Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Patients receiving adjuvant pembrolizumab after nephrectomy for renal-cell carcinoma showed significantly improved disease-free survival compared to patients receiving placebo treatment.

2. Patients treated with pembrolizumab were shown to have a higher percentage of immune-mediated grade 3 or 4 events compared to patients treated with the placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

Patients with locoregional clear-cell renal-cell carcinoma who undergo nephrectomy remain at risk for recurrence after surgery; however, no standard adjuvant treatments are available. Pembrolizumab, an anti-programmed death 1 (PD-1) antibody, is immunotherapy shown to effectively treat advanced renal-cell carcinoma. In this randomized control trial, patients who underwent nephrectomy for renal cell carcinoma and were considered high-risk for recurrence either received 17 cycles of adjuvant pembrolizumab or placebo treatment. The primary measured endpoint was disease-free survival, which was measured from time to first local or distant recurrence, or death of any cause. The study found significantly improved disease-free and overall survival in the group receiving pembrolizumab compared to the placebo. While a higher proportion of patients receiving pembrolizumab experienced severe adverse events, the treatment regimen itself was not associated with any deaths. Together, this phase 3 trial clearly supports the use of pembrolizumab as an adjuvant therapy to nephrectomy in renal-cell carcinoma. The largest limitation to this study was the short follow-up time; therefore, longer intervals are needed to fully assess the effect of adjuvant pembrolizumab on overall survival.

In-Depth [randomized controlled trial]:

This open-label, multicenter, phase 3 randomized control trial enrolled 496 patients from 213 sites in 21 countries. Patients who were at least 18 years of age, previously underwent nephrectomy for locoregional clear-cell renal-cell carcinoma, and were considered high-risk for recurrence were included in the study. Patients who received any previous systemic therapy or had not undergone gone surgery were excluded from the study. Participants were randomized in a 1:1 ratio to receive 17 cycles of 200mg adjuvant pembrolizumab or placebo saline treatment, respectively. The primary assessed endpoint was disease-free survival defined as the time of treatment to first local or distant recurrence, or death for any reason. At 24 months, patients receiving pembrolizumab showed significantly improved disease-free survival compared to their placebo counterparts (hazard ratio for recurrence or death [HR], 0.68; 95% confidence interval [CI], 0.53 to 0.87, P=0.002). Pembrolizumab was able to improve the percentage of patients who remained recurrence-free and alive at 24 months (77.3%) compared to the placebo group (68.1%). Patients receiving pembrolizumab also experienced improved overall survival at 96.6% after 24 months compared to 93.5% in the placebo (HR, 0.54; 95%CI, 0.30 to 0.96). No deaths were directly attributable to the treatment regimen. Finally, a greater proportion of immune-mediated adverse events were shown in the pembrolizumab group (34.6%) compared to the placebo group (5.8%). Together, at its first interim analysis, this study supports the use of adjuvant pembrolizumab after partial or complete nephrectomy in patients with clear-cell renal-cell carcinoma.

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