Twelve-Month Cost per Responder (CPR) Analysis of Nilotinib and Dasatinib As Front-Line Therapy in Patients with Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
Authors: Guerin Annie , Revol Cindy , Ramanakumar Agnihotram V. , Foster Rebekah , Wu Eric Qiong , Mhatre Shivani K , Chen Lei 
Published: October 2019

Abstract
Introduction: Nilotinib and dasatinib, two second-generation tyrosine kinase inhibitors (TKIs), have been associated with higher rates of molecular response compared to imatinib in the treatment of newly diagnosed CML-CP patients based on the ENESTnd and DASISION trials. A published indirect comparison study of efficacy outcomes between nilotinib and dasatinib showed that nilotinib had significantly higher rates of molecular response by 12 months compared to dasatinib: major molecular response (MMR; defined as BCR/ABL1 level ≤0.1% on International Scale [IS]): 56.1% vs. 45.9%; MR4.0 (BCR/ABL1 level ≤0.01% on IS): 20.6% vs.12.0%; and MR4.5 (BCR/ABL1 level ≤0.0032% on IS): 10.2% vs. 3.1% for nilotinib and dasatinib, respectively. However, little is known about the costs associated with achieving molecular response. This study estimated and compared the CPR for the first 12 months of nilotinib and dasatinib for the treatment of Ph+ CML-CP in a front-line setting from a US payer’s perspective.
Methods: A 12 month CPR model of nilotinib and dasatinib was constructed, where MMR by 12 months was used to define a responder and the rates were from the published indirect comparison study. The two model cost components were 12 month treatment costs and treatment-related grade 3/4 adverse event (AE) costs. Treatment costs were estimated based on drug price (wholesale acquisition cost), median dose and discontinuation rate. Drug prices by dose were extracted from the Red Book Online®. Median doses and discontinuation rates were from the ENESTnd, DASISION and the 2nd-line trials of nilotinib and dasatinib. Discontinuation was assumed to occur at a constant rate over the 12 months. Patients who discontinued the initial treatment were assumed to switch to the other second-generation TKI and remain on this for the rest of the first year. No patient was assumed to die within the first 12 months, i.e. no patients discontinued due to death. AE costs were estimated based on AE rates and the costs of treating the AE: treatment-related rates of grade 3/4 AEs were obtained from the clinical trials and direct medical costs were obtained from published literature. Because the definition of AEs may differ across the two trials, AE rates were adjusted relative to the AE rates observed in the imatinib arms of the two trials. The 12 month CPR for each treatment was calculated as the sum of the 1st-line treatment costs, the 2nd-line treatment costs (after a switch), and the grade 3/4 AE costs incurred by responders and non-responders, divided by the MMR rate. All costs were presented in 2014 USD. One-way sensitivity analyses varying the response definition (including MR4.0 and MR4.5) and AE costs were conducted.
Results: The 12 month CPR was $202,840 for nilotinib and $248,919 for dasatinib (difference=$46,079; p <0.05). Costs of neutropenia, thrombocytopenia and anemia were the driving factor behind AE costs; these costs in the nilotinib arm were about half (53%) of the costs for of these AEs in the dasatinib arm. In one-way sensitivity analyses with responders defined based on MR4.0 and MR4.5, the differences in CPR between the two drugs were even greater: CPR for nilotinib was 42% and 70% (both p<0.05) lower than that for dasatinib for MR4.0 and MR4.5, respectively. In one-way sensitivity analyses that varied the costs of AEs to their lower and upper bounds, CPR ranged from $201,277 to $217,298 for nilotinib and $245,245 to $280,568 for dasatnib. Nilotinib’s CPR was 17.9% and 22.6% (both p<0.05) lower than dasatinib’s CPR for the low and high AE cost estimates, respectively.
Conclusion: This analysis demonstrates that, compared to dasatinib, front-line therapy with nilotinib is associated with a lower CPR during the first 12 months in patients with newly diagnosed CML-CP from a US payer’s perspective
Abstract 1304. Table 1. CPR Results Response Rates* Treatment Costs Grade 3 / 4 AE Costs CPR CPR Difference(Nilo – Dasa) Nilo Dasa Nilo Dasa Nilo Dasa Nilo Dasa MMR 56.1% 45.9% $112,024 $110,901 $1,769 $3,353 $202,840 $248,919 -$46,079 p <0.05 MR4.0 20.6% 12.0% $552,394 $952,117 -$399,723 p <0.05 MR4.5 10.2% 3.1% $1,115,619 $3,685,613 -$2,569,994 p <0.05
Nilo: Nilotinib; Dasa: Dasatinib
*Signorovitch, J.E., et al. One-year and longer-term molecular responses to nilotinib and dasatinib for newly diagnosed chronic myeloid leukemia: a matching-adjusted indirect comparison. Abstract presented at American Society for Clinical Oncology, Chicago, May 30-June 3, 2014.

Disclosures
Guerin: Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Revol:Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Ramanakumar:Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Foster:Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Wu:Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Mhatre:Novartis Pharmaceuticals Corporation: Employment. Chen:Novartis Pharmaceuticals Corporation: Employment, Stock options Other.