Adjuvant pembrolizumab continues to improve DFS in clear cell RCC

In patients with clear cell renal cell carcinoma (RCC), adjuvant pembrolizumab continues to improve disease-free survival (DFS) over placebo, according to extended follow-up of the phase III KEYNOTE-564 trial.

“The estimated proportion of participants who were alive and recurrence-free was approximately 10 percent higher with pembrolizumab vs placebo and was consistent over time,” remarked the investigators.

“The efficacy and safety update with 6 additional months of follow-up from the first interim analysis, as well as the spectrum of secondary and exploratory analyses, give further credence to the use of adjuvant pembrolizumab in this population,” they highlighted.

Participants in this multinational, double-blind study were 994 adults (median age 60 years, 70–72 percent male) who had undergone nephrectomy for clear cell RCC ≤12 weeks prior and were disease-free at baseline but had an elevated risk of disease recurrence. They also had an ECOG performance status of 0–1 and had no prior exposure to systemic therapy for advanced RCC. They were randomized 1:1 to receive intravenous pembrolizumab (200 mg) or placebo Q3W for ≤17 cycles. The present analysis was conducted after a median follow-up period of 30.1 months.

A majority of the patients had primary tumour stage T3 (90 and 88 percent in the pembrolizumab and placebo groups, respectively), and 93 and 92 percent, respectively, had undergone radical nephrectomy. Ninety-four percent had N0 lymph node stage, 94 percent had M0 stage disease, and 86 and 87 percent in the pembrolizumab and placebo groups, respectively, had M0 intermediate- to high-risk disease. Eighty-three percent had no sarcomatoid features, and a majority (74 and 77 percent in the pembrolizumab and placebo groups, respectively) had PD-L1 ≥1.

Investigator-assessed DFS in the intent-to-treat population was improved with pembrolizumab vs placebo (median not reached [NR] in either group; hazard ratio [HR], 0.63, 95 percent confidence interval [CI], 0.50–0.80), with post-hoc analysis showing an estimated 75.2 percent vs 65.5 percent remaining alive and recurrence-free at 30 months. [Lancet Oncol 2022;23:1133-1144]

These results follow previously published findings which showed a significant improvement in DFS with pembrolizumab vs placebo following a 24.1-month follow-up period (24-month DFS: 77.3 percent vs 68.1 percent; HR, 0.68, 95 percent CI, 0.53–0.87; p=0.002). [N Engl J Med 2021;385:683-694]

Overall survival, though presently immature, was improved with pembrolizumab vs placebo (median NR in both groups; HR, 0.52, 95 percent CI, 0.31–0.86), with 23 and 43 deaths in the pembrolizumab and placebo groups, respectively, and an estimated 95.7 and 91.4 percent, respectively, alive at 30 months.

Disease recurrence specific-survival (DRSS) 1 (time to local recurrence) was greater in the pembrolizumab than placebo group (4 percent vs 7 percent), as was DRSS 2 (time to visceral recurrence or distant metastasis (20 percent vs 30 percent). A total of 108 recurrence events were documented in the pembrolizumab group, of which 12 and 83 percent, respectively, were local or distant recurrences only, while among the 166 recurrence events documented in the placebo group, 16 and 79 percent, respectively, were local or distant recurrences only.

Following disease recurrence, 14 and 20 percent of pembrolizumab and placebo recipients, respectively, received ≥1 line of subsequent anticancer treatment. Post-hoc analysis showed a longer time to first subsequent therapy or any-cause death with pembrolizumab vs placebo (median NR in both groups; HR, 0.67). The risk of progression or death on next-line therapy was also reduced with pembrolizumab vs placebo (median NR in both groups; HR, 0.57).

No new safety signals

Patients in both groups received a median 17 treatment cycles, with a median treatment duration of 11.1 months. The most common causes of treatment discontinuation in the pembrolizumab vs placebo group were adverse events (AEs; 21 percent vs 2 percent) and disease recurrence (10 percent vs 20 percent).

Grade ≥3 AEs occurred in 32 and 18 percent of pembrolizumab and placebo recipients, respectively. The most common grade ≥3 AEs in pembrolizumab recipients were hypertension and elevated alanine aminotransferase levels (3 and 2 percent, respectively), and hypertension in placebo recipients (3 percent). Serious AEs that were considered treatment related occurred in 12 and <1 percent of pembrolizumab and placebo recipients, respectively. There were no pembrolizumab-related deaths. Immune-mediated AEs occurred in 36 and 7 percent, respectively, the most common being hypo- and hyperthyroidism in pembrolizumab recipients (21 and 13 percent, respectively) and hypothyroidism in placebo recipients (4 percent).

A standard of care

“Patients who are considered disease-free after nephrectomy for RCC are at the highest risk of recurrence during the first 5 years after surgery,” said the investigators. “Patients with localized RCC with one or several high-risk features are in particular need of efficacious adjuvant therapy.”

“To our knowledge, KEYNOTE-564 is the first positive study for adjuvant immunotherapy in RCC,” said the investigators.

“Subgroup analyses showed benefit irrespective of the presence of sarcomatoid features, nuclear tumour grade 4, or M1 with no evidence of disease status at baseline,” they added, acknowledging the small numbers in certain subgroups.