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Check Troponin in RCC Patients Before Checkpoint-VEGFR Inhibitor Combo

— In JAVELIN Renal 101, those with high levels had more heart events with avelumab-axitinib

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A photo of a blue rubber gloved hand holding a test tube of blood labeled: Troponin T - Test

Advanced renal cell carcinoma (RCC) patients with high serum levels of troponin T had a greater risk of serious cardiac events when treated with an immune checkpoint inhibitor and VEGFR inhibitor combination, data from the phase III indicated.

For patients assigned to the avelumab (Bavencio) plus axitinib (Inlyta) arm, 17.1% of those with high troponin T values had a major cardiovascular adverse event (MACE) versus 5.2% of those with lower values (relative risk 3.31, 95% CI 1.19-9.22), reported Brian I. Rini, MD, of Vanderbilt University Medical Center in Nashville, and colleagues.

But this difference was not seen in the sunitinib (Sutent) arm, at 5.1% versus 5.7% for those with high and low troponin T levels, respectively (RR 0.89, 95% CI 0.20-3.98), according to findings appearing in the .

"We suggest that baseline assessment of troponin T levels may be considered when starting treatment with an ICI [immune checkpoint inhibitor] plus a VEGFR inhibitor, particularly in patients with cardiovascular risk factors," Rini and his colleagues wrote. "Patients with high troponin T levels should be monitored closely for cardiac symptoms during treatment, potentially including ECG monitoring, and a cardiologist should be involved in patient management from the outset of treatment."

However, the authors added, cardiac history "should not exclude patients from receiving ICI plus VEGFR combination therapy."

Left ventricular ejection fraction (LVEF) decline in the trial was significantly more frequent in the combination arm (8.5% vs 1.6%), but most patients recovered and the decline was not associated with other significant cardiac events or symptoms, Rini's group reported. Thus, "routine monitoring of LVEF in asymptomatic patients is not recommended."

JAVELIN Renal 101 randomized 866 RCC patients with previously untreated advanced disease 1:1 to either the PD-L1 checkpoint inhibitor avelumab plus VEGFR inhibitor axitinib or to sunitinib, a multi-targeted receptor tyrosine kinase inhibitor. Results of the phase III study led to the of avelumab-axitinib in this setting.

The rationale for the current study, the authors noted, is that checkpoint inhibitors and VEGFR inhibitors have been associated with cardiovascular adverse events, "creating a theoretical potential for an increased incidence of MACE with combination treatment." This study, they said, is the first to prospectively assess LVEF decline and serum cardiac biomarkers in patients treated with a checkpoint inhibitor plus VEGFR inhibitor.

Approximately 60% of patients in each arm of the study had a history of hypertension. At data cutoff, median exposure to avelumab, axitinib, and sunitinib was 37.2, 39.2, and 31.7 weeks, respectively.

Overall, MACE (defined as grade ≥3 cardiovascular adverse events) occurred in 31 patients (7.1%) in the combination arm, and 17 patients (3.9%) in the sunitinib arm, a non-significant difference that was reduced in exposure-adjusted analyses, Rini and his colleagues observed.

Other cardiovascular baseline risk factors and serum cardiac biomarkers were not significantly predictive for MACE, the authors noted, although there was trend toward an association with dyslipidemia in the combination arm.

"Because of the small number of patients with MACE in our study, the predictive value of serum biomarkers other than troponin T cannot be ruled out," wrote Rini and his colleagues. "Larger studies are needed to confirm the findings in this study."

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

This work was sponsored by Pfizer as part of an alliance with Merck KGaA.

Rini reported relationships (including institutional research funding) with Pfizer, Merck & Co., Aravive, AstraZeneca/MedImmune AVEO, Arrowhead Pharmaceuticals, Bristol Myers Squibb, 3D Medicines, Corvus Pharmaceuticals, Dragonfly Therapeutics, Eisai, Exelixis, GlaxoSmithKline, Incyte, Immunomedics, PTC Therapeutics, Roche/Genentech, Synthorx, Shionogi, Surface Oncology, and Seattle Genetics. Other co-authors also reported relationships with industry.

Primary Source

Journal of Clinical Oncology

Rini B, et al "Prospective cardiovascular surveillance of immune checkpoint inhibitor-based combination therapy in patients with advanced renal cell cancer: data from the phase III JAVELIN Renal 101 trial" J Clin Oncol 2022; DOI: 10.1200/JCO.21.01806