ASCO 2021: Results from the KEYNOTE-564 Study of Adjuvant Pembrolizumab in Resected Clear-Cell Renal Cell Carcinoma (RCC)

(UroToday.com) In this session, Dr. Rana McKay discussed late-breaking abstract 5, results from the KEYNOTE-564 (KN-564) study of adjuvant pembrolizumab in resected clear-cell renal cell carcinoma (RCC).


She first began with a discussion of the history of adjuvant therapy in cancer medicine as well as in RCC. The term adjuvant therapy was likely coined by Paul Carbone at the National Cancer Institute in 1963 and is derived from the Latin word adjuvare, which means to help. The first adjuvant therapy clinical trial was published in 1968 by the NSABP evaluated adjuvant alkylating chemotherapy in breast cancer. The overall goals of adjuvant therapy are to improve cure rates by decreasing the risk of recurrence and thus improve patient survival.

Dr. McKay then provided a table of adjuvant immunotherapy trials from the interferon/IL-2 era in RCC, all of which were negative.

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Somewhat similarly to interferon and IL-2, multiple adjuvant trials of tyrosine kinase inhibitors were also negative, with the exception of the S-TRAC study of sunitinib versus placebo, which showed a statistically significant improvement in disease-free survival relative to placebo. This has not been adopted as routine practice, however, by many clinicians given the significant toxicity profile from this therapy and lack of overall survival benefit after longer term follow-up.

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The efficacy of checkpoint inhibitors has been demonstrated in multiple contexts in advanced renal cell carcinoma. These agents are being investigated as adjuvant therapy across multiple cancer subtypes. The only current indications for adjuvant immunotherapy after surgery is in melanoma, but there is promising data emerging in triple-negative breast cancer and esophageal cancer. In KN-562, pembrolizumab for 1 year was evaluated as adjuvant therapy for resected clear cell RCC as compared with placebo. The decision for 1 year of therapy was somewhat arbitrary and is based on prior clinical trial experience. The primary endpoint of the study was disease-free survival as assessed by the investigator. Patients were sorted into pre-specified risk groups.

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Dr. McKay spent some time discussing the rationale behind disease-free survival as an endpoint for randomized controlled trials as well as some measures built into this trial to limit the risk of overestimating the endpoint or bias.

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With regards to efficacy, Dr. McKay noted that the disease-free survival curves began to separate by 12 weeks, and remain apart, but do cross at the end due to the limited number of patients at risk at the later timepoint. There was a benefit to patients regardless of PD-L1 status.

Curves begin to separate by 12 weeks for DFS, at the tail end the curves cross, but the numbers at the end due to a limited number of patients at risk. Longer-term follow-up will be needed to confirm these findings, as well as confirm the currently promising trend towards overall survival benefit with only a small number of events so far.

Multiple trials are ongoing of adjuvant immunotherapy in RCC, which is summarized below.

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Finally, Dr. McKay suggested that these findings are potentially practice-changing. First, this is the first positive phase 3 study of immunotherapy in RCC demonstrating improved disease-free survival with less toxicity than other previously trialed agents like sunitinib. Much work remains to be done, including confirmation of an overall survival benefit, consideration of whether this can be used in other RCC histologies, and what the implications of adjuvant pembrolizumab would be for treatment choices in advanced RCC.

Presented by: Rana R. McKay, MD, Associate Professor of Medicine and Urology and co-lead of the Genitourinary Oncology Program at the Moore’s Cancer Center and University of California San Diego, San Diego, CA

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021