 2L+ settings. Treatment Resistance: Resistance to chemotherapy and targeted agents (including zolbetuximab) will inevitably develop, requiring new mechanisms of action. Quality of Life: The toxicity burden of current therapies is high. A therapy with a superior safety profile would be highly valued 51.

5.0 Internal Capability & Build-vs-Buy Analysis

Assuming a “green-field” starting point, the decision to build internal capabilities versus acquiring or partnering for them is critical. The manufacturing and technical complexity of next-generation biologics strongly favors a “buy/partner” approach.

Table 6: Manufacturing & Capability Comparison by Modality

Capability	Monoclonal Antibodies (mAbs)	Antibody-Drug Conjugates (ADCs)	Autologous CAR-T
Core Process	Standard upstream/downstream biologics manufacturing 73.	mAb production + chemical synthesis of linker-payload + high-potency conjugation and purification 74.	Patient-specific leukapheresis, gene transfer, cell expansion, and cryopreservation 75.
Facility Needs	cGMP suites (ISO 5-8) 76.	All mAb facilities plus segregated, high-containment (BSL-2+) suites for handling cytotoxic payloads 74.	BSL-2+ cGMP suites, complex vein-to-vein logistics, chain-of-custody tracking 75.
Key Challenge	Scale-up and cost of goods.	Supply chain integration (antibody, linker, payload), operator safety, process consistency (DAR) 74.	Patient variability, >$100k cost per dose, rapid turnaround time, scalability (“scale-out” vs. “scale-up”) 75.
Build-vs-Buy	Build: Feasible but slow. Buy: Faster via CDMO.	Build: Extremely high capex and specialized expertise required. Buy: Strongly recommended via specialized ADC CDMOs or partnership 80.	Build: Prohibitively complex and expensive for a new entrant. Buy: Essential via partnership or acquisition.

Analysis: Build: Building cGMP manufacturing from scratch for any of these modalities would take years and hundreds of millions of dollars in capital expenditure, placing us far behind the competition. Buy/Partner: This is the most pragmatic and capital-efficient strategy. Licensing/Co-development: Allows entry with a de-risked asset while sharing costs and leveraging a partner’s expertise. Deal comps in GI oncology show upfront payments of $20-80 million with total deal values often exceeding $500 million 68. ADC-specific deals are even larger, with total values often exceeding $2 billion 69. M&A: Acquiring a company with a promising asset and platform (e.g., Astellas/Ganymed) is the fastest but most expensive route, with valuations often in the range of 1.5-3.0x risk-adjusted peak sales 68. Given our “green-field” status, a licensing or co-development partnership for an early-stage ADC is the optimal path.

6.0 Financial Modeling & Decision Metrics

A formal financial model should be built upon a “Go” decision, but we can outline the core inputs and metrics based on available benchmarks. Base-Case Development Cost (for a new ADC): A risk-adjusted model would incorporate phase-specific costs and success probabilities.

Table 7: Illustrative Development Cost & Timeline for a CLDN18.2 ADC

Phase	Out-of-Pocket Cost (Benchmark)	Probability of Success (Oncology Avg.)	Timeline (Years)
Phase 1	$15 - 30 M 60	~50% (to Phase 2) 72	1-2
Phase 2	$20 - 40 M 60	~30% (to Phase 3) 72	2-3
Phase 3	$80 - 150 M+ 60	~60% (to Approval) 72	3-4
CMC & Other	$100 - 150 M 64	N/A	Parallel
Total (Pre-Launch)	~$215 - 370 M (unrisked)	~11% (Phase 1 to Approval)	~7-9 Years

Decision Metrics: Risk-Adjusted NPV (rNPV): The primary valuation metric. Future cash flows (based on peak sales >$1B, ADC pricing, and market share assumptions) would be discounted at a rate of 12-18% and adjusted by the cumulative probability of success 71, 72. A positive rNPV is required. Internal Rate of Return (IRR): Should exceed the corporate hurdle rate, typically >15-20% for projects of this risk profile 71. Scenario Planning: Best Case: In-license a best-in-class ADC that demonstrates superiority to zolbetuximab in 1L, capturing significant market share and premium pricing. Base Case: Develop a differentiated ADC that is successful in the 2L+ setting and carves out a durable niche, achieving peak sales of $500M-$1B. Worst Case: The partnered asset fails in pivotal trials or shows a “me-too” profile with no commercial viability.

7.0 Strategic Recommendation & Next Steps

Conclusion: Conditional GO The evidence strongly supports a strategic entry into the CLDN18.2 space, but not with a “me-too” approach. The market is large and validated, but the competitive bar is high. We recommend a Conditional GO, contingent on the successful execution of a “buy/partner” strategy focused on a differentiated Antibody-Drug Conjugate (ADC). Rationale: Why “Go”? The commercial opportunity is too significant to ignore. CLDN18.2 is a pillar of precision oncology in gastric cancer, and the market is large enough to support multiple blockbuster drugs, especially those with differentiated profiles. Why “Conditional”? A “Go” decision is only viable if we can secure the right asset. A “green-field” build or a “me-too” mAb strategy would be a strategic failure. Why an ADC? This modality offers the best balance of innovation, clinical validation, and strategic viability. It provides a clear path to differentiate from the first-generation mAb, addresses the unmet need in later-line settings, and has a navigable (though complex) IP and manufacturing path via partnerships. Key De-risking Steps and Early Triggers: Asset Identification: The primary risk is finding a partner with a truly differentiated asset. Success hinges on identifying an ADC with a novel antibody, a superior linker-payload, or a compelling preclinical safety profile. Freedom-to-Operate: Early and thorough FTO analysis is non-negotiable to avoid costly IP disputes down the line. Proof-of-Concept: The early clinical data from a potential partner must show a clear signal of efficacy and a manageable safety profile that is competitive with other ADCs in development.

High-Priority Next Actions:

Timeline	Action Item	Objective
0-3 Months	Initiate Targeted Business Development Outreach: Identify and contact a shortlist of 5-10 companies (public and private) with preclinical or Phase I CLDN18.2 ADC assets.	To screen the landscape for viable partnership opportunities.
0-3 Months	Commission Preliminary FTO Assessment: Engage IP counsel to perform a high-level FTO analysis on the modality and on the IP of 2-3 initial companies of interest.	To quickly identify any insurmountable IP hurdles.
3-6 Months	Conduct Deep Due Diligence: Form a cross-functional team to perform in-depth scientific, CMC, and commercial diligence on the top 1-2 candidates.	To validate the differentiation hypothesis and partnership viability.
6-12 Months	Negotiate and Execute Partnership Agreement: Finalize term sheet and execute a definitive licensing, co-development, or M&A agreement.	To secure the asset and officially launch the CLDN18.2 program.