Renal cell carcinoma is a common malignancy among men and women in the United States.1 The incidence continues to increase with the ever-increasing use of contemporary medical imaging. Although many patients who present with localized disease are cured with definitive surgery, some patients develop distant recurrent disease. And although there have been advancements in systemic treatment strategies for patients with advanced disease, the 5-year overall survival for patients with advanced disease is less than 50% in the modern era.2
Rana R. McKay, MD
The development of adjuvant treatment options that not only delay but also prevent recurrent disease remains an unmet need in the treatment of patients with renal cell carcinoma. Historically, trials of adjuvant cytokine-based treatments have failed to demonstrate improvements in disease-free survival for patients at high risk of recurrence following definitive surgical resection.
Adjuvant Use of Sunitinib: Clinical Trials Show Mixed Results
After we moved into the targeted therapy era in 2005, with vascular endothelial growth factor (VEGF) targeting agents demonstrating efficacy for metastatic renal cell carcinoma, a series of studies were designed to investigate the efficacy of adjuvant VEGF-targeting tyrosine kinase inhibitors. These trials differed regarding patients enrolled, agents utilized, and duration of therapy.
In aggregate, all studies to date were negative, with the exception of the phase III S-TRAC study, which tested the adjuvant use of sunitinib in patients with locally advanced (pT3–4) or node-positive clear cell renal cell carcinoma.3 The study demonstrated an improvement in disease-free survival (6.2 months vs 4.0 months, hazard ratio [HR] = 0.74, 95% confidence interval [CI] = 0.55–0.99, P = .04) with adjuvant sunitinib over placebo, with no benefit in overall survival (HR = 0.92, 95% CI = 0.66–1.28) and increased toxicity. The results of the S-TRAC trial contrasted with those of the large phase III ASSURE trial, which tested the efficacy of sunitinib vs sorafenib vs placebo in patients with renal cell carcinoma at high risk of recurrence.4
The KEYNOTE-564 study is the first positive adjuvant immunotherapy trial in patients with resected renal cell carcinoma and presents an advancement in the care of these patients.— Rana R. McKay, MD
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Although the ASSURE trial enrolled a heterogeneous patient population, including those with either clear cell or variant histology renal cell carcinoma and either pT1b grade 3–4, pT2–T4, or node-positive disease, subset analyses in patients with clear cell renal cell carcinoma with pT3–4 or node-positive disease failed to demonstrate a benefit with adjuvant sunitinib.5 Neither sunitinib nor sorafenib improved overall survival vs placebo in the overall population.
Despite these mixed results with sunitinib, in 2017, the U.S. Food and Drug Administration (FDA) granted approval for adjuvant sunitinib in patients with renal cell carcinoma. However, in clinical practice, utilization of sunitinib remains limited, given no appreciable benefit in overall survival and increased toxicity.
Turning to Immune Checkpoint Inhibitors: Focus on KEYNOTE-564
At the time that approval for adjuvant sunitinib was granted, single-agent immune checkpoint inhibitors had demonstrated efficacy for patients with metastatic renal cell carcinoma and had entered the treatment armamentarium. The first checkpoint inhibitor approved for renal cell carcinoma was nivolumab in 2015, based on the results of the phase III CheckMate 025 study testing the efficacy of nivolumab vs everolimus in patients having received prior VEGF-targeting therapy.6 It was against this backdrop that the KEYNOTE-564 study was designed, and accrual began in 2017.
The KEYNOTE-564 study was a phase III, double-blind, randomized, placebo-controlled trial testing the efficacy of pembrolizumab vs placebo as adjuvant therapy for patients with clear cell renal cell carcinoma at high risk of recurrence following definitive nephrectomy.7 The study, which was reported in The New England Journal of Medicine by Choueiri et al and is summarized in this issue of The ASCO Post, is the first positive adjuvant immunotherapy trial in patients with resected renal cell carcinoma and represents an advancement in the care of these patients. To understand the magnitude of benefit of this regimen, it is important to dissect the components of the clinical trial.
The trial enrolled a heterogeneous patient population regarding risk of recurrence, including patients with high-grade pT2 disease to those with metastatic disease who had undergone complete definitive resection of all metastatic disease and were without evidence of metastatic disease on radiographic imaging. If the University of California Los Angeles Integrated Staging System prognostic algorithm is applied to those eligible to enroll, the trial enrolled patients with an estimated 5-year disease-free survival ranging from less than 20% to 80%.8 Although a broad population was eligible, most of the patients (87%) had pT2 grade 4 or pT3 disease. Additionally, 75% of patients had PD-L1–positive disease. More granular details regarding grade, stage, and burden of disease prior to resection are lacking at the present time; such information will be important to understand which patients derived the most benefit from treatment.
The primary endpoint of the trial was investigator-assessed disease-free survival. According to the FDA guidance for industry on developing drugs and biologics for adjuvant treatment in renal cell carcinoma, disease-free survival is an appropriate endpoint for adjuvant clinical trials in renal cell carcinoma.9 In the context of a blinded study, investigator assessment is acceptable; however, as a secondary endpoint, the trial will evaluate disease-free survival by blinded independent radiology review (data not yet available).
It will be critical to understand how the use of contemporary immune checkpoint blockade combination therapies for advanced disease will impact survival over time.— Rana R. McKay, MD
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KEYNOTE-564 was a positive trial that demonstrated improvement in disease-free survival with adjuvant pembrolizumab compared with placebo (HR = 0.68, 95% CI = 0.53–0.87). Subset analyses were conducted by age, sex, performance status, PD-L1 status, region, metastatic disease status, and type of nephrectomy; they demonstrated a benefit across all subgroups. In addition, subset analyses by T stage, N stage, grade, presence of sarcomatoid differentiation, and other patient groups will be warranted to understand the degree of therapeutic benefit.
A key secondary endpoint was overall survival. At the time of reporting, with just 26% of events needed for the final overall survival analysis, data remain immature. Understanding that longer follow-up will be needed, the hazard ratio for death was 0.54 (95% CI = 0.30–0.96) favoring adjuvant pembrolizumab therapy. It will be critical to understand how the use of contemporary immune checkpoint blockade combination therapies for advanced disease will impact survival over time. At the time of data analysis, 18% of patients in the pembrolizumab arm and 41% of patients in the placebo arm had received subsequent immune checkpoint blockade, and 74% and 68% received subsequent VEGF-targeting therapy.
Treatment with pembrolizumab was well tolerated, and no new safety signals emerged from this study. The rate of grade ≥ 3 adverse events was 32%, and the rate of serious adverse events was 21% with pembrolizumab. No treatment-related deaths were reported.
Challenge of Applying These Data to Clinical Practice
Although these data are promising, they usher a series of questions regarding application in clinical practice:
- Which patients will derive the most benefit from treatment?
- Are the data applicable for variant histology renal cell carcinoma?
- Are there predictive tissue- or blood-based biomarkers to guide therapy selection for patients?
- If disease progression develops following receipt of adjuvant checkpoint blockade, what is the optimal front-line treatment strategy for recurrent disease?
Additional analyses and longer follow-up from the trial will help answer some of these questions. Additionally, there are a series of other adjuvant studies of checkpoint inhibitors (IMmotion010, CheckMate 914, PROSPER, RAMPART) that may provide further information regarding the role of adjuvant immunotherapy in renal cell carcinoma.
Dr. McKay is Associate Clinical Professor, Medicine, at the University of California San Diego.
DISCLOSURE: Dr. McKay has served as a consultant or advisor to Astellas, Medivation, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Caris, Dendreon, Exelixis, Janssen, Merck, Myovant, Novartis, Pfizer, Sanofi, Sorrento Therapeutics, Tempus, and Vividion Therapeutics.
REFERENCES
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9. U.S. Food and Drug Administration: Renal cell carcinoma: Developing drugs and biologics for adjuvant treatment. Draft Guidance for Industry. October 2020. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/renal-cell-carcinoma-developing-drugs-and-biologics-adjuvant-treatment. Accessed October 25, 2021.
