Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of metastatic renal cell carcinoma (SWITCH-II)

Abstract

Background: The previous SWITCH-I study explored the two possible sequences of Sunitinib and Sorafenib for the treatment of advanced/metastatic renal cell carcinoma (mRCC) and showed similar total progression-free-survival (tPFS) and overall survival (OS) times. This trial compared the sequential therapy with the multikinase inhibitors Sorafenib (So) followed by Pazopanib (Pa) or vice versa in mRCC patients (pts). Methods: This multicentre, randomised phase 3 study assessed the sequential use of So-Pa versus Pa-So in pts with mRCC without prior systemic therapy. Pts were randomised to So 400 mg twice daily followed by Pa 800 mg once daily (So-Pa) in case of progression or intolerable toxicity or vice versa (Pa-So). The primary endpoint was noninferiority of tPFS with So-Pa compared to Pa-So, assessed from randomisation to progression or death during second-line therapy defined as hazard ratio (HR)<1.225 as a one-sided 95% confidence interval (CI). Main secondary endpoints included OS, total time to progression (TTP), disease control rate (DCR), 1st-line and 2nd-line PFS as well as safety and tolerability. Results: 377 pts were randomised (So-Pa, n=189; Pa-So, n=188). Median tPFS was 8.6mo (95% CI 7.7-10.2) for So-Pa and 12.9mo (95% CI 10.8-15.2) for Pa-So with a HR of 1.36 (upper limit of one-sided 95% CI 1.68). Therefore, non-inferiority of So-Pa in regard to tPFS was not met. However, marked statistical differences were noted in favour of Pa-So in total TTP, 1st-line PFS and DCR but not for OS and 2nd-line PFS. In the So-Pa arm 106/189 (56%) received Pa as 2nd line and for the Pa-So arm 87/188 (46%) received So as 2nd line. The most frequent any-grade treatment-emergent firstline adverse events for So were diarrhoea (56%), fatigue (37%) and hand-foot skin reaction (35%) and for Pa diarrhoea (60%), hypertension (48%) and fatigue (45%). Conclusions: Non-inferiority of the sequence So-Pa compared to Pa-So in terms of the primary endpoint tPFS was not met. However, superiority of the sequence Pa-So over So-Pa for tPFS was not proven either, since the study design was computed with a HR of<1.225 as a one-sided 95% CI.