Among patients with advanced renal cell cancer treated with a combination of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors, , according to a planned post hoc analysis of data from the phase III JAVELIN Renal 101 trial.
The therapeutic combination is effective against several solid tumors, but ICIs are associated with cardiovascular events, including myocarditis in about 1% of patients. Although rare, the condition has a 46% mortality and 80% of the time occurs within 6 weeks of the start of treatment. It is unknown whether combination with VEGF inhibitors could heighten that risk.
“One of the areas that has been uncertain in kidney cancer with these VEGF combos is, what are the potential cardiac toxicities? How intensive monitoring do we need? How do we predict which patients might be at risk for these relatively rare but potentially serious events? So I think the value of the study is that it is a large prospective study where these measurements and endpoints were prospectively defined,” said lead author Brian Rini, MD, chief of clinical trials at Vanderbilt-Ingram Cancer Center.
The study, published online March 3 in the Journal of Clinical Oncology, doesn’t create specific recommendations for handling patients, Dr. Rini said. He suggests that physicians should consider more intense monitoring of patients on the regimen, along with upfront consultation with cardiologists, as well as keeping other treatment regimens in mind. “It’s hard to go much beyond just sort of an alert that this patient may be at higher risk than a patient without [heightened troponin T levels],” Dr. Rini said.
He also noted the finding that LVEF decline (≥10-point reduction from baseline to a value below the lower limit of normal) didn’t predict major adverse cardiac events (MACE), suggesting that echocardiograms, which have been done routinely since VEGF-targeted therapy was introduced, may not have much value in the general patient population. “It’s not that there’s no risk, but doing a lot of ECHOs on every single patient is just not an efficient way, as opposed to doing it in a more targeted fashion to patients with the relevant history and/or who developed suggestive symptoms,” Dr. Rini said.
The JAVELIN study randomized 442 patients (median age, 62.0; 71.5% male) to intravenous avelumab (Bavencio, Merck/Pfizer, 10 mg/kg) every 2 weeks plus oral axitinib (Inlyta, Pfizer, 5 mg) twice per day, and 439 patients (median age, 61.0; 77.5% male) to oral sunitinib (Sutent, Pfizer, 50 mg) once per day for 4 weeks. MACE were more common in the avelumab/axitinib group (7.1% vs. 3.9%). Left ventricular ejection fraction (LVEF) decline occurred more often in the avelumab/axitinib arm (8.5% vs. 1.6%; P < .0001), but there was no correlation between MACE and LVEF decline in either arm.
Patients in the avelumab/axitinib group with baseline levels of troponin T above the upper limit of normal were more likely to experience a MACE (17.1% vs. 5.2%; relative risk, 3.31; P = .022), but there was no difference in the sunitinib arm.
The study was funded by Pfizer. Dr. Rini has consulted for and received research funding from Pfizer.