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Single-agent immune checkpoint inhibition after surgery reduced the risk of disease recurrence or death in patients with high-risk clear cell renal cell carcinoma (RCC), findings from a phase III study showed.

The KEYNOTE-564 trial met its primary endpoint, demonstrating that adjuvant pembrolizumab (Keytruda) following nephrectomy significantly increased disease-free survival (DFS) versus placebo (HR 0.68, 95% CI 0.53-0.87, P=0.001), reported Toni Choueiri, MD, of the Dana-Farber Cancer Institute in Boston.

At 1 and 2 years, respectively, DFS rates were 85.7% and 77.3% with the PD-1 inhibitor, as compared with 76.2% and 68.1% with placebo, a "clinically meaningful improvement," Choueiri said at a press briefing ahead of the virtual American Society of Clinical Oncology (ASCO) annual meeting.

"Pembrolizumab is a potential new standard of care for patients with RCC in the adjuvant setting," said Choueiri, noting that KEYNOTE-564 is the first positive phase III study of an adjuvant immunotherapy in RCC. Currently, there is no accepted standard adjuvant therapy with a high level of evidence, he said.

The overall survival (OS) rate reached 96.6% at 2 years in the investigational arm versus 93.5% in the placebo arm (HR 0.54, 95% CI 0.30-0.96), though the difference missed prespecified criteria for statistical significance. With 18 deaths in the pembrolizumab arm and 33 in the placebo arm (26% of events for the final OS analysis), the OS data remain immature, said Choueiri.

"Despite surgery, recurrence is common in clear cell renal cell carcinoma, and if it does recur, there is limited curative treatment options," explained Julie Gralow, MD, ASCO's chief medical officer, who was not involved in the study.

Gralow agreed that the results support pembrolizumab as a "potential" new standard in the adjuvant setting.

Significant biomarker testing is in the works, Choueiri said, with patients' tumor tissue having been assessed for PD-L1 expression. "At the end of the day, there are patients that may need surgery alone even if they're higher risk and other patients that would benefit from pembrolizumab," he said.

ASCO-designated discussant Rana McKay, MD, of the University of California San Diego, noted that while sunitinib (Sutent) received , based on a DFS benefit in the S-TRAC trial, the therapy has seen limited use in clinical practice due to the lack of OS benefit, along with increased toxicity and reduced quality of life.

"Are the results of KEYNOTE-564 practice-changing? I would argue that yes, they are," said McKay.

"The data represent a paradigm shift as the first positive phase III study of adjuvant immunotherapy in RCC," she continued. "DFS prolongation represents clinical benefit, given the magnitude of benefit and limited toxicity."

Several questions will need to be addressed, however, said McKay, such as whether to broadly implement the approach for all patients -- including non-clear cell RCC -- and whether adjuvant immunotherapy will affect treatment in the advanced setting, where PD-1-inhibitor-based treatment has become standard.

"Ultimately, this is a quantum leap forward for our patients," McKay concluded.

The open-label, multicenter KEYNOTE-564 trial randomized 994 patients with high-risk clear cell RCC 1:1 to either a year of pembrolizumab (200 mg/kg every 3 weeks) or placebo following surgery. Criteria for high-risk disease included:

• pT2 (grade 4 or sarcomatoid) without nodal involvement or metastatic disease
• pT3-4 (any grade) without nodal involvement or metastatic disease
• Any pT (any grade) with nodal involvement but no metastatic disease
• M1 status but no evidence of disease following surgery

Patients had to undergo randomization within 12 weeks of their nephrectomy, no prior systemic therapy was allowed, and patients had to have good performance status (Eastern Cooperative Oncology Group 0-1). Median follow-up in the current analysis was about 24 months. Investigator-assessed DFS was the primary endpoint, with secondary endpoints including OS and safety.

Most patients in the study were of lower risk -- M0 intermediate-high risk in 86-87%, M0 high risk in 7-8%, and M1 with no evidence of disease in 5.8%.

"Safety results overall were in line with expectations, without any new safety signals," said Choueiri.

At least one adverse event (AE) of any grade occurred in nearly all patients -- 96.3% in the investigational arm and 91.1% in the placebo arm. Grade ≥3 AEs of any cause occurred in 32.4% and 17.7%, respectively.

Treatment-related AEs of any grade were more frequent with pembrolizumab (79.1% vs 53.4% with placebo), as were treatment-related grade ≥3 AEs (18.9% vs 1.2%, respectively). No deaths were attributed to treatment in either arm.

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