# Zolbetuximab or Immunotherapy as the Initial Targeted Therapy in CLDN18.2-Positive, HER2-Negative Advanced Gastric Cancer: Weighing the Options

## TL;DR

This paper compares zolbetuximab and immunotherapy for treating advanced gastric cancer, focusing on their side effects, biomarker reliability, and treatment outcomes.

## Contribution

The paper provides an evidence-based opinion on selecting between zolbetuximab and immunotherapy for HER2-negative, CLDN18.2-positive gastric cancer.

## Key findings

- Zolbetuximab and immunotherapies offer similar survival benefits of 14–18 months compared to chemotherapy alone.
- Immunotherapies show a survival gradient with higher PD-L1 CPS scores, but scoring has high variability.
- Zolbetuximab causes initial infusion-related nausea, while immunotherapies risk delayed immune-related toxicities.

## Abstract

Targeted treatments for advanced gastric cancer have been shown to improve survival when added to conventional chemotherapy. A claudin18.2-targeted drug, zolbetuximab, and two immune checkpoint inhibitors, nivolumab and pembrolizumab, are now approved as initial therapies for advanced gastric cancer. Since these drugs offer similar survival benefits, choice of initial therapy hinges on their side-effect profiles, patient factors, tumor characteristics such as biomarker expression, and logistical practicalities. Zolbetuximab has high rates of nausea and vomiting during the first infusion, but rates are lower with subsequent infusions and can be managed with anti-nausea medications. Nivolumab and pembrolizumab carry a risk of potentially serious immune side effects that can occur weeks after starting treatment. All three therapies work best against tumors that express specific biomarkers or targets. This makes the reliability of biomarker testing and interpretation an important factor when choosing initial therapy for advanced gastric cancer.

Advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma remains a common and deadly form of cancer. Advances in G/GEJ cancer treatment have improved survival outcomes with the claudin-18.2 (CLDN18.2)-targeted agent, zolbetuximab, and immune checkpoint inhibitors (ICIs) targeting the PD-1 receptor. This article offers an evidence-informed opinion on considerations when selecting between these first-line treatments for G/GEJ adenocarcinoma in patients with HER2-negative disease that expresses CLDN18.2 and/or PD-L1, including the reliability of biomarker scoring and interpretation, overall survival (OS) rates, toxicity profiles, and logistical practicalities. Evidence from Phase III trials for zolbetuximab and ICIs suggest similar OS benefits of 14–18 months compared to chemotherapy alone, but there appears to be a gradient of benefit for ICIs with increasing PD-L1 combined positive score (CPS). There is high inter-observer variability in CPS scoring, particularly at lower thresholds. Zolbetuximab is associated with high rates of nausea and vomiting during the initial infusion, whereas ICIs are associated with risk of later-onset immune-related toxicities that can be fatal in rare cases. In considering the available evidence, our opinion is that zolbetuximab is a reasonable option for initial targeted treatment in HER2-/CLDN18.2-positive advanced G/GEJ when PD-L1 CPS score is <10 based on the reliability of biomarker testing, comparable OS, and avoidance of potentially irreversible ICI-induced immune toxicity.