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.

Figure 1

Kaplan–Meier curves of the cumulative incidence of gastrointestinal- immune-related adverse events for all patients in the programmed cell death-1/programmed death-ligand 1 and cytotoxic T-lymphocyte antigen 4 groups. The cumulative incidence was significantly higher in the cytotoxic T-lymphocyte antigen 4 group than in the programmed cell death-1/programmed death-ligand 1 group (P = 0.003). CTLA-4: Cytotoxic T-lymphocyte antigen 4; PD-1: Programmed cell death-1; PD-L1: Programmed death-ligand 1.

Figure 2

Ischemic change caused by an immune checkpoint inhibitor. Endoscopic images of gastrointestinal-immune-related adverse events in the sigmoid colon of a patient. A: The mucosa of the sigmoid colon shows redness, erosion, hemorrhage, and edema; B: Some of the mucosa is pale, with submucosal edema and bleeding.

Figure 3

Overall survival after initiation of immune checkpoint inhibitor treatment. Overall survival (OS) of patients with non-small cell lung cancer (NSCLC) and OS of patients with malignant melanoma (MM). A: In patients with NSCLC, there was no significant difference in OS among the three groups; B: The results were similar when stratified in stage III; C: The results were similar when stratified in stage IV; D: In patients with MM, there was a significant prolongation of OS in the immune checkpoint inhibitor (ICI) continuation group compared to the non-gastrointestinal immune-related adverse event (non-GI-irAE) group (P = 0.035); E: There was no significant difference in OS between the ICI continuation group and the non-GI-irAE group among patients with stage III disease; F: Among patients with stage IV disease, there was a significant prolongation of OS in the ICI continuation group compared to the non-GI-irAE group (P = 0.017). ICI continuation group: Patients who continued ICI treatment after developing GI-irAEs; ICI discontinuation group: Patients who discontinued ICI treatment after developing GI-irAEs; non-GI-irAE group: Patients with no GI-irAEs.