medwireNews: Phase III trial findings support the use of nivolumab plus ipilimumab for treatment-naïve patients with advanced renal cell carcinoma (RCC) with a clear cell component, especially those with intermediate- or poor-risk disease.
After a median of 25.2 months, the 18-month rate of overall survival (OS) was 75% for the 425 patients with an intermediate or poor prognosis who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg for four doses every 3 weeks, followed by nivolumab 3 mg/kg every 2 weeks.
By comparison, the 18-month OS rate was 60% for the 422 patients who instead were randomly assigned to receive sunitinib 50 mg/day for 4 weeks of each 6-week cycle, the CheckMate 214 investigators report.
Indeed, the co-primary endpoint of median OS rate was unreached for patients given nivolumab plus ipilimumab versus 26.0 months for the sunitinib-treated patients, giving a significant hazard ratio (HR) of 0.63 in favour of the combination.
The second co-primary endpoint of objective response rate was also significantly better with nivolumab plus ipilimumab than sunitinib, at 42% versus 27%, with a complete response achieved by 9% and 1% of patients, respectively.
However, the third co-primary endpoint of median progression-free survival (PFS) did not meet the prespecified threshold for significance despite being numerically longer with nivolumab plus ipilimumab, say Robert Motzer, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-workers.
The secondary endpoint of OS in the intention-to-treat group of all 1096 participants, including those with favourable disease, also confirmed an OS benefit with nivolumab plus ipilimumab over sunitinib, with the median value unreached versus 32.9 months, giving a significant HR of 0.68.
But further analysis of the 249 favourable-risk patients alone suggested that OS may have favoured sunitinib, with an 18-month rate of 93% versus 88% for nivolumab plus ipilimumab giving a significant HR of 1.45.
“These results in favorable-risk patients should be interpreted with caution because of the exploratory nature of the analysis, the small subgroup sample, and the immaturity of survival data”, the researchers write, emphasizing that just 37 deaths had occurred at time of data lock, at which point median OS was 32.9 months in the sunitinib arm versus unreached for the combination arm.
Nevertheless, both the objective response rate (52 vs 29%) and median PFS (25.1 vs 15.3 months) again significantly supported sunitinib in the favourable-risk patients, although complete response was less common (6 vs 11%).
These findings “highlight the need to better understand the underlying biologic processes driving responses to these two different treatment regimens”, the team summarises in The New England Journal of Medicine.
Finally, safety analysis showed that treatment-related adverse events of any grade occurred in a comparable 93% of patients given nivolumab plus ipilimumab and 97% of those using sunitinib. Grade 3 or 4 side effects were less common with the combination regimen (46 vs 63%), but treatment-related deaths were more common (eight vs four).
Treatment-related adverse events led to discontinuation in 22% and 12% of participants, respectively, and health-related quality of life findings also favoured the combination arm.
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med; Advance online publication 21 March 2018. DOI: 10.1056/NEJMoa1712126
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