To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC).
Intra-patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non-randomised, open-label, Phase 2b study, treatment-naïve patients with mRCC were initially treated with the standard oral sorafenib dose (400 mg twice daily [BID]). Two dose escalations were planned, each 200 mg BID after 28 d at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events (AEs). The primary endpoint was objective response rate (ORR) in the modified intent-to-treat (mITT) population, which comprised patients with ≥6 mo of treatment including ≥4 mo of therapy at their highest tolerated dose. Secondary endpoints included progression-free survival (PFS) and safety.
Eighty-three patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. ORR was 44.4% (n = 8/18; 95% CI: 21.5-69.2) and 17.9% (n = 12/67; 95% CI: 9.6-29.2) in the mITT and ITT populations, respectively. Median PFS was 7.4 mo (95% CI: 6.0-11.7) (ITT). The most-common AEs of any grade were hand-foot skin reaction (66.3%) and diarrhoea (63.9%).
Sorafenib demonstrated clinical benefit in treatment-naïve patients with mRCC. However, relatively few patients could sustain doses above 400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment-naïve mRCC. Alternative protocols for sorafenib dose escalation could be explored. This article is protected by copyright. All rights reserved.
BJU international. 2016 Dec 15 [Epub ahead of print]
Martin E Gore, Robert J Jones, Alain Ravaud, Markus Kuczyk, Tomasz Demkow, Alessandra Bearz, JoAnn Shapiro, U Phillip Strauss, Camillo Porta
Royal Marsden Hospital, London, UK., University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK., Hôpital Saint-André CHU, Bordeaux, France., Medizinische Hochschule Hannover, Hannover, Germany., Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie, Warszawa, Poland., IRCCS Centro Rif Oncologico, Aviano, Italy., Bayer HealthCare Pharmaceuticals Inc., Whippany, New Jersey, USA., Bayer Vital GmbH, Leverkusen, Germany., IRCCS Policlinico San Matteo, Medicina Interna ed Oncologia Medica, Pavia, Italy.