Durvalumab monotherapy versus active monitoring for resected primary renal cell carcinoma in RAMPART: An international, phase 3, randomized controlled trial.

Abstract

LBA4511 Background: RAMPART is evaluating one year of immune checkpoint inhibitor therapy versus active monitoring in patients with renal cell carcinoma (RCC) at intermediate or high risk of recurrence following nephrectomy according to the Leibovich Score (LS) or following complete resection of limited metastatic disease (M1NED). The trial has already shown that durvalumab and tremelimumab improves disease free survival (DFS), largely driven by effect in the higher risk population (LS high and M1NED). Methods: We recruited participants (pts) from 80 sites and randomised them in a 3:2:2 ratio between: Arm A, active monitoring; Arm B, 1 year (13 cycles) of durvalumab (1500mg); or Arm C, 1 year (13 cycles) of durvalumab (1500mg) plus tremelimumab (75mg, cycles 1 and 2 only). Based on the results of the KEYNOTE-564 trial, pembrolizumab became a treatment option for many of the patients who would be eligible for RAMPART, and recruitment was stopped earlier than planned. We revised the RAMPART design without knowledge of the accumulating trial results. In the modified design there is 80% power to detect a hazard ratio (HR) for the primary outcome of DFS of 0.60 for arm B vs. A, and of 0.55 for arm C vs. A. The overall familywise type I error rate remains strongly controlled at 2.5% (1-sided) across all primary analyses. The analysis plan includes a pre-specified, pre-powered analysis by risk of relapse. Results: Between October 2018 and June 2023, we randomised 790 pts (340, 225, and 225 to arms A, B, and C) from the UK (70%), France (21%), Australia (5%) and Spain (4%). Baseline characteristics were balanced across arms. Median age (range) was 60 (22, 83) years, 72% were male, 84% clear cell histology. Treatment with durvalumab (Arm B) was associated with a 26% relative reduction in the hazard of disease recurrence or death; conventional statistical significance was not reached (DFS HR = 0.74; 95% CI 0.53–1.04; 1p=0.041). DFS at 3 years was 78% with Arm B vs 72% Arm A. In the pre-specified DFS analysis by risk of recurrence, no evidence of a treatment-by-subgroup interaction was observed. This contrasts with the results of Arm C vs Arm A. Table 1 summarises results of the two RAMPART primary analyses. Exposure to treatment, safety, quality of life, overall survival and efficacy in non-clear cell subtypes will be presented. Conclusion: In RAMPART, durvalumab plus tremelimumab was associated with a statistically significant improvement in DFS, which was not observed with durvalumab monotherapy. Clinical trial information: NCT03288532 . Primary analysis results. Arm C vs A Arm B vs A All pts N=565; HR=0.65, 95%CI 0.45-0.93 N=565; HR=0.74, 95 CI 0.53–1.04 Higher Risk N=311; HR=0.52, 95%CI 0.34-0.80 N=312, HR=0.77, 95%CI 0.53–1.12 Intermediate Risk N=254, HR= 1.19, 95% CI 0.61-2.32 N=253, HR= 0.64, 95%CI 0.30–1.34 Test for Interaction HR=0.43, 95%CI 0.19-0.95 HR=1.20, 95%CI 0.52-2.74