MO344: Effect of Cancer Stage on Adverse Kidney Outcomes in Patients With Advanced Melanoma Treated With Immune Checkpoint Inhibitors

Abstract

Abstract BACKGROUND AND AIMS Immune checkpoint inhibitor (ICI) therapy has improved the outcome of advanced melanoma but can also lead to kidney injury. Anti-programmed cell death protein 1 (anti-PD-1) therapy is now used in adjuvant setting for stage 3 melanoma after curative intent surgery, and anti-PD-1 or a combination of anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4)/PD-1 therapy is used in stage 4 melanoma. We aimed to compare the incidence and predictors of adverse kidney outcomes in patients with stage 3 and stage 4 melanoma treated with ICIs. METHOD We conducted a retrospective cohort study including all patients diagnosed with advanced melanoma who initiated ICIs between January 2016 and December 2019 at Mass General Brigham. Acute kidney injury (AKI) was defined as a 1.5-fold rise in creatinine within 1 year of ICI initiation. Sustained AKI was defined as AKI that lasted for > 48 h, and acute interstitial nephritis (AIN) cases (diagnosed by biopsy or clinical criteria) were determined by chart review of all episodes of sustained AKI by two nephrologists. A composite outcome of chronic kidney disease (CKD) was defined by new onset estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or 30% eGFR decline sustained for 90 days. Non-kidney irAEs were defined by diagnosis codes. Competing risk analysis was used to identify risk factors for adverse kidney outcomes. RESULTS A total of 855 patients with advanced melanoma were treated with ICIs between 2016 and 2019. The risk of all-cause AKI was 16.6%. Patients with stage 4 melanoma receiving anti-CTLA-4/PD-1 combination therapy had the highest rates of all-cause AKI (27.2%) and AIN (5.7%). Patients with surgically resected stage 3 melanoma treated with adjuvant anti-PD-1 therapy has the lowest absolute risk of all-cause AKI (7.5%); but the aetiology of AKI was enriched for AIN in stage 3 melanoma (causing 62.5% of all cases of AKI sustained >48 h) (Fig. 1). In the multivariable Fine-Gray model, cancer stage and ICI treatment regimen were the top predictors of AKI. Patients with stage 4 melanoma treated with anti-PD-1 monotherapy were more than two times likely to develop AKI within the first year compared with patients with stage 3 melanoma [aHR 2.18, 95% confidence interval (95% CI) 1.29–3.74; P < .01), while patients with stage 4 melanoma treated with anti-CTLA-4/PD-1 combination therapy were more than four times likely to develop AKI (aHR 4.36, 95% CI 2.58–7.39; P < .01) compared with patients with stage 3 melanoma (Fig. 2). Baseline CKD, diabetes, hypertension, cirrhosis and proton pump inhibitor use were not significantly associated with the risk of developing AKI. For AIN, only anti-CTLA-4/PD-1 combination therapy use was significantly associated with the outcome (aHR 4.17, 95% CI 1.28–13.54; P = .02). There was no increase in the risk of AIN in patients with stage 4 melanoma receiving anti-PD-1 monotherapy compared with stage 3 melanoma (Fig. 2). Among patients surviving > 4 years, 20% developed the composite CKD outcome. We identified a similar trend across the three cohorts for kidney and non-kidney irAEs: patients with stage 3 and stage 4 melanoma treated with anti-PD-1 monotherapy had similar rates of non-kidney irAEs (60% in stage 3 versus 52.7% in stage 4, P = .2), while patients with stage 4 melanoma treated with anti-CTLA-4/PD-1 combination therapy experienced higher rates of non-kidney irAEs (72%, P = .01). CONCLUSION Anti-CTLA-4/PD-1 combination therapy is associated with a higher risk of all-cause AKI and AIN. Incidence of AIN is similar between patients with stage 3 and stage 4 melanoma receiving anti-PD-1 monotherapy. Among patients with stage 3 melanoma, AKI aetiology is enriched for AIN. Survivors are at high risk of CKD regardless of cancer stage.