The Present and Future of Neoadjuvant and Adjuvant Therapy for Locally Advanced Gastric Cancer

Abstract

Gastric cancer is a highly prevalent and lethal disease worldwide. Given the insidious nature of the presenting symptoms, patients are frequently diagnosed with advanced, unresectable disease. However, many patients will present with locally advanced gastric cancer (LAGC), which is often defined as the primary tumor extending beyond the muscularis propria (cT3-T4) or having nodal metastases (cN+) disease and without distant metastases (cM0). LAGC is typically treated with surgical resection and perioperative chemotherapy. The treatment of LAGC remains a challenge, given the heterogeneity of this disease, and the optimal multimodal treatment regimen may be different for different LAGC subtypes. However, many promising treatments are on the horizon based on knowledge of molecular subtypes and key biomarkers of LAGC, such as microsatellite instability, HER2, Claudin 18.2, FGFR2, and PD-L1. This review will expand upon the discussion of current standard neoadjuvant and adjuvant therapies for LAGC and explore the ongoing and future clinical trials for novel therapies, with information obtained from searches in PubMed and ClinicalTrials.gov.

Keywords: adjuvant therapy; biomarkers; gastric cancer; immunotherapy; locally advanced; neoadjuvant therapy; targeted therapy.

Figure 1

Schematic of a future neoadjuvant biomarker-driven clinical trial for LAGC. Patients with resectable, locally advanced, GC/GEJC will be stratified into cohorts based on biomarkers: HER2+, MSI-H, biomarker X, biomarker Y, or none of the above. Biomarker X and Y are placeholders for current (such as FGFR or CLDN 18.2) or future biomarkers of clinical interest in LAGC. Each biomarker cohort will have two differing treatment arms based on data from prior clinical trials. Patients will undergo combination neoadjuvant chemotherapy, immunotherapy, and/or biomarker-directed treatment for 4–6 months and then undergo surgical resection followed by adjuvant therapy based on their cohort. The primary outcome is the achievement of 30% pCR. IO = immuno-oncology therapy. Chemo = chemotherapy.