Clinical trialPhase 3Kidney cancer

Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma

N Engl J Med · 2024994 patients (496 pembrolizumab, 498 placebo)

Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, et al. N Engl J Med. 2024. 390:1359-1371

A newer report of this study has been published: Adjuvant pembrolizumab for the treatment of clear cell renal cell carcinoma: five-year results from the phase III KEYNOTE-564 study (2026)

Study type: Clinical trial
Study name: KEYNOTE-564
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (1:1 ratio)
Sample size: 994 patients (496 pembrolizumab, 498 placebo)
Source: N Engl J Med · 2024
Trial registration: NCT03142334

In plain words

After surgery to remove a kidney, some patients have a high risk of the cancer coming back. In this study, these patients received the immunotherapy drug pembrolizumab or a placebo (an inactive drug) for about a year. Pembrolizumab both lowered the chance of the cancer coming back and helped patients live longer: after 4 years about 91 of every 100 patients in the pembrolizumab group were alive, compared with 86 in the placebo group. On the other hand, serious side effects were more common in the drug group, so the decision should be made after talking with your doctor.

Key results

77.3% vs 68.1%

24-month disease-free survival (first interim analysis, 2021)

HR for recurrence or death 0.68; 95% CI 0.53–0.87; P=0.002 (two-sided); median time to data cut-off 24.1 months

HR 0.72

Disease-free survival (median follow-up 57.2 months)

95% CI 0.59–0.87; consistent with previous analyses

91.2% vs 86.0%

48-month overall survival

HR for death 0.62; 95% CI 0.44–0.87; P=0.005; the benefit was consistent across key subgroups

20.7% vs 11.5%

Serious adverse events of any cause

No deaths were attributed to pembrolizumab

18.6% vs 1.2%

Treatment-related grade 3 or 4 adverse events

Drugs in this study:Pembrolizumab (Keytruda)

Dose and schedule cards

Adjuvant pembrolizumab (KEYNOTE-564)

RCC with a clear-cell component after nephrectomy at intermediate-high risk (pT2 grade 4 or sarcomatoid, or pT3) or high risk (pT4 or N+), or M1 NED after nephrectomy and complete resection of metastasesOn the page “Kidney cancer” · Adjuvant therapy regimens after nephrectomy

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg (or 400 mg)	IV, 30-minute infusion	Day 1 every 3 weeks (400 mg dose: every 6 weeks)

Cycle length: Every 21 days (or every 42 days with the 400 mg dose)
Duration: Up to 12 months, or until recurrence or unacceptable toxicity (in KEYNOTE-564: 200 mg every 3 weeks for up to 17 cycles)

Dose and duration per the FDA label and the trial. The EAU recommends starting treatment preferably within 12 to 16 weeks after nephrectomy, after repeat imaging.

On the page “Kidney cancer” · Adjuvant therapy regimens after nephrectomy

Adjuvant pembrolizumab

After nephrectomy at intermediate-high or high risk of recurrenceCycle length: Every 3 weeksOn the page “Immunotherapy regimens in kidney cancer: pembrolizumab-axitinib, nivolumab-ipilimumab and adjuvant pembrolizumab”

After nephrectomy at intermediate-high or high risk of recurrence

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg (or 400 every 6 weeks)	IV	Every 3 weeks

Cycle length: Every 3 weeks
Duration: Up to 17 doses (about one year)

As in KEYNOTE-564.

Dose source:.

On the page “Immunotherapy regimens in kidney cancer: pembrolizumab-axitinib, nivolumab-ipilimumab and adjuvant pembrolizumab”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pembrolizumab

Pembrolizumab 200 mg IV on day 1 of each 3-week cycle for up to 17 cycles (about 1 year), or until recurrence, unacceptable toxicity or meeting treatment discontinuation criteria.

2Placebo

Placebo (saline) IV every 3 weeks on the same schedule, for up to 17 cycles (about 1 year).

Source of the regimen details: Published abstracts (NEJM 2021 and 2024) and ClinicalTrials.gov NCT03142334

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with renal cell carcinoma with a clear cell component (with or without sarcomatoid features) after partial or radical nephrectomy with negative margins, without previous systemic therapy, with ECOG 0 or 1, and in one of these groups: intermediate-high risk (pT2 grade 4 or sarcomatoid, N0 M0; or pT3 any grade, N0 M0), high risk (pT4 N0 M0; or any pT with N+‎ M0), or M1 NED (a solitary soft-tissue metastasis completely resected at the time of nephrectomy or within 1 year after it). Surgery 28 days or more before consent and no more than 12 weeks before randomisation; no evidence of disease on imaging of the brain, chest, abdomen and pelvis or on bone scan; patients with previous brain or bone metastases, residual renal vein/vena cava thrombus, previous radiotherapy or active autoimmune disease were excluded (ClinicalTrials.gov NCT03142334).

Endpoints

Primary endpoint: disease-free survival by investigator assessment. Key secondary endpoint: overall survival. Other secondary endpoints: safety.

Safety and side effects

In the overall survival analysis, serious adverse events of any cause were more common in the pembrolizumab group (20.7% versus 11.5%), and treatment-related grade 3 or 4 adverse events occurred in 18.6% versus 1.2%. In the first report (2021), grade 3 or higher adverse events of any cause were seen in 32.4% of pembrolizumab patients and 17.7% of placebo patients. No pembrolizumab-related deaths were reported. Immune-related adverse events (such as hypothyroidism) are known effects of this drug class (details in the full text of the paper).

Clinical significance and place in guidelines

KEYNOTE-564 was the first trial to show an overall survival benefit with an adjuvant therapy in renal cell carcinoma. On 17 November 2021 the FDA approved pembrolizumab for the adjuvant treatment of patients at intermediate-high or high risk of recurrence after nephrectomy (or nephrectomy and resection of metastatic lesions). The EAU guideline (2022 update) recommends adjuvant pembrolizumab for patients with ccRCC at risk of recurrence as defined in the trial (weak recommendation; issued before the overall survival data were published). In 2026, pembrolizumab combined with belzutifan was compared with pembrolizumab alone in the LITESPARK-022 trial.

Limitations

The overall survival benefit was obtained at the third interim analysis; patients in the placebo group received varied subsequent therapies; only patients with a clear cell component were enrolled and the results cannot be generalised to non-clear cell types; there is no validated biomarker to select the patients who benefit most.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.