Despite 30 years of investigation, there is no appropriate post-nephrectomy adjuvant therapy for patients with clear cell renal cell carcinoma with an increased risk of recurrence. In KEYNOTE-564, pembrolizumab monotherapy showed to improve disease-free survival, overall survival data and other efficacy and safety endpoints as compared to placebo, supporting adjuvant pembrolizumab as a potential new standard of care in this population.
Post-nephrectomy adjuvant treatment for renal cell carcinoma (RCC) has shown no consistent benefit despite 30 years of clinical investigation. Patients who are considered disease-free after nephrectomy are at the highest risk of recurrence during the first five years after surgery. Patients with localised RCC and high-risk features (higher tumour nuclear grade or presence of sarcomatoid features) or those with resectable soft tissue metastases at diagnosis (M1 stage disease) in addition to the primary renal tumour, could also benefit from adjuvant therapy. KEYNOTE-564 evaluated the use of pembrolizumab monotherapy vs. placebo after nephrectomy for participants with localised RCC or after nephrectomy and metastasectomy for participants with M1 stage RCC. After about 24 months of follow-up, this study showed improved disease-free survival with adjuvant pembrolizumab vs. placebo. The longer-term efficacy and safety results of KEYNOTE-564 with an additional follow-up of six months are here reported.
The multicentre, double-blind, phase III KEYNOTE-564 trial enrolled adult patients with clear cell RCC with an increased risk of recurrence. Eligible participants had undergone nephrectomy no longer than twelve weeks before randomisation, and had not received previous systemic therapy for advanced RCC. Participants were randomly assigned (1:1) to receive pembrolizumab (pembro) 200 mg or placebo intravenously every three weeks for up to seventeen cycles. The primary endpoint was disease-free survival (DFS). The key secondary endpoint was overall survival (OS). Other secondary endpoints were, among others, event-free survival (EFS), disease recurrence-specific survival 1 (defined as the time from randomisation to the first documented local disease recurrence) and 2 (defined as the time from randomisation to the first documented local recurrence with a visceral lesion or distant metastasis with a visceral lesion). Post-hoc exploratory endpoints included, among others, distant metastasis-free survival (MFS), time to first subsequent therapy or any-cause death and time to treatment discontinuation from adverse events (AEs). This study is still ongoing, but no longer recruiting.
Between June 2017 and September 2019, 994 participants were assigned to receive pembrolizumab (N= 496) or placebo (N= 498). Median follow-up was 30.1 months. DFS was better with pembrolizumab vs. placebo (HR[95%CI]: 0.63[0.50-0.80]). At 30 months, the estimated proportion of participants who remained alive and recurrence-free was 75.2% vs. 65.5% in the pembro and placebo groups. OS also favoured pembrolizumab (HR[95%CI]: 0.52[0.31-0.86]), with an estimated proportion of participants alive at 30 months of 95.7% vs. 91.4%. EFS was longer with pembrolizumab vs. placebo (HR[95%CI]: 0.75[0.60-0.95]). Median DFS, OS and EFS were not reached in either group. The analysis of time to local recurrence (disease recurrence-specific survival 1) showed 4% vs. 7% events in the pembro vs. placebo groups. The analysis of time to visceral recurrence or distant metastasis (disease recurrence-specific survival 2) showed 20% vs. 30% events. Distant MFS favoured pembrolizumab over placebo (HR[95%CI]: 0.63[0.49-0.82]. Overall, 14% vs. 20%of the participants received at least one line of subsequent anticancer drug therapy after disease recurrence in the pembro vs. placebo arms. Time to first subsequent therapy or any-cause death was longer in the pembro group (HR[95%CI]: 0.67[0.50-0.90]). The most common reason for discontinuation of study treatment was an AE (22% vs. 2% of participants in the pembro and placebo groups) and disease recurrence (10% vs. 20%). The median time to treatment discontinuation because of AEs was 4.1 vs. 4.9 months. The adverse event profile of pembrolizumab was in line with that reported for this study previously, with no new safety signals. The most common all-cause grade 3-4 AEs were hypertension (3%) and increased alanine aminotransferase (2%) in the pembro group, and hypertension (3%) in the placebo group. Serious AEs attributed to study treatment occurred in 12% of participants in the pembro group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.
KEYNOTE-564 is the first randomised phase III study to report results for a checkpoint inhibitor as adjuvant therapy for participants with renal cell carcinoma. In this longer-term follow-up (30 months), the benefit of pembrolizumab vs. placebo was confirmed. In this setting, adjuvant pembrolizumab resulted in better DFS and OS. Other endpoints, including EFS, MFS or time to subsequent therapy or any-cause death, were also improved with adjuvant pembrolizumab. No new safety signals were observed. Taken together, these findings support adjuvant pembrolizumab as a potential new standard of care for patients with renal cell carcinoma with an increased risk of disease recurrence after surgery.
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