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PARIS -- Adding the tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx) to dual immune checkpoint inhibition improved progression-free survival (PFS) in patients with advanced renal cell carcinoma (RCC), the phase III found.

Among 550 patients with untreated intermediate- or poor-risk disease, those treated with the triplet therapy had a median PFS that was not reached compared with 11.3 months for patients randomized to the two immunotherapy drugs -- nivolumab (Opdivo) and ipilimumab (Yervoy) -- alone (HR 0.73, 95% CI 0.57-0.94, P=0.013), reported Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston.

The objective response rates were 43% and 36%, respectively, with complete responses achieved in 3% of patients in each group. The disease control rates were 86% and 72%; incidence of progressive disease as best response was just 8% in the triplet therapy arm and 20% in the control arm. Median duration of response was not reached in either group.

"This was the first study to use an immune-oncology doublet standard of care as the control," Choueiri pointed out during a session at the European Society for Medical Oncology (ESMO) annual congress. "The results clearly show that the triplet combination ... does demonstrate a statistically significant, and a clinically meaningful, improvement in PFS compared with [nivolumab and ipilimumab alone]."

Follow-up for the secondary endpoint of overall survival involving the entire study population of 855 patients is ongoing.

ESMO discussant Sumanta Kumar Pal, MD, of the City of Hope Orange County Lennar Foundation Cancer Center in Irvine, California, noted that five phase III studies on RCC have been presented at this year's meeting, but COSMIC-313 stands out for several reasons, including the fact that it is the first phase III trial using a contemporary control arm -- in this case, nivolumab with ipilimumab -- and the first to compare triplet therapy to doublet therapy.

"Taken together, these are the first results of a phase III clinical trial ... that met its primary endpoint with the above," he observed.

However, "it will be incredibly informative for clinical decision making to see what the overall survival shows," Pal added.

COSMIC-313 includes 855 previously untreated patients with advanced or metastatic RCC who were judged to be at intermediate (75% of patients) or poor risk (25%) for survival according to International Metastatic RCC Database Consortium (IMDC) criteria, who were randomized 1:1 to the triplet combination or to nivolumab and ipilimumab alone.

All patients received nivolumab plus ipilimumab every 3 weeks for 4 cycles followed by nivolumab every 4 weeks for up to 2 years. Randomization to cabozantinib or placebo was stratified according to region and disease risk.

The PFS analysis included the first 550 patients randomized (the protocol intent-to-treat, or PITT, population). Median foll0w-up was 20.2 months.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 73% of patients receiving the triplet combination compared with 41% receiving the doublet combination. The rate of TRAEs leading to discontinuation of all treatment components in the triplet arm was more than double that in the control arm (12% vs 5%).

Pal pointed out the substantially higher rate of grade 3/4 toxicities in the triplet arm, particularly elevated transaminases. "Put yourselves in the shoes of an investigator treating a patient on this trial," he said. "Imagine the difficulties in terms of attributing these toxicities to either TKI or immunotherapy."

Three patients in each treatment arm experienced grade 5 TRAEs, including gastrointestinal hemorrhage, hepatic failure, and respiratory failure in the triplet arm, and renal failure, myocarditis, and sudden death in the doublet arm.

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