title: Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study.
abstract: 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 days 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 months of treatment including ≥4 months of therapy at their highest tolerated dose. Secondary endpoints included progression-free survival (PFS) and safety.
  
  
  
  In all, 83 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. The ORR was 44.4% [n = 8/18; 95% confidence interval (CI) 21.5-69.2] and 17.9% (n = 12/67; 95% CI 9.6-29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0-11.7) months (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 of >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.
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gore
authors.affiliation: Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Jones
authors.affiliation: Hôpital Saint-André CHU, Bordeaux, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Ravaud
authors.affiliation: Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kuczyk
authors.affiliation: Bayer Vital GmbH, Leverkusen, Germany.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Demkow
authors.affiliation: Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie, Warszawa, Poland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bearz
authors.affiliation: IRCCS Centro Rif Oncologico, Aviano, Italy.
authors.forename: JoAnn
authors.initials: J
authors.lastname: Shapiro
authors.affiliation: IRCCS Policlinico San Matteo, Medicina Interna ed Oncologia Medica, Pavia, Italy.
authors.forename: Uwe Phillip
authors.initials: UP
authors.lastname: Strauss
authors.affiliation: Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ, USA.
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D012107:Research Design; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: #KidneyCancer; dose escalation; renal cell carcinoma; sorafenib; targeted therapy; tyrosine kinase inhibitor