title: Adjusting for the Confounding Effects of Treatment Switching-The BREAK-3 Trial: Dabrafenib Versus Dacarbazine.
abstract: BACKGROUND
  Patients with previously untreated BRAF V600E mutation-positive melanoma in BREAK-3 showed a median overall survival (OS) of 18.2 months for dabrafenib versus 15.6 months for dacarbazine (hazard ratio [HR], 0.76; 95% confidence interval, 0.48-1.21). Because patients receiving dacarbazine were allowed to switch to dabrafenib at disease progression, we attempted to adjust for the confounding effects on OS.
  
  
  METHODS
  Rank preserving structural failure time models (RPSFTMs) and the iterative parameter estimation (IPE) algorithm were used. Two analyses, "treatment group" (assumes treatment effect could continue until death) and "on-treatment observed" (assumes treatment effect disappears with discontinuation), were used to test the assumptions around the durability of the treatment effect.
  
  
  RESULTS
  A total of 36 of 63 patients (57%) receiving dacarbazine switched to dabrafenib. The adjusted OS HRs ranged from 0.50 to 0.55, depending on the analysis. The RPSFTM and IPE "treatment group" and "on-treatment observed" analyses performed similarly well.
  
  
  CONCLUSIONS
  RPSFTM and IPE analyses resulted in point estimates for the OS HR that indicate a substantial increase in the treatment effect compared with the unadjusted OS HR of 0.76. The results are uncertain because of the assumptions associated with the adjustment methods. The confidence intervals continued to cross 1.00; thus, the adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. However, it is clear that a standard intention-to-treat analysis will be confounded in the presence of treatment switching-a reliance on unadjusted analyses could lead to inappropriate practice. Adjustment analyses provide useful additional information on the estimated treatment effects to inform decision making.
  
  
  CONCLUSIONS
  Treatment switching is common in oncology trials, and the implications of this for the interpretation of the clinical effectiveness and cost-effectiveness of the novel treatment are important to consider. If patients who switch treatments benefit from the experimental treatment and a standard intention-to-treat analysis is conducted, the overall survival advantage associated with the new treatment could be underestimated. The present study applied established statistical methods to adjust for treatment switching in a trial that compared dabrafenib and dacarbazine for metastatic melanoma. The results showed that this led to a substantially increased estimate of the overall survival treatment effect associated with dabrafenib.
authors.affiliation: School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom; GlaxoSmithKline, Collegeville, Pennsylvania, USA; GlaxoSmithKline, Uxbridge, United Kingdom n.latimer@sheffield.ac.uk.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Latimer
authors.affiliation: School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom; GlaxoSmithKline, Collegeville, Pennsylvania, USA; GlaxoSmithKline, Uxbridge, United Kingdom.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Abrams
authors.affiliation: School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom; GlaxoSmithKline, Collegeville, Pennsylvania, USA; GlaxoSmithKline, Uxbridge, United Kingdom.
authors.forename: Mayur M
authors.initials: MM
authors.lastname: Amonkar
authors.affiliation: School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom; GlaxoSmithKline, Collegeville, Pennsylvania, USA; GlaxoSmithKline, Uxbridge, United Kingdom.
authors.forename: Ceilidh
authors.initials: C
authors.lastname: Stapelkamp
authors.affiliation: School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom; GlaxoSmithKline, Collegeville, Pennsylvania, USA; GlaxoSmithKline, Uxbridge, United Kingdom.
authors.forename: R Suzanne
authors.initials: RS
authors.lastname: Swann
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D003606:Dacarbazine / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D010091:Oximes / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D010091:Oximes; D003606:Dacarbazine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: BRAF V600E mutation-positive melanoma; Dabrafenib; Dacarbazine; Overall survival; Survival analysis