The Association between Combination-Based Immunotherapy and Thrombotic Events in Patients with Metastatic Renal Cell Carcinoma

Introduction: Immunotherapy has transformed the treatment landscape for metastatic renal cell carcinoma (mRCC). Current guidelines recommend either a dual immune-oncology (IO) checkpoint inhibitor regimen (IO/IO) or a single immune checkpoint inhibitor in combination with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (TKI) (IO/TKI) as the first-line therapy for patients with mRCC. However, both IO and VEGF-R TKI therapies are associated with an increased risk of thromboembolism. Our study aims to compare the risk of thromboembolic events between patients treated with IO/IO and IO/TKI regimens.

Methods: We conducted a retrospective, propensity score-matched cohort study using the TriNetX Analytics Network database. This database is a collaborative research platform containing de-identified electronic health records from over 101 million individuals and 120 healthcare organizations. We included patients with renal cell carcinoma (RCC) who received either an IO/IO or IO/TKI regimen between May 1, 2018, and June 30, 2023. The IO/IO regimen was defined as ipilimumab plus nivolumab, while the IO/TKI regimen included nivolumab or pembrolizumab combined with a TKI such as axitinib, cabozantinib, or lenvatinib. In our cohort, we matched IO/IO cohort and IO/TKI cohort in a 1:1 ratio based on predetermined clinical variables such as age, sex, race, metastatic disease and underlying comorbidities. The index date was the start date of the IO/IO or IO/TKI regimen. Patients with a history of venous thromboembolism, ischemic stroke, or myocardial infarction prior to the index date were excluded from the study. The primary outcomes were arterial thrombotic events, including myocardial infarction and ischemic stroke, and venous thromboembolic vents, including pulmonary embolism and deep venous thrombosis. The secondary outcome was all-cause mortality between the IO/IO and IO/TKI cohorts.

Results: A total of 4,288 patients were eligible for inclusion, with 1,706 patients on the IO/IO regimen matched to those on the IO/TKI regimen. In Cox proportional hazards analyses, there was no significant difference between patients receiving IO/IO and IO/TKI regimens in terms of venous thromboembolism (hazard ratio [HR], 1.15[95% CI: 0.95-1.39]), pulmonary embolism (hazard ratio [HR], 1.04 [95% CI: 0.79-1.36]), deep vein thrombosis (HR, 1.23 [95% CI: 0.89-1.70]), arterial thromboembolism (hazard ratio [HR], 0.96 [95% CI: 0.75-1.24]), myocardial infarction (HR, 0.87 [95% CI: 0.58-1.30]), and ischemic stroke (HR, 0.92 [95% CI: 0.72-1.33]). However, patients receiving the IO/IO regimen were associated with an increased risk of mortality compared to those treated with the IO/TKI regimen (HR, 1.16 [95% CI: 1.01-1.35]).

Conclusion: There was no difference in the risk of venous and arterial thromboembolic events between mRCC patients receiving the IO/IO regimen and those receiving the IO/TKI regimen. However, patients on the IO/IO regimen had an increased risk of mortality compared to those on the IO/TKI regimen.