(UroToday.com) The 2024 GU ASCO annual meeting featured an oral abstract renal cell carcinoma session and a presentation by Dr. Toni Choueiri discussing overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma. Between 1973 and the present, 17 randomized controlled studies with a combined >12,000 enrolled patients investigated adjuvant therapies in RCC, with no observed survival improvement. The randomized, multicenter, double-blind, phase 3 KEYNOTE-564 study showed that adjuvant pembrolizumab improved disease-free survival compared with placebo following nephrectomy in participants with clear cell RCC at an increased risk of recurrence.1 The primary endpoint of disease free survival was met at the first interim analysis (HR 0.68, 95% CI 0.53-0.87) and overall survival (a key secondary endpoint) results were immature at the last analysis. More any-grade and grade 3-4 treatment related adverse events occurred with adjuvant pembrolizumab versus placebo, but no clinically meaningful deterioration of health related quality of life was observed. As such, adjuvant pembrolizumab is approved for use in patients with RCC at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions (M1 NED). At the GU ASCO 2024 annual meeting, Dr. Choueiri reported results from the third prespecified interim analysis with a median follow-up of ~57 months.
Patients were ≥18 years of age and had histologically confirmed clear cell RCC with or without sarcomatoid features, increased risk of recurrence, ECOG performance status of 0 or 1, nephrectomy and/or metastasectomy ≤12 weeks before randomization, and had no prior systemic therapy for RCC. Patients were randomly allocated 1:1 to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for ≥17 cycles (~1 year) or until disease recurrence, intolerable toxicity, or withdrawal of consent. The trial design for KEYNOTE-564 is as follows:
Disease-free survival by investigator assessment was the primary end point, and overall survival was a key secondary end point. Safety was also a secondary end point. From a statistical standpoint, per the multiplicity strategy, an alpha of 0.025 (1-sided) was initially assigned to disease free survival. If the disease free survival null hypothesis was rejected, alpha of 0.025 was passed to overall survival. The overall type I error rate was strongly controlled at 2.5% (1-sided). The primary endpoint of disease free survival was met at the first protocol-specified interim analysis and was not formally tested again. The between arm differences in overall survival were assessed with the stratified log-rank test. For a sample size of ~990 patients, the third protocol-specified interim analysis was planned after ~132 deaths. For today’s presentation, the actual number of deaths was 141 (70.5% of the planned events) after a median follow-up of 57.2 months (range, 47.9-74.5).
There were 994 patients randomized 1:1 to pembrolizumab (n = 496) or placebo (n = 498) between June 30, 2017 and September 20, 2019. As follows is the participant disposition:
The median time from randomization to data cut-off date of September 15, 2023, was 57.2 months (range, 47.9−74.5), and as of December 2020, all participants had completed or discontinued therapy. The baseline characteristics are as follows:
Dr. Choueiri notes that there was a statistically significant improvement in overall survival observed with pembrolizumab vs placebo (medians not reached, HR 0.62, 95% CI 0.44−0.87; p = 0.0024):
A total of 55 overall survival events were observed in the pembrolizumab arm and 86 in the placebo arm. The estimated overall survival rate at 48 months was 91.2% with pembrolizumab and 86.0% with placebo. Additionally, overall survival benefit was observed across key subgroups, including in patients with:
- M0 disease: HR 0.63, 95% CI 0.44−0.90
- M1 no evidence of disease: HR 0.51, 95% CI 0.15−1.75
- PD-L1 CPS <1: HR 0.65, 95% CI 0.31−1.38
- PD-L1 CPS ≥1: HR 0.62, 95% CI 0.42−0.91
- Presence of sarcomatoid features: HR 0.69, 95% CI 0.28−1.70
- Absence of sarcomatoid features: HR 0.57, 95% CI 0.39−0.84
Moreover, the observed disease-free survival benefit with pembrolizumab vs placebo was consistent with prior interim analyses (HR 0.72; 95% CI 0.59−0.87):
With regards to subsequent therapies in the intention to treat population, 79.5% of patients in the pembrolizumab arm versus 81.4% of patients in the placebo arm had subsequent therapy, most commonly another systemic anti-cancer drug therapy:
No new safety signals were observed in this updated analysis:
Dr. Choueiri concluded his presentation discussing overall survival results from the phase 3 KEYNOTE-564 trial with the following take-home points:
- Adjuvant pembrolizumab significantly prolonged overall survival versus placebo in participants with clear cell RCC at increased risk of recurrence following surgery. This included a 38% reduction in risk of death with adjuvant pembrolizumab and survival benefits across key subgroups
- Continued disease-free survival benefit with pembrolizumab versus placebo was observed with further follow-up
- All participants completed or discontinued study therapy by December 2020, and safety findings did not change substantially since the last analysis
- KEYNOTE-564 is the first study to show a statistically significant clinically meaningful survival improvement with an adjuvant therapy in RCC
- These results further support adjuvant pembrolizumab as a standard of care after surgery in this disease setting
Presented: by Toni K. Choueiri, MD, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
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Related Content: Merck’s KEYTRUDA® (pembrolizumab) Reduced the Risk of Death by 38% Versus Placebo as Adjuvant Therapy for Patients With Renal Cell Carcinoma (RCC) at an Increased Risk of Recurrence Following Nephrectomy
KEYNOTE-564 Shows Overall Survival Benefit in Kidney Cancer with Pembrolizumab - Toni Choueiri