Approaching First-Line Treatment in PD-L1 CPS <1 HER2-Positive GEA

In this episode, Dr. Wainberg and Dr. Shameem tackle a clinical gray zone: the roughly 15% of HER2-positive metastatic gastroesophageal adenocarcinoma (GEA) with programmed death-ligand 1 (PD-L1) combined positive score (CPS) <1. Dr. Wainberg asks Dr. Shameem how he treats this subgroup today and whether PD-L1 testing is routine in his practice.

For Dr. Shameem, full biomarker testing is non-negotiable. Along with HER2, he tests for PD-L1, microsatellite instability (MSI), and claudin 18.2 before making a first-line decision. In PD-L1–negative patients, his current choice is trastuzumab plus chemotherapy without pembrolizumab, a position grounded in the KEYNOTE-811 history. The original 2021 accelerated approval was PD-L1–agnostic and based on response rate. The 2023 subset analysis (about 50–52 patients per arm) in CPS <1 showed a hazard ratio of roughly 1.10, which he reads as no benefit and possibly detrimental. The FDA narrowed the label to CPS ≥1, and National Comprehensive Cancer Network (NCCN) guidelines followed.

One clinical nuance: a PD-L1–negative result should prompt a second look at tissue adequacy, since intratumoral heterogeneity can generate false negatives. Dr. Shameem also flags something that caught his attention in HERIZON-GEA-01: The trial enrolled PD-L1 expressors and non-expressors using tumor area positivity (TAP) rather than CPS, and about 30% of the population scored TAP <1. A notable observation that sets up the next episode's trial deep-dive.

In the next episode, “HERIZON-GEA-01 Study Design, Geographic Distribution, and PD-L1 Testing Considerations,” Dr. Elimova walks through the trial design and Dr. Shah discusses the cross-trial PD-L1 testing differences.