Real-world toxicity outcomes with adjuvant pembrolizumab following nephrectomy for renal cell carcinoma.

Abstract

e23447 Background: Adjuvant pembrolizumab improves overall and disease-free survival in high-risk renal cell carcinoma (RCC) patients; however, treatment-related toxicity remains a serious concern. We evaluated toxicity patterns and associated survival outcomes among patients receiving adjuvant pembrolizumab following nephrectomy in a large real-world cohort. Methods: We conducted a retrospective cohort study in Epic Cosmos, identifying the largest-to-date RCC cohort undergoing nephrectomy who received post-nephrectomy adjuvant pembrolizumab. The study period spanned from the FDA approval date (Nov 17, 2021) to Dec 20, 2025, ensuring at least one month of follow-up prior to the query date. Patients were excluded if they had metastatic systemic therapy exposure and/or metastatic diagnosis codes at any time before or within 90 days after nephrectomy. Overall survival (OS) was estimated using the Kaplan–Meier method. Logistic regression models with false discovery rate (FDR) correction were used to identify factors associated with toxicity (initiation of post-adjuvant high-dose systemic corticosteroids was used as a proxy for clinically significant immune-related adverse events). Results: The cohort included 2,656 patients with a median age of 64 years; 67.8% were male, and 86.5% were White. During follow-up, 400 patients (15.1%) initiated high-dose systemic corticosteroids, which was higher than reported in the KEYNOTE-564 trial (7.4%). Steroid use was associated with significantly worse OS compared with no steroid use (OR 1.99, 95% CI 1.21–3.27; p < 0.01). Laboratory factors significantly associated with toxicity requiring high-dose steroids included high eosinophils (OR: 2.44 [1.51-3.95], FDR < 0.01), eosinophil-to-lymphocyte ratio (OR: 2.44 [1.33-4.35], FDR = 0.02), RDW (OR: 1.07 [1.02-1.22], FDR = 0.01), and BUN (OR: 1.02 [1.003-1.03], FDR = 0.03). Higher values of albumin (OR: 0.62 [0.47-0.81], FDR < 0.01), hemoglobin (OR: 0.90 [0.84-0.96], FDR < 0.01), MCHC (OR: 0.89 [0.82-0.96], FDR = 0.02), and hematocrit (OR: 0.97 [0.94-0.99], FDR = 0.03) were associated with lower toxicity risk. None of the baseline clinical/ demographic features were significant, including age, sex, or BMI. Conclusions: In this large real-world cohort of patients with RCC receiving adjuvant pembrolizumab following nephrectomy, treatment-related toxicity requiring high-dose corticosteroids occurred in approximately 15.1% of patients and was associated with significantly worse overall survival. Baseline inflammatory and hematologic markers were associated with toxicity risk. These findings highlight the importance of early toxicity risk stratification and proactive management in the adjuvant immunotherapy setting.