Gastrointestinal Toxicities of Immune Checkpoint Inhibitors Are Associated With Enhanced Tumor Responsiveness and Improved Survival

Abstract

Background Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancies. However, they are associated with the development of multiple gastrointestinal immune-related adverse events (GI-irAEs). We aimed to evaluate the types and severity of GI-irAEs associated with ICI therapy, to identify potential risk factors for developing GI-irAEs and to determine the relationship of GI-irAEs development to tumor responsiveness and overall survival. Methods All patients who received ICIs for advanced malignancies at our center were included. Medical records were reviewed, and data extraction included: baseline demographic characteristics, immunotherapy regimens, development of GI-irAEs, response to treatment, and overall survival. Overall survival was calculated from the date of treatment initiation and estimated by the Kaplan-Meier method. Results Five hundred sixty-seven patients received ICI therapy for stage IV malignancies. Forty-one (7%) patients experienced at least one GI-irAE. Among those experiencing GI-irAEs, 23 (56%) developed hepatitis, 17 (42%) developed colitis, four (10%) developed pancreatitis, and two (5%) developed gastritis. Patients who developed GI-irAEs experienced a better response to ICI therapy compared to patients who did not develop GI-irAEs (41% vs. 27%, P = 0.003). The 2-year overall survival rate of stage IV cancer patients who developed GI-irAEs was 62% (95% confidence interval (CI): 49 - 79) and 36% for those who did not develop GI-irAEs (95% CI: 32 - 41) (P = 0.002). The median follow-up time of surviving patients was 28 months. Twelve (29%) of the patients receiving dual ICI therapy developed GI-irAEs. Conclusion Hepatitis, colitis, and pancreatitis were the most commonly encountered GI-irAEs with ICI therapy. Development of these GI-irAEs was associated with superior tumor responsiveness and better overall survival.

Immune checkpoint inhibitor gastritis is often associated with concomitant enterocolitis, which impacts the clinical course

“…[17][18][19][20][21][22] In earlier retrospective cohorts of 41 and 80 patients with GI-related irAEs, gastritis represented only approximately 5% of all GI luminal irAEs. 23,24 In the absence of more robust data on upper GI irAEs, clinical guidelines from the US National Comprehensive Cancer Network, 25 American Society of Clinical Oncology, 26 and European Society for Medical Oncology 27 do not detail specific guidance on ICI gastritis. There is a need to understand the patterns of clinical presentation of ICI gastritis, including copresentation with enteritis/colitis, and the utility of imaging, endoscopy, and tissue biopsy in its diagnosis.…”

“…There are scarce data about gastrointestinal (GI) irAEs involving the upper GI tract, limited to case reports 3–16 and a few small series 17–22 . In earlier retrospective cohorts of 41 and 80 patients with GI‐related irAEs, gastritis represented only approximately 5% of all GI luminal irAEs 23,24 …”