Prognosis of Immune-related Adverse Events in Patients With Advanced Gastric Cancer Treated With Nivolumab or Pembrolizumab: A Multicenter Retrospective Analysis

Abstract

Background: Immune-checkpoint inhibitors (ICI), including nivolumab and pembrolizumab, are among the standard treatments for previously treated advanced gastric cancer (AGC). This study aimed to evaluate the frequency of immune-related adverse events (irAEs) and the correlation between irAEs and their efficacy in AGC cases. Patients and Methods: Patients were divided into two groups according to irAE occurrence. The frequency of irAEs and the treatment outcome (response rate [RR], progression-free survival [PFS], and overall survival [OS]) were evaluated. The survival rates were evaluated by landmark analysis considering lead-time bias. Results: Among 108 patients who received nivolumab or pembrolizumab, 17 (15.7%) had irAEs. In a 4-week landmark analysis, the RR, median PFS, and median OS were 28.5%, 3.9 months (95% CI=2.8-9.3), and 12.2 months (95% CI=3.8-NA) in patients with irAEs, while 3.0% (2/65), 1.8 months (95% CI=1.4-2.1), and 3.5 months (95% CI, 2.9-5.1) in patients without irAEs, respectively. In multivariate analysis, irAEs were associated with better PFS (HR=2.08, 95% CI=1. 34-3.21). Conclusion: The occurrence of irAEs was associated with a better clinical outcome of ICIs in patients with AGC.Through development of immune-checkpoint inhibitors (ICIs), the prognosis of various cancer types, including gastric and gastroesophageal junction cancers, has improved (1, 2). Nivolumab, which is a monoclonal antibody targeting programmed cell death-1 (PD-1), has been shown to have efficacy and safety in heavily pretreated patients with gastric cancer (2). In a phase III placebo-controlled ATTRACTION-2 study in Asia, nivolumab monotherapy obtained an overall response rate (ORR) of 11.2% and increased the 12-month OS to 27% versus 11% by placebo [hazard ratio (HR)=0.63; p<0.0001], independent of PD-L1 positivity (2). In nonrandomized phase II KEYNOTE-158 study for advanced noncolorectal cancer with deficiency in DNA mismatch repair (dMMR) or high microsatellite instability (MSI-H), pembrolizumab monotherapy showed an ORR of 34.3%, median progression-free survival (mPFS) of 4.1 months, and median overall survival (mOS) of 23.5 months (3). In addition, 24 patients with dMMR/MSI-H gastric cancer 475 This article is freely accessible online.

Prognostic factors to predict the survival in patients with advanced gastric cancer who receive later‐line nivolumab monotherapy—The Asahikawa Gastric Cancer Cohort Study (AGCC)

“…13 Patients who had experienced AEs also survived longer in comparison to patients without AEs, as reported in a previous study. 14 Patients with TRAEs showed a mean OS time of 10.0 months in our cohort. Although the best response and AE were associated with the OS, as previously reported, they were not predictive factors because those factors were only obtained after the initiation of nivolumab treatment.…”

Prognostic impact of immune-related adverse events on patients with and without cardiovascular disease: a retrospective review

“…IrAEs are pathologically characterized by macrophagic and lymphocytic infiltration into the normal tissues and result from the unintended effects of ICI-induced activation of the immune system. Since 2015, various studies have reported that irAEs are associated with a longer prognosis regardless of the treatment regimen [ 5 , 6 ]. Shimozaki et al reported that the development of multiple irAEs was associated with longer survivals than a single irAE [ 19 ].…”

“…IrAEs have reportedly occurred in nearly all organs and are particularly common in non-cardiovascular organs such as the colon, lungs, endocrine glands, skin, and liver. Recently, several studies have reported that the development of irAEs was associated with clinical benefits for patients receiving ICI therapy [ 4 – 6 ]. Meanwhile, cancer and cardiovascular diseases often coexist because of shared risk factors such as hypertension, obesity, smoking, and diabetes [ 7 ], and multiple types of anti-cancer drugs and therapies can cause cardiovascular disorders.…”

Correlation between immune-related adverse events and therapeutic effects of nivolumab in patients with malignant pleural mesothelioma

“…The treatment with nivolumab may lead to immune-related adverse events (irAEs), which sometimes results in the interruption or discontinuation of the treatment [ 8 ]. Previous reports in melanoma, non-small-cell lung cancer, and gastric cancer patients have shown that the presence of irAEs with nivolumab were positively associated with their progression-free survival (PFS) and OS [ 9 – 13 ]. However, the correlation between irAEs and outcome of nivolumab for patients with MPM is still unknown.…”