1. Fuerst, Mark L.

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Immunotherapy after surgery significantly improves disease-free survival (DFS) for patients with the most common type of kidney cancer, clear-cell renal cell carcinoma (RCC), offering an effective treatment for patients currently with few other options.

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Surgical removal of the tumor by partial nephrectomy or the entire kidney by radical nephrectomy is commonly used to treat RCC. However, patients with intermediate- to high-risk advanced disease are at risk for relapse. Currently, there are no standard treatment options post-surgery.


The immune checkpoint inhibitor pembrolizumab improves immune system response to tumor cells by blocking the programmed death-1 (PD-1) protein on the tumor cell surface. Targeting PD-1 has proven to be effective efficacy and safe for the treatment of metastatic RCC.


"Surgery is the standard of care treatment for locoregional RCC. Nearly half of patients experience disease recurrence after surgery. There is no globally accepted standard adjuvant therapy supported by high levels of evidence," said lead author Toni Choueiri, MD, Director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, at a press briefing during the 2021 ASCO Annual Meeting.


About the Study

Choueiri described the results of KEYNOTE-564 (Abstract LBA5), a Phase III, double-blind, multicenter trial of pembrolizumab versus placebo following nephrectomy in patients with RCC. This is the first Phase III study with a checkpoint inhibitor in the adjuvant setting to show improvement in DFS for patients with high-risk, fully resected RCC.


The study included 994 patients who were randomized to receive either pembrolizumab 200 mg (496 patients) or placebo (498 patients) every 3 weeks for at least 1 year. They all had histologically confirmed clear cell RCC, with intermediate-high risk, high risk, or M1 NED (no evidence of disease after primary tumor plus soft tissue metastases completely resected within 1 year from nephrectomy). The patients had undergone surgery less than 12 weeks prior to randomization, had no prior systemic therapy, and had ECOG PS 0 or 1. The study's primary endpoint was DFS; overall survival (OS) was a key secondary endpoint.


Key Findings

At the study's first interim analysis with 24 months median follow-up, the risk of disease recurrence or death was reduced by 32 percent compared with placebo. The 24-month estimated DFS rate was 77.3 percent with pembrolizumab as compared to 68.1 percent with placebo.


"The primary endpoint was met," said Choueiri. "At month 12 and at month 24, the difference in DFS is about 9-10 percent between both arms favoring pembrolizumab." Overall, the DFS benefit was consistent across subgroups.


While OS data were immature, "we noticed that despite median OS not being reached, the HR was 0.54. The estimated preliminary OS rate at 24 months was 96.6 percent with pembrolizumab and 93.5 percent with placebo. There were 18 events in the pembrolizumab arm and 33 in the placebo arm," said Choueiri. Additional follow-up for OS is planned.


All-cause adverse events were higher in the pembrolizumab arm (96.3%) than in the placebo arm (91.1%), as expected. Grade 3-5 all-cause adverse events were also more common with pembrolizumab (32.4%) versus placebo (17.7%). No treatment-related deaths occurred in the pembrolizumab arm.


The key take-aways, according to Choueiri: "Adjuvant pembrolizumab following surgery demonstrated a statistically significant and clinically meaningful improvement in DFS versus placebo. Safety results were in line with expectations and no new safety signals occurred. KEYNOTE-564 is the first positive Phase III study of an adjuvant immunotherapy in RCC. Pembrolizumab is a potential new standard of care for RCC patients in the adjuvant setting and may provide a promising treatment for patients for whom there are few therapy options."


ASCO Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, FACP, FASCO, commented: "The KEYNOTE-564 study is the first Phase III trial to show improved DFS from the addition of an immune checkpoint inhibitor in the adjuvant setting for RCC, which is the most common type of kidney cancer.


"Despite surgery, recurrence is common in clear-cell RCC, and if it does recur, there are limited curative treatment options for patients. The results of the KEYNOTE-564 trial support consideration of pembrolizumab as a potential new standard of care in the adjuvant setting to reduce disease recurrence in certain patients with kidney cancer."


Mark L. Fuerst is a contributing writer.