Randomised Phase II study comparing alternating cycles of sunitinib and everolimus vs standard sequential administration in first-line metastatic renal carcinoma (SUNRISES study)

Rodriguez-Vida A, Bamias A, Esteban E, et al.
BJU Int 2020 Jul 12
DOI: 10.1111/bju.15165

Abstract

Objective

Targeted therapies have been a mainstay of the renal cell carcinoma (RCC) treatment paradigm for the better part of two decades. Multikinase inhibitors of the vascular endothelial growth factor receptor tyrosine kinases (VEGF-TKIs) comprise nearly all targeted therapies in RCC, having been prospectively tested through large, multi-institutional phase III trials. Tivozanib is a VEGF-TKI with high selectivity for VEGF receptors 1–3. Tivozanib has been under investigation for nearly 15 years, with a robust portfolio of preclinical and clinical data. This review seeks to characterize tivozanib within the context of RCC by highlighting preclinical and early clinical trials alongside the phase III trials in RCC, TIVO-1, and TIVO-3. We also aim to explore further trials of tivozanib, whether in combination with other agents and/or in differing disease settings, while providing insight into the utility of tivozanib as a clinical tool for the management of RCC.

Patients and Methods

SUNRISES, a randomised open-label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment naïve patients with clear cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety.

Results

Accrual was low due to the advent of new generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1 year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm.

Conclusions

The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.

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