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Adjuvant Pembrolizumab Improves Overall Survival Among Patients with Clear-Cell Renal Cell Carcinoma Who Are At Increased Risk for Disease Recurrence After Nephrectomy

Findings from the KEYNOTE-564 study
24 Apr 2024
Immunotherapy
Renal Cell Cancer

After a median follow-up of 57.2 months, the KEYNOTE-564 study showed a significant and a clinically meaningful improvement in overall survival (OS) with an adjuvant treatment with pembrolizumab; pembrolizumab was associated with a 38% lower risk of death than placebo among patients with clear cell renal cell carcinoma (ccRCC) who were at increased risk for disease recurrence after surgery. 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.

Survival benefits with pembrolizumab were also seen in a number of subgroups, including in patients who had less-adverse prognostic features, such as M0 stage disease, an ECOG performance status score of 0, or an absence of sarcomatoid features. The benefit that was associated with pembrolizumab with regard to disease-free survival (DFS) continued to be observed in the third interim analysis, which was consistent with previous findings according to Dr. Toni K. Choueiri of the Dana–Farber Cancer Institute in Boston, MA, US and colleagues, who published the findings on 17 April 2024 in The New England Journal of Medicine.

Adjuvant treatment after surgery for localised RCC has historically been a challenging area with limited success. Among the multiple VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs), only sunitinib showed an efficacy benefit in one of two randomised trials. Although the phase III S-TRAC study showed a significant improvement in DFS (the study primary endpoint) with adjuvant sunitinib as compared with placebo, whereas the larger phase III, placebo-controlled ASSURE study of sunitinib did not; no prolongation in OS has been reported with an adjuvant VEGFR TKI.

Pembrolizumab, an anti–PD1 antibody, was approved in 2021 as adjuvant treatment for patients with RCC who were at an intermediate-to-high or high risk for recurrence after nephrectomy, with or without the resection of metastatic lesions. This approval was based on the significant and clinically meaningful improvement in DFS that was observed with pembrolizumab in the phase III, double-blind, randomised, placebo-controlled KEYNOTE-564 study. Data for the key secondary endpoint of OS in the KEYNOTE-564 study were not sufficiently mature at the time of the previous interim analyses. In the latest article, the study team presents the results of the third prespecified interim analysis of this study.

Other treatment approaches with adjuvant immune checkpoint inhibition after surgery in RCC have also been investigated, including monotherapy with an anti–PD-L1 antibody atezolizumab for up to 1 year in the phase III IMmotion010 study and the combination of anti–PD1 and anti–CTLA-4 antibodies nivolumab plus ipilimumab for up to 6 months in the phase III CheckMate 914 study. However, neither of these studies showed a difference in DFS.

In phase III, double-blind, placebo-controlled KEYNOTE-564 study, the investigators randomly assigned in a 1:1 ratio patients with ccRCC who had an increased risk of recurrence after surgery to receive pembrolizumab at a dose of 200 mg or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in DFS according to investigator assessment (the primary endpoint) was shown previously; OS was the key secondary endpoint and safety was a secondary endpoint as well.

A total of 496 patients were assigned to receive pembrolizumab and 498 to receive placebo. As of 15 September 2023, the median follow-up was 57.2 months. Benefit in DFS was consistent with that in previous analyses (hazard ratio [HR] for recurrence or death 0.72; 95% confidence interval [CI] 0.59 to 0.87).

A significant improvement in OS was observed with pembrolizumab as compared with placebo (HR for death 0.62; 95% CI 0.44 to 0.87; p = 0.005). The estimated OS at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups.

Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7% versus 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% versus 1.2%). No deaths were attributed to pembrolizumab therapy.

Fewer participants in the pembrolizumab group than in the placebo group received subsequent treatment, which was probably a reflection of the prolonged DFS benefit and fewer relapses with adjuvant pembrolizumab. Among patients with documented recurrence, the percentage of patients who were known to have received any subsequent treatment was similar in the two groups (79.5% with pembrolizumab and 81.4% with placebo). Most of the recurrence events included distant metastasis (88.8% in the pembrolizumab group and 85.2% in the placebo group). The receipt of treatment after disease relapse was probably for early metastatic disease owing to the close monitoring.

The authors commented that although improved DFS has been reported before with adjuvant anti–PD1 or anti–PD-L1 treatment (e.g. among patients with melanoma), the KEYNOTE-564 study also provides evidence of an OS benefit with such treatment. Cross-tumour comparisons are very complex owing to the distinct immune responsiveness and tumour microenvironment of different cancers. The survival benefit with early-line perioperative pembrolizumab was shown in patients with resectable non–small cell lung cancer in the phase III KEYNOTE-671 study of neoadjuvant pembrolizumab or placebo plus cisplatin-based chemotherapy, followed by adjuvant pembrolizumab or placebo.

They concluded that phase III KEYNOTE-564 study showed improved OS with an adjuvant pembrolizumab among patients with ccRCC who were at increased risk for disease recurrence after nephrectomy with or without metastasectomy. These results further support the use of adjuvant pembrolizumab as a standard intervention after surgery in this disease context.

In an accompanied editorial article, Drs. Martin H. Voss and Robert J. Motzer of the Memorial Sloan Kettering Cancer Center in New York, NY, US stressed out that 56.6% of the patients in the placebo group were alive and free from recurrence at 48 months. Most patients in the pembrolizumab group were able to complete the full 12 months of treatment without high-grade side effects. Yet, the selection criteria of the KEYNOTE-564 study, if implemented, will lead to notable overtreatment, exposing approximately one in two patients to undue risks of short-term and long-term immune-mediated adverse events, including rare serious adverse events beyond the time of treatment administration.

A new space for drug development has effectively emerged, and dedicated studies involving patients who have a relapse after the receipt of adjuvant pembrolizumab are needed to guide sequencing in the first-line treatment of metastases. One third of the patients in the pembrolizumab group had disease recurrence during the KEYNOTE-564 study. An important question is whether exposure to adjuvant pembrolizumab will lessen the likelihood of optimised outcomes with subsequent use of immunotherapy doublets once patients have a relapse.

It is needed to characterise the patients who are at highest risk and to develop new adjuvant strategies to treat micrometastatic disease more aggressively. Biomarker investigations in pembrolizumab-treated patients with documented recurrence during the KEYNOTE-564 study will be important and may inform the interpretation of ongoing studies testing adjuvant combination therapy.

The study was funded by Merck Sharp and Dohme, a subsidiary of Merck.

References

 

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