Abstract

Management of gastric cancer has undergone significant changes over the past few years. TCGA classified gastric cancer into four molecular subtypes: chromosomal instability (50% of cases), MSI-H (21%), genomically stable (20%) and EBV-positive (9%).  Molecular profiling is recommended prior to the start of systemic treatment, testing predictive markers such as HER 2-expression, microsatellite instability status, programmed death ligand-1 expression (combined positive score, CPS), and Epstein-Barr virus expression.

CheckMate 649 trial established the role of immunotherapy in advanced gastric cancers. Adding nivolumab to chemotherapy in the first line setting resulted in significantly improved OS and PFS in all randomly assigned patients, with the greatest magnitude seen in patients with high PD-L1–expressing tumours. In the PD-L1 CPS ≥ 5 population, median overall survival was 14.4 months with nivolumab/chemotherapy vs 11.1 months with chemotherapy (HR = 0.71, P < .0001)

Destiny-Gastric 01 trial demonstrated the efficacy of antibody-drug conjugate, trastuzumab deruxtecan, for patients with pretreated HER2-positive gastric or gastroesophageal junction adenocarcinomas, showing a response rate of 51% and median OS 12.5 vs 8.4 months (HR = 0.59, P=0.01) when compared to the physician’s choice of therapy.

In the phase 2 FIGHT trial, mFOLFOX6 plus bemarituzumab, a humanized IgG1 monoclonal antibody against FGFR-2b, showed a trend towards improved PFS (9.4 vs 7.4 month; HR 0.68, p=0.073) versus mFOLFOX6 plus placebo.  This regimen is now being investigated in a phase 3 trial.

The recently announced SPOTLIGHT trial demonstrated efficacy of zolbetuximab, an IgG1 monoclonal antibody against CLDN18.2, a transmembrane protein.  Zolbetuximab plus mFOLFOX6 showed improved PFS and OS in CLDN18.2+ve gastric cancer patients compared to placebo plus mFOLFOX6 in the first line setting. The results of GLOW trial (zolbetuximab combined with CAPOX) is being awaited.

Immunotherapy has also changed the treatment landscape for oesophageal cancers. CheckMate 648 trial showed first line nivolumab regimen improved survival in advanced oesophageal squamous cell carcinomas, both among patients with tumour-cell PD-L1 expression of 1% or more (15.4 vs 9.1 months; HR 0.54, P<0.001) and in the overall population (13.2 vs 10.7 months; HR 0.74; P=0.002).  In Keynote 590, pembrolizumab regimen demonstrated improved survival in oesophageal carcinoma patients with PD-L1 CPS of 10 or more (13·9 vs 8·8 months; HR 0·57, p<0·0001) and in all randomised patients (12.4 vs 9.8 months; HR 0·73, p<0·0001).

Many ongoing trials are investigating combination targeted and immunotherapies in gastroesophageal cancers, and will continue to change the treatment landscape in the coming years.