Nivolumab and cabozantinib outperform everolimus in advanced RCC

Nivolumab and cabozantinib, used separately as monotherapy, offer a survival benefit over everolimus in patients with advanced renal cell carcinoma (RCC) after failure of first-line anti-VEGF therapy, according to the results of two late-breaking phase III trials presented at the European Cancer Congress (ECC) 2015 in Vienna, Austria.

The CheckMate 025 study randomized 821 patients with advanced RCC, who had failed one or two previous anti-VEGF therapies, to receive nivolumab or everolimus until disease progression or intolerable toxicity. [ECC 2015, abstract 3LBA; N Engl J Med 2015, doi:10.1056/NEJMoa1510665]

“This is the first phase III study to demonstrate a survival benefit with an immune checkpoint inhibitor vs current standard treatment in previously treated advanced RCC,” said lead investigator Professor Padmanee Sharma of the MD Anderson Cancer Centre, Houston, TX, US.

“Importantly, the primary endpoint of overall survival [OS] met the prespecified criterion for superiority, leading to premature termination of the study,” she highlighted. “The median OS was 25.0 months in the nivolumab group vs 19.6 months in the everolimus group [hazard ratio (HR), 0.73; p=0.0018].”

“The survival benefit with nivolumab was observed irrespective of programmed death-ligand 1 [PD-L1] expression,” added Sharma. “The median OS was 21.8 months with nivolumab vs 18.8 months with everolimus in patients with PD-L1 expression level ≥1 percent, and 27.4 vs 21.2 months among those with PD-L1 expression level <1 percent.”

The objective response rate (ORR) was also higher with nivolumab vs everolimus (25 vs 5 percent; p<0.0001), but the median progression-free survival (PFS) was similar between the two arms (4.6 months for nivolumab vs 4.4 months for everolimus; p=0.1135).

“Overall grade 3/4 adverse events [AEs] were less frequent in patients receiving nivolumab vs everolimus [19 vs 37 percent],” reported Sharma. “Quality of life of patients in the nivolumab group improved over time and differed significantly from those in the everolimus group at each assessment.”

Meanwhile, cabozantinib was compared with everolimus in the METEOR (Metastatic RCC Phase III Study Evaluating Cabozantinib vs Everolimus) trial of 658 advanced RCC patients who had progressed within 6 months after receiving VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy. [ECC 2015, abstract 4LBA; N Engl J Med 2015, doi:10.1056/NEJMoa1510016]

After a minimum follow-up of 11 months, the primary endpoint of PFS nearly doubled in patients receiving cabozantinib vs everolimus (median, 7.4 vs 3.8 months; p<0.001).

“The PFS benefit offered by cabozantinib was even more prominent in patients who received sunitinib as their only prior VEGFR-TKI [9.1 months vs 3.7 months for everolimus],” reported lead investigator Professor Toni Choueiri of the Dana-Farber Cancer Institute, Boston, MA, US.

“Similarly, the ORR was significantly higher with cabozantinib than with everolimus [21 vs 5 percent; p<0.001],” he added. “The interim OS analysis demonstrated a strong trend favouring cabozantinib [hazard ratio, 0.67; p=0.005].”

The most frequent grade 3/4 AEs for cabozantinib were hypertension (15 percent), diarrhoea (11 percent), fatigue (9 percent) and hand-foot syndrome (8 percent), while those for everolimus were anaemia (16 percent), fatigue (7 percent) and hyperglycaemia (5 percent).

“The OS benefit of 25 months offered by nivolumab sets a new benchmark for advanced RCC patients previously treated with anti-VEGF therapy,” commented discussant Dr. Cora Sternberg of the San Camillo and Forlanini Hospitals, Rome, Italy. “The impressive efficacy of cabozantinib as shown in the METEOR trial makes it a potential new treatment option for these patients.”