As reported in the Journal of Clinical Oncology by Brian I. Rini, MD, and colleagues, prospective cardiovascular monitoring in the phase III JAVELIN Renal 101 trial in advanced renal cell carcinoma (RCC) showed that patients with higher baseline troponin T levels receiving the combination of the immune checkpoint inhibitor avelumab plus the VEGFR inhibitor axitinib were at increased risk of major adverse cardiovascular events. A nonsignificant increase in risk was observed with combination therapy vs the VEGFR inhibitor sunitinib alone.
As stated by the investigators, “Both immune checkpoint inhibitors and VEGFR inhibitors are approved for advanced RCC treatment and can cause cardiovascular events; thus, combination therapy could lead to major adverse cardiovascular events.”
Brian I. Rini, MD
Study Details
In the trial, previously untreated patients were randomly assigned to receive avelumab at 10 mg/kg every 2 weeks plus axitinib at 5 mg twice daily (n = 442) or sunitinib at 50 mg orally once daily for 4 weeks on/2 weeks off (n = 444); the current analysis included 434 vs 439 patients in the safety population. Patients with left ventricular ejection fraction (LVEF) below the lower limit of normal (LLN) were excluded from the trial. LVEF was assessed at baseline and day 1 of every two cycles, with LVEF decline defined as a ≥ 10-point reduction from baseline to a value below the LLN. Cardiac biomarkers consisting of troponin I or T, B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP), and creatine kinase MB (CK-MB) were measured at baseline and on cycles 1, 2, and 3; on days 1, 15, and 29 of all three cycles; and when clinically indicated. Low vs high levels of biomarkers were defined as those below the investigator-defined LLN vs upper limit of normal ranges. Major adverse cardiovascular events were defined as grade ≥ 3 cardiovascular adverse events.
Key Findings
Major adverse cardiovascular events occurred in 31 patients (7.1%) in the combination arm vs 17 patients (3.9%) in the sunitinib arm (risk difference = 0.033, 95% confidence interval [CI] = –0.034 to 0.099). Cardiac deaths occurred in six patients (1.4%) vs one patient (0.2%; risk difference = 0.012, 95% CI = –0.055 to 0.078).
Major adverse cardiovascular events occurred in 6 (17.1%) of 35 patients with high baseline troponin T values vs 7 (5.2%) of 135 with low values in the combination group (relative risk [RR] = 3.31, 95% CI = 1.19–9.22). No significant association was observed in the sunitinib group, with major adverse cardiovascular events occurring in 2 (4.9%) of 41 patients with high values vs 9 (5.5%) of 165 with low values (RR = 0.89, 95% CI = 0.2–3.98).
No significant associations with risk of major adverse cardiovascular events were observed for troponin I, BNP, NT-proBNP, CK-MB, or other baseline cardiovascular risk factors. A trend towards increased risk was observed among patients with vs without baseline dyslipidemia in the combination group: major adverse cardiovascular events occurred in 10 (12.2%) of 82 with dyslipidemia vs 21 (6.0%) of 352 without dyslipidemia (RR = 2.04, 95% CI = 1.00–4.17).
LVEF declines were observed in 37 patients (8.5%) in the combination group vs 7 (1.6%) in the sunitinib group (P < .0001). By week 14, 22 patients (59.5%) in the combination group had recovered to LVEF above LLN. No association between LVEF decline and risk of major adverse cardiovascular events or other cardiovascular events or symptoms was observed in either treatment group.
The investigators concluded, “Patients with high baseline troponin T levels receiving immune checkpoint and VEGFR [inhibitor] combinations may need to be monitored more closely for major adverse cardiovascular events. Routine monitoring of LVEF in asymptomatic patients is not recommended.”
Dr. Rini, of the Division of Hematology and Oncology, Vanderbilt University Medical Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Pfizer as part of an alliance between Pfizer and the health-care business of Merck KGaA. For full disclosures of the study authors, visit ascopubs.org.
