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 present at the American Society of Clinical Oncology 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 Dr Toni Choueiri, 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.
“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.
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.
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.
“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.
Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study
Authors: Toni K. Choueiri, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Tom Ferguson, Yen-Hwa Chang, Jaroslav Hajek, Stefan N. Symeonides, Jae-Lyun Lee, Naveed Sarwar, Antoine Thiery-Vuillemin, Marine Gross-Goupil, Mauricio Mahave, Naomi B. Haas, Piotr Sawrycki, Eric (Pingye) Zhang, Jaqueline Willemann Rogerio, Kentaro Imai, David I. Quinn, Thomas Powles; Dana-Farber Cancer Institute.
Relapse after surgery for high-risk clear cell RCC (ccRCC) is associated with shortened life expectancy. Effective perioperative therapy to reduce this risk remains an unmet need. Adjuvant immune therapy is an attractive potential strategy for these pts. We conducted the KEYNOTE-564 trial to evaluate pembro vs placebo as adjuvant therapy for pts with RCC.
KEYNOTE-564 is a phase III multicenter trial of pembro vs placebo in pts with histologically confirmed ccRCC, with intermediate-high risk (pT2, Gr 4 or sarcomatoid, N0 M0; or pT3, any Gr, N0 M0), high risk (pT4, any Gr, N0 M0; or pT any stage, any Gr, N+ M0), or M1 NED (no evidence of disease after primary tumor + soft tissue metastases completely resected ≤1 year from nephrectomy) (Leibovich et al, 2003; Fuhrman et al, 1982). Pts had undergone surgery ≤12 wks prior to randomization; had no prior systemic therapy; had ECOG PS 0 or 1. Study treatment was given for up to 17 cycles (≈1 yr). The primary endpoint was disease-free survival (DFS) per investigator assessment in all randomized pts (ITT population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability were secondary endpoints, assessed in all treated pts.
Between Jun 30, 2017 and Sept 20, 2019, 994 pts were randomized 1:1 to pembro (n=496) or placebo (n=498). As of data cutoff date of Dec 14, 2020, median (range) follow-up, defined as time from randomization to data cutoff, was 24.1 (14.9−41.5) mo. No pts remain on study treatment. Baseline characteristics were generally balanced between arms. At first prespecified interim analysis, the primary endpoint of DFS was met (median not reached [NR] for both arms, HR 0.68, 95% CI 0.53−0.87; P=0.0010 [one-sided]). The estimated DFS rate at 24 mo was 77.3% with pembro vs 68.1% with placebo. Overall, DFS benefit was consistent across subgroups. A total of 51 OS events were observed (18 in the pembro arm, 33 in the placebo arm). Median OS was NR for both arms (HR 0.54, 95% CI 0.30−0.96; P=0.0164 [one-sided]); the p-value did not cross the statistical hypothesis testing boundary. The estimated OS rate at 24 mo was 96.6% with pembro vs 93.5% with placebo. 470 pts (96.3%) and 452 pts (91.1%) experienced ≥1 all-cause adverse events (AEs) with pembro vs placebo, respectively. Grade 3-5 all-cause AEs occurred in 158 pts (32.4%) with pembro and 88 pts (17.7%) with placebo. No deaths related to pembro occurred.
Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs placebo in pts with intermediate-high, high risk or M1 NED RCC. Additional follow-up is planned for the key secondary endpoint of OS. KEYNOTE-564 is the first positive phase III study with a checkpoint inhibitor in adjuvant RCC, and these results support pembro as a potential new standard of care for pts with RCC in the adjuvant setting. Clinical trial information: NCT03142334
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