Background and Importance Oral vascular endothelial growth factor receptor – tyrosine kinase inhibitors (VEGFR-TKIs) are standard treatments for metastatic renal cell carcinoma. The VEGF pathway plays an important role in the physiological function and homeostasis of the cardiovascular and kidney systems, resulting in anti-angiogenesis-related adverse events (AEs). Limited studies have evaluated anti-angiogenesis-related AEs involving VEGFR-TKIs using real-world data, which may provide important evidence for drug choice and monitoring in the treatment of metastatic renal cell carcinoma.

Aim and Objectives This study aimed to investigate the incidence and patterns of anti-angiogenesis-related AEs associated with the use of VEGFR-TKIs in patients with a metastatic renal cell carcinoma using real-world data.

Material and Methods This cross-sectional study included patients with a diagnosis of metastatic renal cell carcinoma who received axitinib, cabozantinib, pazopanib, sorafenib, and sunitinib at the third level hospital in South Korea between January 2007 and December 2019. Anti-angiogenesis-related AEs were rated ‘possible’ or higher on the WHO-Uppsala Monitoring Centre (WHO-UMC) causality assessment scale. The severity of AEs was graded using the CTCAE v.5.0. To compare the incidence of AEs associated with different VEGFR-TKIs, we divided the enrolled patients into those who had not previously received a VEGFR-TKI (VEGFR-TKI-naïve) and those who had previously received a VEGFR-TKI (VEGFR-TKI-experienced).

Results A total of 988 patients were included (75% men, median 61 years). 644 patients were VEGFR-TKI-naïve and 314 patients were VEGFR-TKI-experienced. Anti-angiogenesis-related AEs of any grade occurred in 65.1% of VEGFR-TKI-naïve patients and 54.8% of VEGFR-TKI-experienced patients. In addition, severe AEs occurred in 34.6% of VEGFR-TKI-naïve patients and 36.0% of VEGFR-TKI-experienced patients. Regardless of treatment history, the most common AE was hypertension, with a 48.6% of VEGFR-TKI-naïve and 35.0% of VEGFR-TKI-experienced. For VEGFR-TKI-experienced patients, the overall rate of anti-angiogenesis-related AEs for sorafenib (24.3%) was lower than that for other VEGFR-TKIs (p < 0.05). Female gender (adjusted hazard ratio [aHR] 1.23, 95% confidence interval [CI] 1.02-1.48) and high blood pressure (aHR 1.47, 95% CI 1.23-1.76) were risk factors for VEGFR-TKI-associated AEs.

Conclusion and Relevance More than half of patients with renal cell carcinoma receiving VEGFR-TKI experienced anti-angiogenesis-related AEs. Any grade of AEs occurred more frequently in VEGFR-TKI-naïve patients, while severe AEs occurred more frequently in VEGFR-TKI-experienced patients.

Conflict of Interest No conflict of interest