A Prospectivly Randomized Phase-II Trial of Axitinib versus Everolimus as Second Line Therapy in Metastatic Renal Cell Carcinoma (BERAT Study)

Introduction Inhibition of neo-angiogenesis is a cornerstone of medical treatment in metastatic renal cell carcinoma (mRCC). While 1st line therapies were previously dominated by inhibitors of the vascular endothelial growth factor (VEGF) axis, 2nd line options were less clearly defined. We investigated the role of everolimus (EVE) or a tyrosine kinase inhibitor (TKI) in 2nd line treatment of mRCC patients. Methods Key inclusion criteria were: measurable mRCC , ECOG 0-1, IMDC risk: good or intermediate and adequate organ function. Patients who progressed on or were intolerant to bevacizumab + interferon were subject for randomization between TKI and EVE treatment. Cross-over occurred at time of progression during 2nd line treatment. Improvement of 2nd line PFS-rate at 6 mo. from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, ORR, OS, safety and patient reported outcomes. Results In 2012-2015 a total of 22 patients were included. The study was stopped for poor accrual. 10 patients (46%) were randomized to receive 2nd line treatment with everolimus (n=5) or Axitinib (n=4)/ Sunitinib (n=1). ECOG 0 was recorded in 20 % (EVE) and 60% (TKI). Severe adverse events (SAE) occurred in approx. 60% in each arm. ORR was 1/5 (20%) for TKI and 0/5 (0%) for Everolimus. PFS rate at 6 mo. was 20 % in each arm. Median PFS was 3.7 mo. (EVE) and 2.2 mo. (TKI) [HR 1.0 (95%-CI: 0.26-3.85)]. The OS was comparable between arms HR 1.12 (95%-CI: 0.27-4.61). Discussion/Conclusion The rapid change of the treatment landscape, the limited use of BEV/IFN in 1st line and the duration of 1st line treatment jeopardized BERAT trial recruitment. The small number of patients is a major limitation of our trial. Our observation indicated the poor prognosis in progressive patients and the limited efficacy of TKI or mTOR inhbitors in 2nd line treatment.