Immunotherapy in Gastroesophageal Cancers: Current Evidence and Ongoing Trials.

OPINION STATEMENT: Data supporting the use of immunotherapy in the treatment of gastroesophageal cancer continues to evolve. The promising results from adjuvant immunotherapy and trials combining immunotherapy plus chemotherapy in the 1L setting have led to broad US FDA approvals. Among the PD-L1 negative subgroups, the magnitude of benefit is diminished; effective therapy for this population remains an unmet need. A detailed biologic understanding of the PD-L1 negative (and low) population represents a barrier to developing effective combination therapies, although combination angiogenesis inhibitors and immunotherapy look encouraging. Early phase clinical trials, particularly with pembrolizumab plus lenvatinib (EPOC 1706), demonstrated a clear signal independent of PD-L1, and a confirmatory phase III trial of pembrolizumab plus lenvatinib is planned. Conceptually, it is important to think of immune checkpoint inhibitor therapy as targeted therapy, most active in clearly defined biomarker-selected populations. Pre-planned analyses have reliably shown a clear trend toward a greater magnitude of benefit in patients with higher PD-L1 expression, particularly CPS ≥ 5 and ≥ 10. Whether there is a linear relationship at higher cutoffs is not well known, though it likely represents smaller and smaller populations. Although beyond the scope of this clinically oriented review, recognition of the spatial and temporal heterogeneity in PD-L1 expression is important and repeat testing from progression samples across lines of therapy should be considered. Questions about additional predictive biomarkers, particularly plasma-derived, remain. Responses by tumor histology and location also differ, and special attention to these factors as well as MSI-H, HER2, and EBV subgroups in future trials is warranted. Questions regarding the incorporation of immunotherapy after progression on 1L immunotherapy plus chemotherapy combinations will arise as these combinations are used more frequently, and this represents a key area of future investigation. Overall, the role of immunotherapy continues to expand in GEA, and we welcome any additional tools for this difficult-to-treat group of cancers.