medwireNews: Patients with localized renal cell carcinoma (RCC) at high risk for recurrence do not derive a significant disease-free survival (DFS) benefit from the postoperative use of nivolumab plus ipilimumab versus placebo, shows the phase 3 CheckMate 914 study.
“Despite previously demonstrated long-term efficacy of dual immune checkpoint inhibition with nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma,” the current data “do not support a role for this combination” – at the tested dose and duration – as an adjuvant option for this patient population, write the researchers in The Lancet.
“The results of our study contrast with those of the KEYNOTE-564 trial, which observed a disease-free survival benefit with adjuvant pembrolizumab” in patients with localized high-risk RCC, they continue.
But the findings are “consistent” with those of two other phase 3 RCC studies – namely the IMmotion010 study of adjuvant atezolizumab and the PROSPER study of perioperative nivolumab – which “showed no improvements in disease-free survival,” says the team.
In the double-blind CheckMate 914 trial, 816 adults with localized RCC at high risk for recurrence after partial or radical nephrectomy were randomly assigned to adjuvant treatment with 12 doses of nivolumab 240 mg given every 2 weeks alongside four doses of ipilimumab 1 mg/kg every 6 weeks or matching placebo.
After a median follow-up of 37.0 months, there was no significant difference between the dual immunotherapy and placebo groups with respect to the primary endpoint of DFS by blinded independent central review; the median durations were unreached and 50.7 months, respectively, and the hazard ratio (HR) for disease recurrence or death was a nonsignificant 0.92.
Robert Motzer (Memorial Sloan Kettering Cancer Center, New York, USA) and colleagues note that exploratory prespecified subgroup analyses showed no difference between treatments, except “in a small subgroup of 40 patients with sarcomatoid features,” among whom the significant HR for recurrence or death of 0.29 favored the nivolumab–ipilimumab combination.
Regarding safety, the incidence of treatment-related adverse events (TRAEs) of grade 3 or 4 was higher in the combination than placebo arm, at 28% versus 2%, as was the rate of discontinuation due to TRAEs of any grade, at 29% versus 1%.
Moreover, four deaths in the nivolumab plus ipilimumab group were considered related to treatment compared with none in the placebo group.
“However, the overall safety of adjuvant nivolumab plus ipilimumab in patients with localised renal cell carcinoma in this trial was consistent with the known profile for the combination in patients with advanced renal cell carcinoma,” write Motzer and team.
The investigators summarize that their findings do not support nivolumab plus ipilimumab in the adjuvant RCC setting, and they conclude: “Factors that might have contributed to our reported outcomes include heterogeneity of the patient population studied, the dosing schedule and duration of treatment chosen in this trial, and decreased adverse event tolerability in the setting of adjuvant treatment for localised renal cell carcinoma.”
The authors of a related commentary say that “[t]he study was well done, with a robust statistical analysis plan.”
But Thomas Powles, from Barts Cancer Centre in London, UK, and co-authors say that this and other negative adjuvant RCC studies “raise uncertainty and challenge many assumptions.”
They continue: “A plateau in drug development in renal cell carcinoma might be being reached, with the current group of drugs being taken as far as they can go.
“Robust biomarker studies to identify individuals who might benefit from therapy have been lacking, and such research is essential to improve the rational application of immunotherapy in the adjuvant setting.”
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