Checkpoint inhibitors are a type of immunotherapy that includes inhibitors of programmed cell death protein 1 or PD-1 ligand 1 (PD-1 or PD-L1). When added to first-line standard chemotherapy, anti–PD-1 antibodies have demonstrated improved survival in patients with gastroesophageal junction (GEJ) adenocarcinoma. There is no consensus on which subgroups benefit most from this approach to treatment, but some studies have shown that patients whose tumors have higher levels of expression of PD-L1 derive greater benefit from anti–PD-1 antibodies. Conversely, in 2024, the US Food and Drug Administration’s Oncologic Drugs Advisory Committee concluded that the risk-to-benefit ratio is unfavorable for anti–PD-1 agents with chemotherapy in patients whose tumors do not express PD-L1. However, it should be noted that differing trial assays and prespecified cut points for primary endpoints have led to a spectrum of recommendations within guidelines and from regulatory authorities.
Combined positive score (CPS) is the most common method for assessing PD-L1 expression in GEJ adenocarcinoma. Most patients with CPS 1 or higher (PD-L1 positive) are offered anti–PD-1 agents. In a JAMA editorial, Samuel Klempner, MD, and colleagues shared their perspective on the impact of the GEMSTONE-303 trial on first-line treatment of patients with GEJ adenocarcinoma. While multiple anti–PD-1 agents are approved for treatment of GEJ, sugemalimab is the first anti–PD-L1 agent investigated for first-line treatment of this tumor type. In GEMSTONE-303, patients with CPS 10 or higher treated with sugemalimab had a 5.3-month improvement in median overall survival. Results were similar in the chemotherapy control group, suggesting that PD-L1 expression is not prognostic in this population. The rate of immune-related treatment-emergent adverse events was comparable to anti–PD-1 agents in this patient population.
High level
Early studies of other anti–PD-L1 agents (ie, durvalumab and atezolizumab) had less promising results, but these drugs have now been used successfully in the perioperative setting, supporting clinical equivalence of PD-1 or PD-L1 agents in treatment of GEJ adenocarcinoma. Future research should investigate rational approaches to improving the activity of both anti–PD-1 and anti–PD-L1 agents in the treatment of GEJ adenocarcinoma.
Ground level
The GEMSTONE-303 trial established sugemalimab as a safe and effective alternative to anti–PD-1 agents. While the results do not indicate a specific advantage over approved treatments, this research does add to the growing body of evidence supporting use of PD-1 or PD-L1 monoclonal antibodies in addition to chemotherapy for treatment of patients with GEJ adenocarcinoma.
