Immune-Related Adverse Events as Clinical Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

Abstract

Background. Immune checkpoint inhibitors (ICI) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs) and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in ICI-treated mRCC patients. Methods. We performed a retrospective study of 200 ICItreated mRCC patients at Winship Cancer Institute from 2015-2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using common terminology criteria in adverse events (CTCAE) version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate. Results. Most patients (71.0%) were males and one-third of patients (33.0%) experienced ≥1 irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (HR=0.52, p=0.013), higher chance of CB (OR=2.10, p=0.023) and showed a trend towards longer PFS (HR=0.71, p=0.065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS, PFS, and higher chance of CB. In 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p=0.045). Patients who experienced irAEs had significantly longer median OS (44.5 versus 18.2 months, p=0.005) and PFS (7.5 versus 3.6 months, p=0.003) without landmark compared to patients who did not. Conclusions. We found that ICI-treated mRCC patients who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared to patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in ICI-treated mRCC patients. Future, prospective studies are warranted to validate these findings. The Oncologist 2021;9999:• •

Incidence and Outcome of Neurologic Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in Patients With Melanoma

“…This is also supported by other publications. [36][37][38][39][40][41][42] Of the 76 patients with n-irAEs, 24 (31.5%) died during the study period; only 1 patient died directly because of the neurologic toxicity (grade 5). Most (53%) of the patients died after the development of myositis or encephalitis, both known to be potentially fatal, yet there was no obvious temporal relationship.…”

Emerging Management Approach for the Adverse Events of Immunotherapy of Cancer

“…Vitiligo and other dermatologic irAEs may be positive prognostic indications for melanoma patients [160]. Thyroid cancer, renal cell carcinoma, and other malignancies irAEs [161][162][163] showed similar relationships with efficacy. In patients with metastatic renal cell carcinoma, side effects linked with non-IO treatments, such as Sunitinib, have comparable relationships and effects on baseline thyroid function [164].…”

Pancreatic adverse events in patients treated with immune checkpoint inhibitors

“…Nevertheless, exocrine and endocrine pancreatic dysfunction have been rarely reported among the different ICIs 9 . The incidence of diabetic ketoacidosis (DKA) and pancreatitis ranged between 0% and 0.6% and between 0% and 2.5%, respectively, among different studies 13–17 …”

“…9 The incidence of diabetic ketoacidosis (DKA) and pancreatitis ranged between 0% and 0.6% and between 0% and 2.5%, respectively, among different studies. [13][14][15][16][17] In this case series, we report seven cases of pancreatic exocrine and endocrine irAEs that were treated at our institute.…”