Adjuvant pembrolizumab is associated with a 38% lower risk of death than placebo in patients with clear-cell renal cell carcinoma (RCC) who have an increased risk of recurrence after surgery.

The welcome overall survival findings from the KEYNOTE-564 trial support the FDA decision to approve adjuvant pembrolizumab in 2021 based on the trial’s primary end point of disease-free survival.

KEYNOTE-564 randomised 994 participants to receive either adjuvant IV pembrolizumab (200 mg) or IV placebo every 3 weeks for up to 17 cycles or until disease recurrence, unacceptable toxic effects, or a decision to discontinue pembrolizumab.

The median duration of trial regimen was 11.1 months.

Eligible participants had undergone nephrectomy with or without metastasectomy within the 12 weeks before randomisation and had an intermediate-to-high or high risk of disease recurrence based on tumour and metastatic stage and sarcomatoid features.

After a median follow-up of 57.2 months, 55 participants in the pembrolizumab group and 86 participants in the placebo group had died.

“The risk of death was estimated to be 38% lower with pembrolizumab than with placebo, and a significant improvement in the key secondary end point of overall survival was observed (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005).”

The study, published in the NEJM [link here] showed the overall survival benefit was seen across key sub-groups including disease risk category, metastatic staging and presence or absence of sarcomatoid features.

The updated hazard ratio for disease recurrence or death was 0.72 (95% CI, 0.59 to 0.87).

About 80% of patients with documented recurrence went on to receive subsequent therapy including systemic anticancer drug therapy (79.5% and 84.3% in the pembrolizumab and placebo arms), radiation therapy (24.2% and 19.8%), and further surgery (27.3% and 29.1%).

Subsequent anti–PD-1 or anti–PD-L1 antibody-based therapy was received by 41.0% of the pembrolizumab group and 69.7% of the placebo group while subsequent VEGF- or VEGFR-targeted therapy was received by 92.4% of the pembrolizumab group and 84.8% the placebo group.

Regarding safety, adjuvant pembrolizumab was associated with a higher incidence of adverse events of any grade (79.1% v 53.0% with placebo) and of grade 3 or 4 AEs (18.6% v 1.2%).

Discontinuation of pembrolizumab due to AEs occurred in 21.1% of treated patients.

Immune-mediated adverse events such as hypo- and hyperthyroidism and infusion reactions were reported in 36.5% of pembrolizumab-treated patients; the median time to the onset of immune-mediated adverse events was 2.1 months.

Scores on patient-reported outcomes, the Functional Assessment of Cancer Therapy Kidney Symptom Index–Disease-Related Symptoms (FKSI-DRS) questionnaire and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) remained generally stable over the reported trial period.

The study investigators also noted that “…previously reported and updated participant-reported outcomes in this trial indicate that adjuvant pembrolizumab therapy did not result in a clinically meaningful deterioration in health-related quality of life.”

The authors, including Professor Howard Gurney (Macquarie University, NSW) and Dr Thomas Ferguson (Fiona Stanley Hospital, WA) concluded that their results further support the use of adjuvant pembrolizumab as a standard intervention after surgery in RCC.

As previously reported in the limbic [link here], there have been disappointing results from other studies of immunotherapy in RCC such as PROSPER-RCC (nivolumab), IMmotion010 (atezolizumab) and CheckMate 914 (nivolumab plus ipilimumab).

Landmark study

An accompanying editorial in the journal [link here] said KEYNOTE-564 was a “landmark study” as the first trial of adjuvant therapy shown to provide an overall survival benefit.

“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,” it said.

However there were still ongoing challenges including the risk of short-term and long-term immune-mediated adverse events and how to optimise outcomes with subsequent immunotherapy doublets once patients have a relapse.

“Efforts are needed to characterise the patients who are at highest risk and to develop new adjuvant strategies to treat their micrometastatic disease more aggressively,” it said.

“Finally, a new space for drug development has effectively emerged, and dedicated trials involving patients who have a relapse after the receipt of adjuvant pembrolizumab are needed to guide sequencing in the first-line treatment of metastases.”

“These should integrate biopsies with biomarker exploration at the time of relapse.”

The study was funded by Merck Sharp and Dohme.