Abstract
Checkpoint inhibitors (CPIs) increase antitumor activity by unblocking regulators of the immune response. This action can provoke a wide range of immunologic and inflammatory side effects, some of which can be fatal. Recent studies suggest that CPI-induced immune-related adverse events (irAEs) may predict survival and response. However, little is known about the mechanisms of this association. This study was undertaken to evaluate the influence of tumor diagnosis and preexisting clinical factors on the types of irAEs experienced by cancer patients treated with CPIs. The correlation between irAEs and overall survival (OS) was also assessed. All cancer patients treated with atezolizumab (ATEZO), ipilimumab (IPI), nivolumab (NIVO), or pembrolizumab (PEMBRO) at Virginia Mason Medical Center between 2011 and 2019 were evaluated. irAEs were graded according to the Common Terminology Criteria for Adverse Events (Version 5) and verified independently. Statistical analyses were performed to assess associations between irAEs, pre-treatment factors, and OS. Of the 288 patients evaluated, 59% developed irAEs of any grade, and 19% developed irAEs of grade 3 or 4. A time-dependent survival analysis demonstrated a clear association between the occurrence of irAEs and OS (P < 0.001). A 6-week landmark analysis adjusted for body mass index confirmed an association between irAEs and OS in non-Small Cell Lung Cancer (NSCLC) (P < 0.03). An association between melanoma and skin irAEs (P < 0.01) and between NSCLC and respiratory irAEs (P = 0.03) was observed, independent of CPI administered. Patients with preexisting autoimmune disease experienced a higher incidence of severe irAEs (P = 0.01), but not a higher overall incidence of irAEs (P = 0.6). A significant association between irAEs and OS was observed in this diverse patient population. No correlation was observed between preexisting comorbid conditions and the type of irAE observed. However, a correlation between skin-related irAEs and melanoma and between respiratory irAEs and NSCLC was observed, suggesting that many irAEs are driven by a specific response to the primary tumor. In patients with NSCLC, the respiratory irAEs were associated with a survival benefit.
Highlights
Immune checkpoint inhibitors (CPIs) that target the cytotoxic Tlymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway have demonstrated remarkable efficacy across a wide variety of cancer types [1]
CPIs can lead to immune-related adverse events that result in significant morbidity and discontinuation of therapy [2]
No exclusions were imposed based on preexisting conditions or other comorbid conditions that frequently preclude participation in clinical trials, which represent the “real world” experience of the immune-related adverse events (irAEs) in cancer patients treated with CPIs and the outcomes
Summary
Immune checkpoint inhibitors (CPIs) that target the cytotoxic Tlymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway have demonstrated remarkable efficacy across a wide variety of cancer types [1]. In addition to inducing durable anti-tumor responses and improving survival of patients, treatment with CPIs is often better tolerated than conventional cytotoxic chemotherapeutic agents. CPIs can lead to immune-related adverse events (irAEs) that result in significant morbidity and discontinuation of therapy [2]. Recent studies suggest that CPI-induced irAEs can predict survival and response, little is known about the mechanisms of this association [3, 4]. We undertook this study to evaluate the relationship between tumor type, preexisting clinical factors, the occurrence and type of irAEs, and OS in a diverse set of cancer patients treated with CPIs. Accurately measuring the prognostic significance of preexisting clinical factors could help identify those patients at higher or lower risk for developing irAEs [5,6,7,8]
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