title: Evaluating cost benefits of combination therapies for advanced melanoma.
abstract: BACKGROUND
  Although a number of monoimmunotherapies and targeted therapies are available to treat BRAF+ advanced melanoma, response rates remain relatively low in the range of 22-53% with progression-free survival (PFS) in the range of 4.8-8.8 months. Recently, combination targeted therapies have improved response rates to about 66-69%, PFS to 11.0-12.6 months and overall survival (OS) to 25.1-25.6 months. While combination immunotherapies have improved response rates of 67 compared with 19-29% with monotherapies and improved PFS of 11.7 compared with 4.4-5.8 months with monotherapies, the OS benefit is yet to be established in phase 3 trials. As healthcare costs continue to rise, US payers have a predominant interest in assessing the value of available treatments. Therefore, a cost-benefit model was developed to evaluate the value of treating BRAF+ advanced melanoma with two combination therapies: nivolumab + ipilimumab (N+I) and dabrafenib + trametinib (D+T).
  
  
  METHODS
  The model was used to estimate total costs, total costs by expenditure category, cost per month of PFS and cost per responder for the payer, and societal perspectives of treating advanced melanoma patients with the BRAF V600 mutation using combination targeted therapy (D+T) or combination immunotherapy (N+I). The model followed patients from initiation of treatment to the point of progression or death. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness of the results and to understand the dispersion of simulated results.
  
  
  RESULTS
  Based on a hypothetical payer with one million covered lives, it was expected that fourteen metastatic melanoma patients with the BRAF V600 mutation would be treated each year. Cost-benefit with N+I and D+T was simulated from the payer perspective. The cost per month of PFS for N+I was $22,162, while that for D+T was $17,716 (-$4,446 cost difference); the cost per responder for N+I was $388,746 and that for D+T was $282,429 (-$106,316 cost difference). The cost per month of PFS and per responder from the societal perspective resembled the patterns observed from the payer's perspective: the cost per month of PFS for N+I was $22,843, while that for D+T was $18,283 (-$4,560 cost difference). The cost per responder for N+I was $400,695 and that for D+T was $291,473 (-$109,222 cost difference). The totals of travel and treatment time for N+I and D+T were 58 hours and 3.9 hours per patient, respectively, of which total infusion time for N+I accounted for a majority - 59% - of the 58 hours. Sensitivity analyses indicated that results were most sensitive to model inputs for median PFS, body weight, and drug cost. Moreover, D+T is likely associated with a lower cost per month of PFS and cost per responder than N+I, except at low body weights (less than 57 kg).
  
  
  CONCLUSIONS
  The model presented in this study was used to analyze the clinical and economic benefit of using combination therapies in advanced melanoma patients with the BRAF V600 mutation. This analysis suggests D+T therapy is associated with less patient time and lower costs relative to N+I to gain similar PFS and overall response rate (ORR) benefits.
authors.affiliation: Precision Health Economics, 101 Tremont St. Suite 400, Boston, MA 02108, USA;
authors.forename: Ivar S
authors.initials: IS
authors.lastname: Jensen
authors.affiliation: Precision Health Economics, 209 Delburg St. Suite 106, Davidson, NC 28036, USA;; University of North Carolina at Charlotte, 9201 University City Blvd,Charlotte, NC 28223, USA;
authors.forename: Emily
authors.initials: E
authors.lastname: Zacherle
authors.affiliation: Precision Health Economics, 209 Delburg St. Suite 106, Davidson, NC 28036, USA;; University of North Carolina at Charlotte, 9201 University City Blvd,Charlotte, NC 28223, USA;
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Blanchette
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, BLDG 315, 5550B, East Hanover, NJ 07936, USA;
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: University of California at Los Angelos, 11100 Santa Monica Blvd. Suite 500, Los Angelos, CA 90025, USA.
authors.forename: Wes
authors.initials: W
authors.lastname: Yin
keywords: BRAF V600E mutation-positive; combination therapy; cost-benefit model; dabrafenib; immunotherapy; metastatic melanoma; targeted therapy; trametinib