medwireNews: Adjuvant treatment with pembrolizumab is associated with a significant overall survival (OS) benefit relative to placebo in individuals with high-risk, clear cell renal cell carcinoma (RCC), shows the KEYNOTE-564 trial.
This finding follows on from the previously reported significant improvement in disease-free survival (DFS) with pembrolizumab in this study that led to the US approval of the PD-1 inhibitor in the adjuvant setting.
“These results further support the use of adjuvant pembrolizumab as a standard intervention after surgery in this disease context,” write Toni Choueiri (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and associates in The New England Journal of Medicine.
The authors of a related editorial congratulate the investigators “on this landmark report,” and say that “[t]he anticipated effect of KEYNOTE-564 as the first trial of adjuvant therapy that has shown a benefit with regard to overall survival after nephrectomy cannot be overstated.”
Martin Voss and Robert Motzer, both from the Memorial Sloan Kettering Cancer Center in New York, USA, continue: “The lack of such success in phase 3 trials that have investigated other adjuvant immunotherapies may relate to differences in mechanism of action, trial design, population risk, and dose exposure.”
The double-blind phase 3 trial comprised 994 patients who were at increased risk for recurrence after undergoing surgery for RCC. The participants were randomly assigned to receive either pembrolizumab 200 mg or placebo every 3 weeks for up to 17 cycles.
The current report focused on the third prespecified interim analysis, conducted at a median follow-up of 57.2 months, which showed a significant 38% reduction in the risk for death with the use of adjuvant pembrolizumab compared with placebo.
Adjuvant pembrolizumab was associated with higher rates of OS than placebo at 24, 36, and 48 months, at 96.3% versus 93.9%, 93.9% versus 89.5%, and 91.2% versus 86.0%, respectively, equating to between-group differences of 2.4, 4.4, and 5.2 percentage points.
“The estimated survival curves for the pembrolizumab group and placebo group began separating at 15 months and continued to diverge beyond 2 years of follow-up,” highlight Choueiri and colleagues.
They add that the DFS benefit of pembrolizumab observed in previous analyses was also evident in the current one, with a significant reduction in the risk for recurrence or death of 28% with use of the PD-1 inhibitor.
Turning to the safety data, the team notes that “[b]ecause all the participants had completed or discontinued the trial regimen more than 2 years earlier, the safety findings remained consistent with previous interim analyses.”
The rates of treatment-related adverse events (AEs) of grade 3 or higher and discontinuations due to AEs were higher in the pembrolizumab than placebo arm, at 18.6% versus 1.2%, and 21.1% versus 2.2%, respectively.
But there were no deaths due to pembrolizumab and the incidence of AE-related discontinuation “was lower than that observed with certain adjuvant VEGFR-[tyrosine kinase inhibitors], including sorafenib, sunitinib, and pazopanib,” say the researchers.
Nevertheless, “it was not negligible and the safety profile should be taken into consideration in treatment decisions,” they conclude.
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