"Diagnostics offer an opportunity…'Tevimbra' for gastric cancer"

In HER2-gastric cancer, diagnostic results dictate the treatment option

The introduction of the TAP 2 assessment is under discussion…Tevimbra's clinical significance attracts attention

The treatment landscape for metastatic gastric cancer is rapidly shifting toward a biomarker-driven precision medicine era. While treatment previously centered on cytotoxic chemotherapy, the recent advancements in which therapeutic strategies diverge based on diverse biomarkers, such as HER2, PD-L1, Claudin 18.2, and FGFR, has highlighted the importance of patient-tailored, personalized medicine.

With the introduction of immuno-oncology (IO) agents and targeted therapies, the diagnostic process (identifying 'which type of patient' it is, as much as 'which drug to use') has entered a stage where it dictates the success or failure of treatment. As treatment options vary depending on HER2 positivity, PD-L1 expression levels, and Claudin 18.2 expression status, diagnostic accuracy and turnaround time are directly linked to therapeutic opportunities.

DailyPharm met with Professor Min-hee Ryu and Professor Jaewon Hyung of the Department of Oncology and Professor Young Soo Park of the Department of Pathology from the Stomach Cancer Multidisciplinary Team at Asan Medical Center to discuss shifting therapeutic strategies driven by the expansion of precision diagnostics in gastric cancer, the clinical implications of Tumor Area Positivity (TAP)-based evaluation, and the evolving immuno-oncology landscape, including 'Tevimbra (tislelizumab)'.

The Stomach Cancer Center's Multidisciplinary Team at Asan Medical Center. From left, Professor Min-hee Ryu of the Department of Oncology, Professor Young Soo Park of the Department of Pathology, and Professor Jaewon Hyung of the Department of Oncology 

As biomarkers expand, the testing and interpretation processes are becoming increasingly complex. In particular, since gastric cancer is recognized as a relatively fast-progressing malignancy, concerns are being raised that a prolonged diagnostic process may delay the optimal initiation timing for first-line therapy.

Consequently, the importance of a multidisciplinary approach, in which multiple companion diagnostics (CDx) are performed concurrently at initial staging and the departments of pathology, medical oncology, surgery, and radiology collectively deliberate on the treatment direction, is growing. Asan Medical Center also operates a Stomach Cancer Center Multidisciplinary Team involving multiple clinical specialties, primarily focusing on patients with advanced gastric cancer to formulate optimal therapeutic strategies.

In the cancer immunotherapy landscape, PD-L1 evaluation methodology has also become a new point of discussion. While the current domestic reimbursement environment is centered on Combined Positive Score (CPS)-based evaluation, certain recently introduced therapies use a Tumor Area Positivity (TAP)-based approach, raising the possibility that both assessment modalities will coexist in clinical practice for a period. In particular, the TAP-based SP263 assay is attracting attention for its real-world clinical utility and interpretive efficiency, as it is performed on automated platforms that enable a relatively rapid turnaround time.

Tevimbra is also a therapeutic agent that uses TAP-based evaluation, and discussions suggest it could serve as a novel alternative for diagnostic efficiency while maintaining continuity with existing CPS-based checkpoint inhibitors. Furthermore, it demonstrated survival benefits in the first-line treatment of HER2-negative metastatic gastric cancer through the RATIONALE 305 study and is included in the US NCCN Guidelines as a recommended first-line treatment option (Category 2A) for patients with HER2-negative, PD-L1-expressing gastric and gastroesophageal junction (GEJ) cancers.

In certain patient subgroups with high PD-L1 expression levels (CPS ≥ 5), Tevimbra is recommended as a preferred regimen (Category 1), and its potential is demonstrated in subgroup analyses of patients with peritoneal metastasis, which is also highlighted as a key point of interest.

Experts assess that gastric cancer management is moving beyond simply adding new agents and is undergoing a rapid restructuring of the entire diagnosis-to-treatment process. They explain that the expansion of biomarker testing has heightened the clinical significance of pathological interpretation and that multidisciplinary collaboration has become a virtual necessity to avoid missing the critical window for treatment initiation.

 Q. Why is multidisciplinary care essential in gastric cancer?

Professor Min-hee Ryu 

Professor Ryu: While some gastric cancer patients undergo only surgery or receive only systemic chemotherapy, the majority undergo surgery and chemotherapy either sequentially or concurrently. In the multidisciplinary team, we discuss the sequencing of modalities or, when a diagnosis is challenging, synthesize the opinions of pathology and radiology specialists to establish the diagnostic and therapeutic pathway.

Furthermore, there are instances where the presence or absence of metastasis is ambiguous, making it difficult for a single clinical specialty to determine a treatment plan independently. In cases where multiple modalities must be introduced sequentially, discussions are necessary to clarify the treatment order or resolve any diagnostic ambiguity.

Professor Park: The significant advantage of multidisciplinary care is that it provides a one-stop solution, rather than forcing patients to navigate multiple departments to gather separate opinions as they did in the past.

As the life expectancy of cancer patients extends, we are seeing more patients presenting with multiple malignancies. For example, when a gastric tumor is detected in a patient who had lung cancer five years ago, multiple specialties convene to deliberate on whether to treat it as a primary gastric cancer or evaluate it as a metastasis from the previous malignancy. Consequently, it takes less time to establish a therapeutic strategy compared to the past, and the selected strategies are far more precise.

Professor Hyung: Cancer treatment methods are diverse, including chemotherapy, radiation therapy, and surgical resection. In the case of metastatic cancer, systemic chemotherapy is not the sole mandate; instead, various departments collaborate to consider clinical intervention methods, and there are cases where the treatment prognosis improves when an intervention is introduced at the optimal timing. These aspects represent the advantages of the Asan Medical Center's Stomach Cancer Center Multidisciplinary Team.

Q. With various therapeutic agents, such as immuno-oncology products and ADCs, recently introduced for gastric cancer, how have treatment goals or patient management approaches shifted following their introduction?

Professor Ryu: Recently, as the efficacy of targeted therapies and immunotherapies has been validated in gastric cancer alongside cytotoxic agents, the importance of companion diagnostics to determine patient eligibility has grown substantially. While therapies were previously deployed uniformly without patient stratification, the paradigm has shifted toward screening and selecting patients who are highly likely to derive clinical benefit based on diagnostic readouts, driving improvements in therapeutic outcomes.

Professor Hyung: For a long period following the ToGA trial, novel treatment options for gastric cancer remained limited, but the recent introduction of checkpoint inhibitors has dramatically altered the therapeutic landscape. In particular, the implementation of companion diagnostic concepts linked to PD-L1 expression has enabled personalized care, and the efficacy of immuno-oncology combination regimens is being validated. Furthermore, whereas we previously relied on a limited number of assays focused on HER2, we now consider a diverse array of biomarkers concurrently, such as Claudin 18.2, enabling tailored therapy to be far more sophisticated. Durable long-term responses are also being observed in some patients, which I view as a clinically profound shift.

Professor Park: It is not that gastric cancer lacks biomarkers; various indicators such as EBV and MMR already existed alongside HER2 and PD-L1, and with the recent addition of novel targets like Claudin 18.2, biomarkers are becoming increasingly segmented. However, in the case of PD-L1, because different antibody clones, such as 22C3, 28-8, and SP263, are paired with distinct therapeutic agents, there is a logistical burden of performing multiple assays concurrently. In this regard, gastric cancer remains a malignancy where immunohistochemistry (IHC)-based testing plays a pivotal role.

Q. What are TAP and CPS, and how do these PD-L1 evaluation methodologies differ?

Professor Young Soo Park

Professor Park: TAP is a methodology that determines positivity or negativity based on an area concept rather than a numerical count. Conversely, CPS is a numbers-based evaluation. While both serve as criteria to evaluate PD-L1, their analytical approaches differ.

TAP measures the surface area of positively stained cells within the total tumor area, whereas CPS is a calculated ratio based on the raw count of positive cells. To date, the TAP method is generally known to demonstrate slightly higher concordance and reproducibility compared to CPS.

In large tertiary hospitals with high daily case volumes, the difference in interpretation time between CPS and TAP may not be substantial, given extensive experience with CPS scoring. However, for pathologists who are initially adopting the workflow or in institutions with lower sample volumes, I believe TAP offers distinct advantages.

In particular, because TAP is an area-based measurement, it possesses high potential for integration with AI-driven interpretation or deep learning-based analytics in the current environment, where slide scanning and digital pathology workflows are expanding.

Professor Ryu: Because immune-checkpoint inhibitors are linked to companion diagnostics, regulatory approvals and reimbursements are structured around the specific assay methodologies and scoring criteria used for each agent. Currently, Opdivo and Keytruda are reimbursed based on the CPS criteria used in their registrational trials. At the same time, Tevimbra was developed using TAP, requiring ongoing discussions about how its reimbursement criteria will be established. In South Korea, HIRA tends to enforce criteria identical to those used in regulatory approval trials; therefore, it is highly likely that clinicians will continue to use the exact testing methodology aligned with each therapeutic agent. It appears that the two evaluation systems will co-exist for a certain period, aligned to their corresponding drugs.

Professor Hyung: While there is a global trend toward a more flexible application by acknowledging a degree of interchangeability between diverse assays, South Korea maintains relatively stringent companion diagnostic standards, meaning that the diversity of testing modalities will likely be directly reflected in clinical practice. Ultimately, in real-world settings, an approach that synthesizes the patient's performance status and biomarker profiles to select the therapeutic option that best matches each metric will become critical.

Q. What shifts do you anticipate new evaluation methodologies like TAP will bring to therapeutic strategies, clinical decision-making, and the future trajectory of PD-L1 assessment?

Professor Park: Rather than an entirely unprecedented concept, TAP extends existing PD-L1 evaluation methodologies, such as CPS. However, its area-based approach makes it more intuitive and accessible. Due to the structure in South Korea, in which the exact assays and scoring criteria from pivotal trials are strictly applied, selective CPS and TAP utilization depending on the therapeutic agent will persist.

Another critical aspect is the operational difference between the assays. The SP263 clone used for TAP is deployed on fully automated instrumentation enabling same-day staining. In contrast, the 22C3 or 28-8 pharmDx assays utilized for CPS rely on semi-automated platforms that can be more time-consuming or necessitate send-out testing to external reference labs. Taking these factors into account, the adoption of TAP should be viewed not as a matter of absolute superiority, but as a choice reflecting real-world clinical utility and accessibility.

Professor Ryu: In clinical oncology, therapeutic decisions are based on pathology reports, making interpretive consistency and reproducibility paramount. Data to date suggest that TAP and CPS exhibit a substantial correlation. I believe both modalities are viable. However, when considering workflow convenience, staining intensity, crispness, and adaptability for digital pathology or AI-driven scoring, TAP may offer a slight competitive edge. In particular, SP263-based TAP is known to yield relatively distinct staining, which holds promise for practical clinical implementation.

Professor Hyung: Because manual single-cell counting is highly labor-intensive, rapid and consistent interpretation will become increasingly critical moving forward. In that respect, the TAP method offers distinct advantages. Furthermore, given the growing trend toward digital pathology and AI-driven analytics, the area-based approach is technically easier to integrate, underscoring its strong future utility.

Q. Multiple immune-checkpoint inhibitors have recently been introduced into the metastatic gastric cancer treatment landscape. In what ways do you think Tevimbra, as a later entrant to the market, distinguished from existing therapeutic options?

Professor Jaewon Hyung 

Professor Hyung: Although Tevimbra has entered real-world clinical use, our institutional experience remains early, and without head-to-head comparative data, any definitive conclusions must be drawn cautiously. However, since a statistically significant improvement in overall survival (OS) was reported in its clinical trials and major guidelines like the NCCN recommend it on par with other checkpoint inhibitors, it is highly likely to deliver a comparable level of therapeutic efficacy.

Notably, in gastric cancer, numerous observational data indicate that the efficacy of checkpoint inhibitors is relatively diminished in patients presenting with concurrent peritoneal metastasis and malignant ascites. There is anticipation that Tevimbra could serve as a valuable therapeutic agent, demonstrating added potential to address this specific area of high unmet medical need.

Professor Ryu: Another frequently discussed aspect regarding Tevimbra is the peritoneal metastasis cohort. Historical data for conventional immune checkpoint inhibitors have indicated relatively limited efficacy in patients with peritoneal disease; conversely, subset analyses of Tevimbra have suggested signal activity and efficacy even in this cohort. Granted, variations in sample size exist, and whether these subgroup data can be directly generalized remains a separate issue. Nevertheless, demonstrating a potential therapeutic signal in peritoneal metastasis, setting it apart from legacy checkpoint inhibitors, is clinically noteworthy.

Q. What are your perspectives on the current reimbursement criteria for immune-checkpoint inhibitors and the necessity of securing reimbursement for Tevimbra moving forward?

Professor Ryu: From a clinician's perspective, expanding the therapeutic arsenal is inherently beneficial for patients. Furthermore, I believe institutional equity is crucial in this domain. While immune-checkpoint inhibitors generally share a similar mechanism of action, Tevimbra is characterized by its demonstrated potential for efficacy even in patients with peritoneal metastasis, as previously discussed. Therefore, Tevimbra must be integrated into the system as a therapeutic option on par with Opdivo or Keytruda. If one agent is reimbursed while another remains non-reimbursed, real-world clinical prescribing will inevitably lean heavily toward the insurance-covered medication.

Professor Hyung: Diversifying therapeutic options yields clear advantages for both patients and treating physicians. Particularly in gastric cancer, the prevalence of peritoneal metastasis is substantial, and patients with metastasis have a poor prognosis. Consequently, if a treatment offers even a slight therapeutic advantage in this patient group, it would be highly beneficial in real-world clinical practice.