Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival

Abstract

BACKGROUND

Despite the popularity of immune checkpoint inhibitors (ICIs) in the treatment of advanced cancer, patients often develop gastrointestinal (GI) and non-GI immune-related adverse events (irAEs). The clinical characteristics and survival outcomes of GI-irAEs have not been fully elucidated in previous reports. This necessitates the evaluation of the impact of GI-irAEs on patients receiving ICI treatment.

AIM

To evaluate the clinical characteristics of GI-irAEs and their impact on survival in patients treated with ICIs.

METHODS

In this single-center, retrospective, observational study, we reviewed the records of 661 patients who received ICIs for various cancers at Nagoya University Hospital from September 2014 to August 2020. We analyzed the clinical characteristics of patients who received ICI treatment. We also evaluated the correlation between GI-irAE development and prognosis in non-small cell lung cancer (LC) and malignant melanoma (MM). Kaplan-Meier analysis was used to compare the median overall survival (OS). Multivariate Cox proportional hazards models were used to identify prognostic factors. A P value < 0.05 was considered statistically significant.

RESULTS

GI-irAEs occurred in 34 of 605 patients (5.6%) treated with an anti-programmed cell death-1/programmed death-ligand 1 (anti-PD-1/PD-L1) antibody alone and in nine of 56 patients (16.1%) treated with an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody alone or a combination of anti-PD-1 and anti-CTLA-4 antibodies. The cumulative incidence and median daily diarrhea frequency were significantly higher in patients receiving anti-CTLA-4 antibodies (P < 0.05). In 130 patients with MM, OS was significantly prolonged in the group that continued ICI treatment despite the development of GI-irAEs compared to the group that did not experience GI-irAEs (P = 0.035). In contrast, in 209 patients with non-small cell LC, there was no significant difference in OS between the groups. The multivariate analyses showed that a performance status of 2-3 (hazard ratio: 2.406; 95% confidence interval: 1.125–5.147; P = 0.024) was an independent predictive factor for OS in patients with MM.

CONCLUSION

Patients receiving anti-CTLA-4 antibodies develop GI-irAEs more frequently and with higher severity than those receiving anti-PD-1/PD-L1 antibodies. Continuing ICI treatment in patients with MM with GI-irAEs have better OS.

Keywords: Colitis; Cytotoxic T-lymphocyte antigen 4; Diarrhea; Drug-related side effects and adverse reactions; Immune checkpoint inhibitors; Prognosis

Core Tip: We compared the clinical characteristics of gastrointestinal immune-related adverse events (GI-irAEs) in patients receiving anti-programmed cell death-1/programmed death-ligand 1 (anti-PD-1/PD-L1), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), or a combination of anti-PD-1 and anti-CTLA-4 antibodies. We also examined the correlation between GI-irAE development and the prognosis of patients with non-small cell lung cancer (LC) and malignant melanoma (MM). GI-irAEs occurred more frequently and with higher severity in patients receiving anti-CTLA-4 antibodies than in those receiving anti-PD-1/PD-L1 antibodies. Patients with MM, but not non-small cell LC, who continued immune checkpoint inhibitor treatment after developing GI-irAEs had better overall survival.