Outcomes based on age in patients with metastatic renal cell carcinoma treated with first line targeted therapy or checkpoint immunotherapy: Older patients more prone to toxicity.

OBJECTIVES: Older patients with metastatic renal cell carcinoma (mRCC) were underrepresented in pivotal trials. MATERIALS AND METHODS: Consecutive patients with mRCC treated at Aarhus University Hospital with first line tyrosine kinase inhibitors (TKI), mTOR inhibitors, or checkpoint immunotherapy (CPI) were retrospectively analyzed in age-subgroups; ≥ 75, 65-74, and < 65 years, with overall survival (OS), time-to-treatment discontinuation (TTD), and progression-free survival (PFS) as endpoints. Hazards ratios were adjusted (aHR) for International Metastatic RCC Database Consortium (IMDC) risk factors, histology, and age. RESULTS: Of 838 patients, 159 (19%) were ≥ 75 years, 324 (39%) 65-74 years, and 355 (42%) < 65 years. Treatments were TKI in 729 (87%) patients, mTOR in 43 (5%) and CPI in 67 (8%). Older patients ≥ 75 years compared with 65-74 years and < 65 years had lower toxicity-adjusted median doses of pazopanib, 300 mg vs. 400 mg vs. 600 mg, respectively, (p < 0.001), and sunitinib, 25 mg vs. 37.5 mg vs. 50 mg, respectively (p < 0.001); numerically fewer doses of CPI, median 2 vs. 5 vs. 5, respectively, (p = 0.2); a higher proportion had dose reduction/interruption, 76% vs. 55% vs. 41%, respectively, (p < 0.001); and shorter mean time to dose reduction/interruption, 0.5 months vs. 1.9 months vs. 3.4 months, respectively, (p < 0.001). After adjusting IMDC prognostic factors and histology in multivariate analyses, age did not impact OS (aHR 1.0; 95% CI 0.99-1.02, p = 0.2), TTD (aHR 1.0; 95% CI 0.99-1.01, p = 0.4) or PFS (aHR 1.0, 95% CI 0.99-1.01; p = 0.9). CONCLUSION: Older patients with mRCC were more prone to toxicity; but age did not impact outcomes. Proactive dose modification/interruption and awareness may help to reduce toxicity while maintaining efficacy.

Pazopanib-Induced Liver Toxicity in Patients With Metastatic Renal Cell Carcinoma: Effect of UGT1A1 Polymorphism on Pazopanib Dose Reduction, Safety, and Patient Outcomes.

BACKGROUND: Pazopanib can induce liver toxicity in patients with metastatic renal cell carcinoma (mRCC). We assessed the effect of a TA repeat polymorphism in the UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) gene encoding uridine diphosphate glucuronosyltransferase 1A1 on liver toxicity, dose reductions, and patient outcomes. PATIENTS AND METHODS: Patients with mRCC treated with first-line pazopanib developing liver toxicity underwent genotyping for the UGT1A1 polymorphism. Liver toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and overall survival were assessed using the Kaplan-Meier and log-rank methods. RESULTS: Of 261 patients, 34 (13%) had developed liver toxicity after a median of 29 days (range, 5-155 days). Grade 4, 3, and 2 alanine aminotransferase or bilirubin had increased in 2 (6%), 17 (50%), and 8 (24%) patients, respectively. The UGT1A1 assessment demonstrated that 18 patients (53%) had TA6/TA7, 7 (21%) had TA7/TA7, and 9 (26%) had wild-type TA6/TA6. The UGT1A1 polymorphism was associated with improved median progression-free survival (TA6/TA6, 5.5 months; TA6/TA7, 34.2 months; TA7/TA7, 22.3 months; unknown UGT1A1 status, 9.2 months; UGT1A1 polymorphisms combined vs. unknown status, P = .021). UGT1A1 polymorphism was associated with improved median overall survival (TA6/TA6, 8.1 months, TA6/TA7 or TA7/TA7 not reached, unknown UGT1A1 status, 16.6 months; UGT1A1 polymorphisms combined vs. unknown status, P = .033). Patients with UGT1A1 polymorphism safely resumed pazopanib at ultra-low doses determined by the degree of liver toxicity and UGT1A1 polymorphism. CONCLUSIONS: UGT1A1 polymorphisms were associated with improved outcomes, despite pazopanib interruption and dose reductions. UGT1A1 assessment could improve the management of pazopanib-induced liver toxicity in patients with mRCC.