A Tale of Immune-Related Adverse Events With Sequential Trials of Checkpoint Inhibitors in a Patient With Metastatic Renal Cell Carcinoma

Abstract

Immune checkpoint inhibitor (CPI) therapy is approved for the treatment of many cancers. As its use becomes more prevalent, sequential trials with different CPIs as monotherapy or combination therapy will become more common. It is thought that the increased cumulative dose of CPIs over multiple trials increases the risk of immune-related adverse events (irAEs). However, it is not known if using one CPI combination increases the risk of developing irAEs during the subsequent trial of a different CPI combination. Here, we present a patient with multiple episodes of high-grade irAEs over the course of sequential trials of combination CPIs. A 65-year-old female patient with metastatic renal cell cancer received two trials of combination CPIs. During the first trial with durvalumab and tremelimumab, she had CPI-induced grade 2 skin rashes and primary hypothyroidism with a mild elevation in lipase, normal antithyroid antibody profile, and normal blood glucose. Due to progression after the first trial, her regimen was changed to ipilimumab and nivolumab combination therapy. She subsequently presented to the emergency room with diabetic ketoacidosis on the sixth week following treatment initiation and was diagnosed with new-onset insulin-dependent type 1 diabetes mellitus (DM) with a negative antibody profile for DM. Immune CPIs cause irAEs by increasing immune activity against self-antigens. Sequential trials of CPIs may increase the risk of irAEs by increasing the cumulative CPI dose, or by organ injury inflicted by the first set of CPIs which is tipped "over the edge" by subsequent trials. We believe that the latter mechanism could be responsible for our case. Sequential CPI therapy should be planned carefully with increased surveillance for the early diagnosis and treatment of irAEs.

Keywords: immune checkpoint inhibitors; immune-related adverse events; type i diabetes mellitus.

Figure 1. Random blood glucose of the patient over complete treatment cycles.

Months are scaled for the treatment cycle. DT: durvalumab and tremelimumab combination, D: durvalumab alone, T: tremelimumab alone, IN: ipilimumab and nivolumab combination, DKA: diabetic ketoacidosis.