GC – Gastric carcinoma

Introduction

In October 2021, the EMA granted marketing authorization for nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy for HER2-negative advanced or metastatic gastric adenocarcinoma in patients whose tumors express PD-L1 CPS ≥5.
Pembrolizumab is indicated in combination with trastuzumab and fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-positive adenocarcinoma of the gastroesophageal junction in adults with PD-L1-expressing tumours (CPS ≥ 1) and in combination with fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-negative adenocarcinoma of gastric or gastroesophageal junction in adults with PD-L1-expressing tumours (CPS ≥ 1).

Accordingly, we will determine CPS ≥ 1 and ≥ 5 for this entity.

Scores

Interpretation guidance for gastric carcinoma

Use a high magnification: Since staining in the membrane may be very weak, the tissue under investigation should also always be screened at higher magnifications.

For differentiated signet ring cell adenocarcinomas in particular, the large intracytoplasmic mucin vacuoles can also cause difficulties in evaluation, leading to situations where the cytoplasm border displaced to the cell’s periphery is misinterpreted as staining in the membrane.

PD-L1 prevalence in gastric carcinoma

In current study data that include HER2-negative adenocarcinomas of the stomach, the gastroesophageal junction, and the esophagus, PD-L1 prevalence for nivolumab is found to be 60% relative to CPS ≥5¹.

For pembrolizumab, the prevalence in relation to CPS ≥ 1 is 88%, according to current studies that include HER2-positive adenocarcinomas of the stomach and gastro-oesophageal junction³ . For HER2-negative adenocarcinomas of the stomach and gastro-oesophageal junction, the prevalence is approx. 78%⁴.

Test system validation/antibody selection in gastric carcinoma

The publication of a harmonization study performed in Germany is not yet final. In terms of the study antibodies, it can be seen that, for the squamous cell carcinomas and AEG tumors investigated, as has already been shown with other entities, SP142 stains comparatively fewer tumor cells than the other antibodies. On the other hand, SP263 provides us with a stronger expression pattern overall.

Guidance for practice

Specific interpretation guidance for gastric carcinoma

Support for interpretation is available from Agilent DAKO² at the following link: Agilent DAKO Interpretation Handbook

Please note the following:

• A least 100 carcinoma cells should be available for interpretation.
• Necrotic cells, plasma cells, and granulocytes are excluded from CPS and TPS scoring.
• When evaluating esophageal cancer, a carcinoma in situ component is excluded from CPS scoring.

The following tables provide you with full details and guidance for interpreting the CPS score. (Agilent DAKO ⁴, page 26)

Interpretation guidance for CPS definition numerator

	Tumor cells	Immune cells	Other cells
Included in numerator	Convincing partial or complete linear membrane staining (at any intensity) of viable invasive tumor cells	Membrane and/or cytoplasmic* staining (at any intensity) of mononuclear inflammatory cells (MICs) within tumor nests and adjacent supporting stroma Lymphocytes (including lymphocyte aggregates) Macrophages ‡ Only MICs directly associated with the response to the tumor are scored.	Excluded
Excluded from numerator	Non-staining tumor cells Tumor cels with only cytoplasmic staining	Non-staining MICs MICs (including lymphoid aggregates) associated with ulcers, chronic cystitis, or other, non-tumor-associated processes MICs associated with carcinoma in situ MICs associated with benign structures neutrophil/eosinophil granulocytes and plasma cells	Carcinoma in situ normal/benign cells Stromal cells (including fibroblasts) Necrotic cells and/or cellular debris

* In MICs, membrane and cytoplasmic stainings often cannot be distinguished due to the high nucleus-plasma relation. For this reason, both membrane and cytoplasmic stained MICs are contained in the score.
† “Neighboring MICs” is the definition of cells that are inside the same 20x field as the tumor. However, MICs that are not directly associated with the reaction to the tumor should be ruled out.
‡ Macrophages and histiocytes are assigned to the same kind of cell.

The following tables provide you with full details and guidance for interpreting the CPS score. (Agilent DAKO ⁵, page 24)

Interpretation guidance for CPS definition denominator

	Tumor cells	Immune cells	Other cells
Included in denuminator	All viable invasive tumor cells	Excluded	Excluded
Excluded from denuminator	Any necrotic or non-viable tumor cells Dysplastic cells	All immune cells of any type	Carcinoma in situ normale/benign cells Stromal cells (including fibroblasts) necrotic cells and/or cellular debris

QuIP Proficiency Test PD-L1 GC

Literature

1. Janjigian, Y. Y. et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. The Lancet 398, 27–40 (2021).

2. Agilent Technologies Inc. PD-L1 IHC 28-8 pharmDx Interpretation Manual–Gastric Adenocarcinoma, Gastroesophageal Junction (GEJ) Adenocarcinoma, and Esophageal Adenocarcinoma. PD-L1 IHC 28-8 pharmDx is CE-IVD marked for in vitro diagnostic use. (2021).

3. Janjigian et al., Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. The Lancet 402,2197-2208 (2023)

4.Rha et al., Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. The Lancet Oncology 24,11, 1181-1195 (2023)