A randomized phase II study to compare the efficacy of upfront bi-monthly rotations between pazopanib (PAZ) and everolimus (EVE) versus sequential treatment of first-line PAZ and second-line EVE until progression in patients with metastatic clear cell renal cell cancer (ccRCC) (ROPETAR trial)

Background: Targeted agents have improved survival in ccRCC patients but resistance always develops. Since accumulating evidence suggests that resistance is partially reversible after drug withdrawal we tested the hypothesis that bi‐monthly rotations of treatment with PAZ and EVE delays resistance compared with the standard of PAZ followed by EVE at progression. Methods: Phase 2, open‐label, randomized (1:1), multicenter study. Eligibility: 18 years, treatment naive progressive metastatic ccRCC, ECOG PS 2. First‐line treatment consisted of either a bi‐monthly alternating treatment schedule with PAZ 800mg/d and EVE 10mg/d (rotating arm, ROT) or PAZ 800mg/day (control arm, CON). After progression according RECIST 1.1 (PD) patients made a final rotation to either PAZ or EVE monotherapy (ROT) or initiated EVE (CON) as second‐line treatment. Primary endpoint was survival until first PD or death (PFS1). Secondary endpoints included time to second PD or death (PFS2) and toxicity.Accrual of 100 patients was planned to detect an increase in 1‐year PFS of 50 to 80% (power 90%, α = 0.05, 2‐tailed test). Results: Between 2012 and 2014, 101 patients were randomized. Overall Memorial Sloan Kettering Cancer Center risk categories (MSKCCrc): favorable 26%, intermediate 58% and high‐risk 15%. Baseline characteristics and risk categories were well‐balanced. One year PFS1 for ROT was 46% (95% CI:34‐62) and 31% (95% CI:20‐48) for CON (p = 0.13; 2‐sided). Median PFS1 for ROT was 7.4mo (95% CI:5.1‐19.0) and 8.9mo (95% CI:6.6‐11.9) for CON (p = 0.32). Hazard ratio stratified by MSKCCrc (sHR) for PFS1 was 0.81 (95% CI:0.49‐1.32;p = 0.39) in favor of ROT. Median PFS2 for ROT was 23.0mo (95% CI: > 10.9) and 14.5mo (95% CI: > 11.9) for CON. sHR for PFS2 was 1.05 (95% CI:0.59‐1.84;p = 0.88). Mucositis (35% vs 8%), anorexia (39% vs 20%) and dizziness (14% vs 0%) were more prevalent in ROT during first‐line treatment. Conclusions: Bi‐monthly rotating treatment with PAZ and EVE did not lead to a delay in drug resistance, prolonged PFS or less toxicity.