Pembrolizumab Delays Disease and Distant Metastasis in RCC

Thomas Powles, MD, MBBS, MRCP

Adjuvant pembrolizumab (Keytruda) continued to show an improvement in disease-free survival (DFS) benefit over placebo after 30 months of follow-up in patients with renal cell carcinoma (RCC), according to updated results from the phase 3 KEYNOTE-564 trial. The DFS benefit was continued across prespecifi ed subgroups.

A similar benefit was observed in an exploratory analysis of distant metastasis-free survival (DMFS) and was demonstrated across recurrence risk subgroups.

“Adjuvant pembrolizumab continues to demonstrate these impressive results with disease-free survival, particularly across subgroups of patients,” Thomas Powles, MD, MBBS, MRCP, said when presenting longer-term findings from the trial at the European Association of Urology Congress 2022.¹ Powles is a professor of genitourinary oncology, director of Barts Cancer Centre at St. Bartholomew’s Hospital, and lead for solid tumour research at Cancer Research UK Barts Centre in London, England.

KEYNOTE-564 (NCT03142334) is a double-blind multicenter trial of pembrolizumab vs placebo after surgery in patients with RCC. The study enrolled 994 patients with clear cell RCC who had intermediate-high or high-risk disease or M1 no evidence of disease status after surgery as well as no prior systemic treatment and an ECOG performance status of 0 or 1. Patients were randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for approximately 1 year (n = 496) or matching placebo (n = 498).

The primary end point was DFS by investigator assessment and secondary end points were overall survival (OS) and safety. Exploratory end points included DMFS and second progression-free survival (PFS2).

Baseline characteristics were well balanced between the 2 arms. Overall, the majority of patients were male (71%), had M0 intermediate high disease (86.5%), no sarcomatoid features (55.9%), positive PD-L1 expression by combined positive score (75.3%), T3 disease stage (88.6%), and lymph node–negative disease (93.8%).

The DFS end point was met as of the first protocol-specified interim analysis.² At 24 months, the estimated DFS rate was 77.3% with adjuvant pembrolizumab compared with 68.1% with placebo (HR, 0.68; 95% CI, 0.53-0.87; 2-sided P = .002).

Updated Findings

After a median of 30.1 months of follow-up (range, 20.8-47.5), the 24-month DFS rates were 78.3% in the pembrolizumab arm and 67.3% in the placebo arm. The median DFS was still not reached in either arm (HR, 0.63; 95% CI, 0.50-0.80; nominal P < .0001).¹

Across subgroups, DFS favored the pembrolizumab arm for all key subgroups. Significant benefit for the use of pembrolizumab was seen in patients with M1 no evidence of disease (HR, 0.28; 95% CI, 0.12-0.66), T1 disease stage (HR, 0.19; 95% CI, 0.04- 0.89), and those who underwent partial nephrectomy (HR, 0.22; 95% CI, 0.05-1.04). However, all of these were in smaller groups of patients.

DMFS was higher in the placebo arm than in the pembrolizumab arm; the majority of recurrence events were distant metastasis, approximately 87%.

At 24 months, the rate of DMFS was 80.1% in the pembrolizumab arm and 69.9% in the placebo arm and the median was not reached in either arm (HR, 0.63; 95% CI, 0.49-0.82).

Among patients with M0 disease, the DMFS rate was 20.8% in the pembrolizumab arm compared with 29.0% in the placebo arm, and for patients with M1 no evidence of disease, the rates were 20.7% and 55.2%, respectively. A total of 7 patients in the pembrolizumab arm and 10 in the placebo arm died without distant recurrence.

By risk status, the 24-month DMFS rate in the intermediate-high risk group was 82.7% with pembrolizumab compared with 74.0% with placebo (HR, 0.67; 95% CI, 0.50-0.90). In the high-risk group, DMFS was 50.8% with pembrolizumab and 36.6% with placebo at 24 months (HR, 0.66; 95% CI, 0.36-1.23). For patients with M1 no evidence of disease, the 24-month DMFS rates were 81.4% and 47.4% with pembrolizumab and placebo, respectively (HR, 0.28; 95% CI, 0.11-0.73). The median DMFS was not reached with pembrolizumab in any recurrence risk subgroup (TABLE¹ ).

Powles commented that going against expectations, the majority of benefit was not seen in the M1 subgroup, though a signifi cant difference also was seen in this group. As of the second interim analysis, only 33% of the 200 deaths required for the final OS analysis had occurred at the time of data cutoff, so the median was not yet reached in either arm. At 24 months, the OS rate was 96.2% in the pembrolizumab arm compared with 93.8% in the placebo arm (HR, 0.52; 95% CI, 0.31-0.86; P = .0048).

“We’re looking at overall survival but we’re not yet calling it significant despite the numbers looking very impressive. From our perspective, we’d like to see a mature survival signal and 30 months is not yet mature. [However,] 0.52 is a provocative number. It’s half the number of events in 1 arm vs the other and clearly if this trend continues, it’s going to be statistically signifi cant in the future, but who knows what the future holds,” Powles said.

Median PFS2 also was not reached in either treatment arm with a 24-month rate of 92.7% with adjuvant pembrolizumab and 88.6% with placebo (HR, 0.57; 95% CI, 0.39- 0.85). “It does seem that early intervention with immune therapy does appear to be having an effect on the biology of the disease,” Powles said.

Safety Signals

No new safety signals were reported with the updated findings, and there was no notable increase observed in any-grade or grade 3/4 treatment-related adverse events (TRAEs).

The most common any-grade TRAEs in the pembrolizumab arm were fatigue (20.3%), pruritus (18.6%), and hypothyroidism (17.4%). Comparatively, in the placebo arm, the most common TRAEs were fatigue (14.3%), pruritus (11.5%), and diarrhea (10.3%). More common grade 3/4 AEs in the pembrolizumab arm included diarrhea, fatigue, and rash. The median time to fi rst onset in the pembrolizumab arm was shortest with hypothyroidism (3.1 weeks; range, 2.1-60.9) and longest with myalgia (12.8 weeks; range, 0.1-46.4).

_REFERENCES:

_{1. Powles T, Tomczak P, Park SH, et al. Pembrolizumab (pembro) as adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): Updated results from the 30-month follow-up of KEYNOTE-564. Presented at: EAU Congress 2022; July 1-4, 2022; Amsterdam, Netherlands.}

_{2. Choueiri TK, Tomczak P, Park SH, et al; KEYNOTE-564 Investigators. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391}