The survival benefits and the risk of severe renal injury of immune checkpoint inhibitors in patients with cancer: The real-world evidence from the National Clinical Cohort Collaborative (N3C).
Authors: Chen Yao , Li Xiaochun , Madhira Vithal , Shugg Tyler , Jalal Shadia Ibrahim , Eadon Michael , Bates Benjamin , Sharafeldin Noha , Topaloglu Umit , Song Qianqian , Su Jing 
Published: June 2024

e24142

Background: The survival benefits and the risks of severe immune-related adverse events (sirAEs) of Immune checkpoint inhibitors (ICI) vary dramatically among cancer patients. Among sirAEs, acute kidney injury (AKI) incidences are rising, often cause sustained renal damage, and are responsible for the deterioration of patients’ overall health and quality of life. There is an urgent need to support oncologists and nephrologists in choosing the right ICI drugs for the right patients. We aim to comprehensively scrutinize the tradeoff between the survival benefits and the severe AKI risk for ICI patients by leveraging the national electronic medical records (EMR) from the National Clinical Cohort Collaborative (N3C) registry. Our work provides real-world evidence for clinical decisions on ICI use. Methods: Cancer patients treated with ICI are followed up for at least 6 months using N3C data (01/01/2018 - 01/19/2024). Primary outcomes included severe AKI within 6 months of initiation or mortality up to the last follow-up. We fit multivariable Cox proportional hazards models to evaluate the effect of various ICI types, adjusting for age, gender, race, cancer types, smoking status, and comorbidities. Results: Our study cohort included 55,767 patients who received an ICI, with 25,197 deaths and 6,458 severe AKI events. The most common ICI used were PD-1 inhibitors (74.3%), PD-L1 inhibitors (16.6%), CTLA-4 inhibitors (0.3%), and combination treatments of PD-1 and CTLA-4 inhibitors (8.8%). Observed long-term severe AKI incidences exceeded prior reports, with 96%, 92%, 88%, and 71% at 1, 3, 6, and 36 months. Survival benefits of PD-1, CTLA-4 and their combinations versus PD-L1 inhibitors were comparable (HR: 0.94 [95%CI: 0.91–0.97]; HR: 0.81 [95%CI: 0.63–1.02]; HR: 1.09 [95%CI: 1.04–1.15]). Severe AKI risks were higher with CTLA-4 and combination therapy (HR: 1.48 [95%CI: 0.96–2.28]; HR: 1.96 [95%CI: 1.78–2.16]) compared to PD-L1 inhibitors, with PD-1 inhibitors also showing increased risk (HR: 1.15 [95%CI: 1.07–1.23]). We also scrutinize risk factors associated with significant AKI risk, including a history of AKI, congestive heart failure, dementia, complicated diabetes, hypertension, liver disease, other immunocompromised diseases, and cancers of the gynecologic type, prostate cancer, and gastrointestinal cancers, and being of Black race. Conclusions: Our work provides up-to-date and comprehensive real-world evidence of the survival benefits and severe renal injury risks for clinical decisions of ICI therapy. PD-L1 inhibitors are associated with a lower risk of severe AKI compared to PD-1, CTLA-4 inhibitors, and their combination. Future research should focus on identifying patient subgroups that may benefit from specific ICI therapies while minimizing adverse outcomes.