Immune-Checkpoint Inhibition in the Treatment of Gastro-Esophageal Cancer: A Closer Look at the Emerging Evidence

Abstract

To date, several trials have evaluated the safety and efficacy of immune-checkpoint inhibitors (ICI) for the treatment of gastroesophageal cancers (GEC). In the US, ICIs have established indications for second-line treatment of microsatellite unstable tumors, while their use in third-line settings was recently withdrawn. Notably, the use of ICIs for first-line therapy of GEC is rapidly evolving, which currently includes high PD-L1 expressing tumors, irrespective of HER2 status, and in the adjuvant setting after neoadjuvant chemoradiotherapy in select patients. In this article, we review the results of studies that have evaluated the utility of ICI in the third-line, second-line, first-line, and peri-operative treatment settings of GECs. Considerations should be made before making any cross-trial comparisons since these trials vary in chemotherapy backbone, anatomical and histological eligibility, biomarker assessment, PD-L1 diagnostic antibodies, and definition of PD-L1 positivity. Regardless, the totality of the data suggest that first-line ICI use may most benefit GEC patients with high PD-L1 combined positivity score (CPS) ≥5 or ≥10, irrespective of histology or anatomy. Moreover, although PD-L1 by CPS has a good negative predictive value for significant benefit from ICIs, it has a low positive predictive value. Therefore, there is a pressing need to identify better biomarkers to predict benefit from ICIs among these patients.

Systematic review and meta-analysis of endoscopic ultrasonography in staging diagnosis of esophageal cancer after neoadjuvant radiotherapy and chemotherapy

“…At present, the most commonly used methods for preoperative staging of esophageal cancer mainly include computed tomography (CT), endoscopic ultrasonography (EUS) and positron emission tomography (PET) (16)(17)(18)(19)(20)(21). Among them, CT, especially enhanced CT, is the most commonly used examination method to exclude distant metastasis of esophageal cancer patients, which can accurately find the most common liver, brain and lung metastasis (21,22).…”

Use of Real‐World Evidence in a Virtual Bridging Analysis for a Human Epidermal Growth Factor Receptor 2–Targeted Antibody–Drug Conjugate in Gastric Cancer

“…In the current study, exposure–efficacy simulations for patients with gastric cancer receiving the T‐DXd 6.4‐mg/kg dose suggested a similar incidence of ORR in Western patients and patients from Japan with gastric cancer, and a numerically lower rate of confirmed ORR in Western patients compared with patients from Japan. These results are potentially attributable to lower use of checkpoint inhibitors, which are approved for third‐line therapy for gastric cancer in some Asian countries, including Japan, but not in the United States, 26 and a higher proportion of patients having HER2 IHC 2+ status in the Western population. Exposure–safety simulations for patients with gastric cancer receiving the T‐DXd 6.4‐mg/kg dose suggested a lower rate of any‐grade ILD in Western patients than in patients from Japan, but comparable grade 3 or greater ILD rates, and a lower incidence of grade 3 or greater neutropenia and grade 3 or greater thrombocytopenia and a higher incidence of serious adverse events in Western patients than in patients from Japan.…”

Surgical intervention after neoadjuvant therapy in esophageal cancer: a narrative review

“…Immunotherapy has evolved as a promising new treatment modality across cancer types ( 33 ). An available study ( 34 ) indicates that immune check-point inhibitors (ICIs) such as pembrolizumab and nivolumab can be used as a first-line treatment for patients with locally advanced EC. In 2020, Kojima et al ( 35 ) randomized 628 patients with advanced EC to pembrolizumab or chemotherapy.…”

“…Patients were identified in a phase 3 trial, with a positive score ≥10 had significantly higher 12-month OS with pembrolizumab versus chemotherapy (43% vs. 20%) and significantly lower rates of adverse events with treatment (18.2% vs. 40.9%). In 2019, a multicenter phase III trial ( 34 ) involving 419 patients randomized to nivolumab or chemotherapy showed a median follow-up for OS of 10.5 months in the nivolumab group and 8.0 months in the chemotherapy group. At a minimum follow-up of 17.6 months, OS was significantly improved with nivolumab versus chemotherapy (10.9 vs. 8.4 months, P=0.019).…”