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Cost-Effectiveness Analysis of Pertuzumab Plus Trastuzumab and Docetaxel Compared With Trastuzumab and Docetaxel in the Adjuvant Treatment of Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer in Colombia

Open AccessPublished:September 30, 2022DOI:https://doi.org/10.1016/j.vhri.2022.08.002

      Highlights

      • The addition of pertuzumab to docetaxel plus trastuzumab improves survival in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer.
      • The docetaxel plus trastuzumab plus pertuzumab scheme has a low probability of being cost-effective compared with docetaxel plus trastuzumab from the perspective of the Colombian health system.
      • The payment of pertuzumab by the Colombian health system in chemotherapy schemes for human epidermal growth factor receptor 2–positive metastatic breast cancer has a high probability of loss in net monetary benefit.

      Abstract

      Objectives

      The addition of pertuzumab to the scheme of docetaxel plus trastuzumab (TH) in patients with metastatic breast cancer with overexpression of human epidermal growth factor receptor 2 increases survival. Nevertheless, this addition could represent a high cost for the health system of a middle-income country such as Colombia. Therefore, it is necessary to evaluate the efficiency of the pertuzumab plus TH (PTH) scheme in comparison with TH.

      Methods

      A partitioned survival model-based cost-utility analysis was performed. Progression-free survival and overall survival curves for each scheme were obtained from the CLEOPATRA study. The time horizon was 30 years with a discount rate of 5% for costs and quality-adjusted life-years. Total direct costs were calculated using national tariffs. Utilities were obtained from external sources. Model uncertainty was evaluated by deterministic and probabilistic sensitivity analysis. A willingness to pay value of 5180 US dollars was used.

      Results

      The discounted total average costs of TH and PTH were $24 109 and $60 846, respectively. These regimens’ average life-years were 5.78 and 8.38, and their quality-adjusted life-years were 3.28 and 4.51, respectively. The incremental cost-effectiveness ratio was $29 867. One-way sensitivity analysis showed that the cost of pertuzumab was the variable that explained the uncertainty in the model. The probability that PTH is cost-effective in the probabilistic sensitivity analysis is 0.0724.

      Conclusions

      The addition of pertuzumab to the TH regimen in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer has a low probability of being cost-effective from the payer’s perspective in the Colombian health system.

      Keywords

      Introduction

      Breast cancer is the first cause of cancer-related mortality in Colombia, and it represents a significant burden on the health system. This condition accounted for 17.2 deaths per 100 000 inhabitants by 2018, according to the National Institutes of Health.
      • Jimenez Herrera M.P.
      Informe de evento cáncer de mama y cuello uterino en Colombia, 2018. Instituto Nacional de Salud.
      Moreover, the incidence was 63.9 cases per 100 000 women older than 15 years, with 13 376 new cases that year. According to the stage, the costs can vary from 8 996 987 to 144 400 865 Colombian pesos.
      • Gamboa O.
      • Buitrago LA.
      • Lozano T.
      • et al.
      Direct costs of breast cancer care in Colombia.
      Although breast cancer confines a single organ, it is not a unique type of disease.
      • Yeo S.K.
      • Guan J.L.
      Breast cancer: multiple subtypes within a tumor?.
      With overexpression of human epidermal growth factor receptor 2 (HER2 positive), breast cancer has been associated with significant clinical and histological aggressiveness, an increased risk of lymphatic and hematogenous spread, less hormone dependence, and an increased risk of recurrence and death.
      • Fletscher Covaleda P.M.
      Informe de Evaluación de Tecnología Sanitaria Inclusión del pertuzumab al tratamiento habitual (trastuzumab + docetaxel) de mujeres con cáncer de mama metastásico HER2 positivo. Universidad Santo Tomas.
      It is estimated that 1 in every 5 women affected with breast cancer is HER2 positive.
      Fondo Colombiano de Enfermedades de Alto Costo
      Situación del cáncer en la población adulta atendida en el SGSSS de Colombia 2020.
      This receptor has become one of the most important therapeutic targets.
      • Fletscher Covaleda P.M.
      Informe de Evaluación de Tecnología Sanitaria Inclusión del pertuzumab al tratamiento habitual (trastuzumab + docetaxel) de mujeres con cáncer de mama metastásico HER2 positivo. Universidad Santo Tomas.
      Targeted biological therapies such as trastuzumab, pertuzumab, and lapatinib are commonly used to treat HER2-positive cancers.
      National Comprehensive Cancer Network
      Breast cancer guidelines.
      These anti-HER2 targeted antibodies have improved the prognosis of patients with HER2-positive metastatic breast cancer (MBC). These agents demonstrated mortality and progression reduction.
      • Fletscher Covaleda P.M.
      Informe de Evaluación de Tecnología Sanitaria Inclusión del pertuzumab al tratamiento habitual (trastuzumab + docetaxel) de mujeres con cáncer de mama metastásico HER2 positivo. Universidad Santo Tomas.
      ,
      • Gogate A.
      • Rotter J.S.
      • Trogdon J.G.
      • et al.
      An updated systematic review of the cost-effectiveness of therapies for metastatic breast cancer.
      ,
      • Swain S.M.
      • Miles D.
      • Kim S.B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (Cleopatra): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      These benefits have led to the proposal of combined therapeutic regimens (ie, using 2 different antibodies) to enhance efficacy in this subgroup of patients. For this reason, the clinical practice guidelines of the National Comprehensive Cancer Network recommend a combined scheme with 2 immunotherapy agents for the management of these patients.
      National Comprehensive Cancer Network
      Breast cancer guidelines.
      Nevertheless, they have significantly increased costs for health systems.
      • Fletscher Covaleda P.M.
      Informe de Evaluación de Tecnología Sanitaria Inclusión del pertuzumab al tratamiento habitual (trastuzumab + docetaxel) de mujeres con cáncer de mama metastásico HER2 positivo. Universidad Santo Tomas.
      Studies in high-income countries have shown that the addition of pertuzumab can be prohibitively expensive, even for them. For this reason, regulatory agencies such as the National Institute of Clinical Excellence in the United Kingdom or Ontario’s Committee to Evaluate Drugs recommend against funding with health system resources.
      Ministry of Health and Long-Term Care
      Pertuzumab/trastuzumab.
      , In Colombia, a model-based economic evaluation by Saenz
      • Saenz A.S.A.
      Cost-effectiveness model of pertuzumab in combination with trastuzumab and docetaxel compared with trastuzumab in combination with docetaxel for the 1st line treatment of HER2+ metastatic breast cancer in Colombia.
      in 2014 showed that the addition of pertuzumab to the trastuzumab and docetaxel scheme was not cost-effective. Nevertheless, the effectiveness data were drawn from the 2014 CLEOPATRA study with a shorter follow-up. In addition, the cost data for that drug were provided by the manufacturer and were not subject to regulation. Currently, the 4 drugs recommended as the first line in managing the different stages of this condition (ie, trastuzumab, pertuzumab, docetaxel, and trastuzumab emtansine) are regulated by the Colombian Ministry of Health. An economic evaluation with more extended follow-up data and regulated drug costs could provide technical elements for decision makers in the Colombian context.
      The objective of this study is to estimate the cost-effectiveness of pertuzumab plus trastuzumab and docetaxel (PTH) versus trastuzumab plus docetaxel (TH) in patients with MBC from the payer’s perspective in Colombia under the context of regulated prices.

      Methods

      Setting and Location

      A model-based cost-effectiveness analysis was conducted to estimate the efficiency of PTH versus TH schemes from the public payer’s perspective in the Colombian health system.
      The Colombian health system is based on a market mechanism. The Ministry of Health is the regulator, the health-promoting entities (Entidad Promotora de Salud) are the insurers/payers, and the health institutions (Institución Prestadora de Salud [IPS]) are the service providers. Entidad Promotora de Salud and IPS may be public or private. In addition, the IPS can be of the primary, secondary, or tertiary level of complexity. The context of this economic evaluation is for tertiary-level health institutions.

      Patients

      The population of this evaluation corresponds to the inclusion criteria used in the CLEOPATRA study: women aged 18 years or older diagnosed of MBC, HER2 positive with Eastern Cooperative Oncology Group 0 to 1. Patients should not have been treated with biologics in the previous 12 months. Patients may have positive or negative receptors for estrogen and progesterone.
      • Swain S.M.
      • Miles D.
      • Kim S.B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (Cleopatra): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      Analysis by patient subgroup was not performed.

      Alternatives

      The alternatives evaluated were TH versus PTH. The dose of docetaxel was 75 milligrams per square meter of body surface (mg/m2). Trastuzumab was administered at a loading dose of 8 mg per kilogram (mg/kg), followed by a 6 mg/kg maintenance dose. The loading dose of pertuzumab was 840 mg and then 420 mg. All drugs were administered intravenously in cycles once every 3 weeks. Patients received endocrine therapy if they were estrogen or progesterone receptor positive. These alternatives were chosen because they are recommended by the National Comprehensive Cancer Network guidelines and the breast cancer Colombian clinical guidelines.
      National Comprehensive Cancer Network
      Breast cancer guidelines.
      ,
      Ministerio de Salud de Colombia
      Guía de práctica clínica (GPC) para la detección temprana, tratamiento integral, seguimiento y rehabilitación del cáncer de mama.
      The time horizon was 30 years. This time horizon is based on the recommendation of the Colombian economic evaluation guideline, which establishes that it should be modeled over the entire life expectancy.
      Instituto de Evaluación Tecnológica de Colombia
      Guidelines for the economic evaluation of healthcare technologies in Colombia: technical support documents.
      According to the CLEOPATRA study, the mean age of the patients was 54 years.
      • Swain S.M.
      • Miles D.
      • Kim S.B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (Cleopatra): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      In Colombia, life expectancy for women is 80 years.
      Departamento Administrativo Nacional de Estadística
      Estimaciones del cambio demográfico.
      Thus, this time horizon covers the life expectancy of women in our country. According to the same methodological guideline, a discount rate for costs and health outcomes of 5% was used.
      This economic evaluation was based on a clinical trial (CLEOPATRA) that lasted approximately 10 years, so additional analysis with this temporal horizon was performed.

      Effectiveness, Health Outcomes, and Preferences

      To identify systematic reviews or clinical trials that evaluated the effectiveness, a literature review was performed in PubMed, EBSCO, and Science Direct between August 1 and October 13, 2021. The search terms used were as follows: ("pertuzumab"[Supplementary Concept] OR "pertuzumab"[All Fields]) AND ("breast neoplasms"[MeSH Terms] OR ("breast"[All Fields] AND "neoplasms"[All Fields]) OR "breast neoplasms"[All Fields] OR ("breast"[All Fields] AND "cancer"[All Fields]) OR "breast cancer"[All Fields]) AND (clinical trial[Filter] OR meta-analysis[Filter] OR randomized controlled trial[Filter] OR systematic review[Filter]). Only phase 3 or 4 studies were considered. Studies must be published in English or Spanish.
      Although no systematic review was found, 5 potential pivotal studies were evaluated for the model. The CLEOPATRA study was chosen for modeling progression-free survival (PFS) and overall survival (OS) because it has the most prolonged follow-up period.
      The CLEOPATRA study was a phase III, randomized, double-blind, placebo-controlled, multicenter international clinical trial conducted to investigate the use of PTH as a first-line treatment for participants with HER2-positive MBC. Median OS was 37.6 months (95% confidence interval [CI] 34.3-not estimable) in the placebo group but was not reached (95% CI 42.4-not estimable) in the pertuzumab group. The hazard ratio was 0.66, and 95% CI was 0.52-0.84. Median PFS was 12.4 months (95% CI 10.4-13.5) in the placebo group and 18.7 months (16.6-21.6) in the pertuzumab group (hazard ratio 0.69; 95% CI 0.58-0.81).
      • Swain S.M.
      • Miles D.
      • Kim S.B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (Cleopatra): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      The measure of effectiveness calculated was life-years gained. Each alternative’s total life-years are years in the progression-free period (PFP) and postprogression period (PPP). The years in PFP are estimated by calculating the area under the curve (AUC) of the PFS curve. The years in PPP are estimated by calculating the AUC between the PFS and OS curves.
      According to the methodological economic guideline for economic evaluation in Colombia, health outcomes were measured in quality-adjusted life-years (QALYs).
      Instituto de Evaluación Tecnológica de Colombia
      Guidelines for the economic evaluation of healthcare technologies in Colombia: technical support documents.
      This outcome is appropriate for this type of pathology where the quality of life is a significant aspect of patient care. Unfortunately, in our country, we do not have reliable data on the utilities of the different health states in this condition. For this reason, utility weights were extracted from the Cost-Effectiveness Registry of the Center for the Evaluation of Value and Risk at Tufts Medical Center.
      Center for the Evaluation of Value and the Risk in Health
      Cost Effectiveness Analysis Registry.
      Two clinical trials evaluated the utilities of these patients for PFP and PPP.
      • Attard C.L.
      • Pepper A.N.
      • Brown S.T.
      • et al.
      Cost-effectiveness analysis of neoadjuvant pertuzumab and trastuzumab therapy for locally advanced, inflammatory, or early HER2-positive breast cancer in Canada.
      ,
      • Hassett M.J.
      • Li H.
      • Burstein H.J.
      • Punglia R.S.
      Neoadjuvant treatment strategies for HER2-positive breast cancer: cost-effectiveness and quality of life outcomes.

      Choice of Model and Assumptions

      A partitioned survival model (PSM) was used. This model is widely accepted and validated for economic evaluations in oncology.
      • Woods B.S.
      • Sideris E.
      • Palmer S.
      • et al.
      Partitioned survival and state transition models for healthcare decision making in oncology: where are we now?.
      ,
      • Rui M.
      • Wang Y.
      • Fei Z.
      • et al.
      Will the Markov model and partitioned survival model lead to different results? A review of recent economic evidence of cancer treatments.
      This model uses Kaplan-Meier (KM) curves for OS and PFS. The AUC under the PFS curve indicates the average time in PFP. In contrast, the AUC between the OS and PFS curves indicates the average time in the PPP.
      The KM curves from the CLEOPATRA study were used in our evaluation.
      • Swain S.M.
      • Miles D.
      • Kim S.B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (Cleopatra): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      These curves were selected because they provide long-term information (ie, approximately 10 years). This duration decreases the risk derived from the extrapolation of these curves in this type of model.
      The proportion of patients without progression or alive during the follow-up period was obtained from the PFS and OS curves. These values were obtained using the free-to-use WebPlotDigitizer website (web based tool developed by Ankit Rohatgi version 4.5).
      • Rohatgi A.
      WebPlotDigitizer-Extract data from plots, images, and maps. WebPlotDigitizer.
      The values in the OS curves for the TH and PTH were 250 and 222, respectively. The PFS curves for TH and PTH yielded 194 and 208 values, respectively.
      The values were entered into TreeAge Pro 2021 software (TreeAge Software, LLC, Williamstown, Massachusetts). The curves were then reproduced in the software for validation.
      The visual validation was performed by comparing the fitness between the curves generated by the software and the original ones, furthermore verifying that the medians of the study curves were the same as the original curves. The curves are presented in the Appendix in Supplemental Materials found at https://doi.org/10.1016/j.vhri.2022.08.002.
      The model structure is presented in Figure 1.
      Figure thumbnail gr1
      Figure 1Model structure.
      HER2 indicates human epidermal growth factor receptor 2.

      Resources and Costs

      According to the perspective used, only direct health costs were considered. The health resources were identified for PFP and PPP. The health resources included the acquisition and administration of drugs, severe adverse events, analytical tests, chest x-ray before chemotherapy, mammography, thoracoabdominal computerized tomography, and magnetic resonance.
      The reference case was assumed to calculate medication dosage with a body surface area of 1.6 m2 and bodyweight of 59 kg (50.6 and 62.5 kg). The quantities of health resources and their costs are presented in Table 1
      • Swain S.M.
      • Miles D.
      • Kim S.B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (Cleopatra): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      ,
      Center for the Evaluation of Value and the Risk in Health
      Cost Effectiveness Analysis Registry.
      • Attard C.L.
      • Pepper A.N.
      • Brown S.T.
      • et al.
      Cost-effectiveness analysis of neoadjuvant pertuzumab and trastuzumab therapy for locally advanced, inflammatory, or early HER2-positive breast cancer in Canada.
      • Hassett M.J.
      • Li H.
      • Burstein H.J.
      • Punglia R.S.
      Neoadjuvant treatment strategies for HER2-positive breast cancer: cost-effectiveness and quality of life outcomes.
      • Woods B.S.
      • Sideris E.
      • Palmer S.
      • et al.
      Partitioned survival and state transition models for healthcare decision making in oncology: where are we now?.
      ,
      Instituto de Seguros Sociales
      Acuerdo 256 del 2001. Manual de tarifas de la Entidad Promotora de Salud del Seguro Social-EPS-ISS.
      Comisión Nacional de precios de medicamentos y dispositivos médicos
      Circular número 12 de 2021.
      • León Guzmán E.
      • Gamboa Garay O.A.
      • Gamboa Garay C.A.
      • et al.
      Análisis de impacto presupuestal de la radioterapia para el tratamiento de cáncer de mama en Colombia.
      • Aristizábal J.C.
      • Giraldo A.
      Comparison of three bioimpedance techniques with hydrodensitometry for assessment of body composition in young adult women.
      • Aristizabal J.C.
      • Estrada-Restrepo A.
      • García A.G.
      Development and validation of anthropometric equations to estimate body composition in adult women.
      • Montoya-Restrepo M.E.
      • Gómez Wolff L.R.
      • Sánchez Jiménez A.V.
      • García García H.I.
      Características y supervivencia de pacientes con cáncer de seno metastásico HER2-positivo en la era post-trastuzumab.
      • Yi M.
      • Huo L.
      • Koenig K.B.
      • et al.
      Which threshold for ER positivity? a retrospective study based on 9639 patients.
      • Lema M
      • Preciado B
      • Quiceno D
      • et al.
      Management costs of febrile neutropenia in oncology patients in Colombia.
      .
      Table 1Parameter of model.
      Parameter
      Costs are expressed as US dollars.
      ValueLower valueUpper valueReference
      Clinical parameters
      Body surface area (m2)1.624
      Body weight (kg)5950.662.525,26
      Probability of febrile neutropenia in trastuzumab0.058
      Probability of febrile neutropenia with pertuzumab0.11
      Proportion of patients with positive estrogen receptor0.380.6027,28
      Costs ($)
      Costs are expressed as US dollars.
      Cost of diagnostics tests
      Cell blood count3.472.894.1621
      Total bilirubin1.691.412.0
      Aspartate aminotransferase level1.1811.42
      Alanine aminotransferase level1.531.281.84
      Alkaline phosphatase1.291.081.55
      Serum creatinine1.050.881.26
      International normalized ratio and activated partial thromboplastin time3.172.643.8
      Chest x-ray6.995.838.39
      Mammography24.720.629.6
      Thoracoabdominal Computerized tomography44.5937.1553.5
      Magnetic resonance imaging thoracoabdominal124103.3149
      Cost of medications and procedures
      Docetaxel (cost per mg)1.91.582.2822
      Trastuzumab (cost per mg)2.102.5
      Pertuzumab (cost per mg)4.9806
      Trastuzumab emtansine (cost per mg)14.4017.317,18
      Administration of a cycle of chemotherapy83.87010121
      Tamoxifen (cost per tablet)0.190.090.6423
      Oxygen (cost per one month)18.2115.1721.85
      Acetaminophen (cost per tablet)0.00360.00300.01723
      Morphine (cost per vial)0.0760.060.09
      Acetaminophen/codeine (cost per tablet)0.0850.0500.42
      Tramadol (cost per tablet)0.400.390.47
      Bisacodyl (cost per tablet)0.0220.0110.056
      Metoclopramide (cost per tablet)0.020.010.02
      Oncologist (cost per visit)4.53.755.421
      Psycho-oncology (cost per visit)2.181.812.61
      Palliativist (cost per visit)4.233.535.08
      Social work (cost per visit)1.891.582.27
      Radical mastectomy (cost per package)755629906
      Febrile neutropenia (cost per event)9251421.70829
      Quantities (through the entire time horizon)
      Cell blood count814115
      Total bilirubin8141
      Aspartate aminotransferase level8141
      Alanine aminotransferase level8141
      Alkaline phosphatase8141
      Serum creatinine8141
      International normalized ratio and activated partial thromboplastin time8141
      Dose of docetaxel75 mg/m250 mg/m2100 mg/m28,16
      Dose of trastuzumab (load)8 mg/kg--
      Dose of trastuzumab (maintenance)6 mg/kg--
      Dose of pertuzumab (load)840 mg--
      Dose of pertuzumab (maintenance)420 mg--
      Dose of trastuzumab emtansine (mg/kg)3.6--
      Cycles docetaxel814115
      Cycles trastuzumab1515016
      Cycles trastuzumab emtansine4.511617
      Cycles pertuzumab1815616
      Mammography10112017,18
      Utilities
      Postmastectomy0.87--
      PFS under treatment with docetaxel plus trastuzumab0.938---15
      PFS under treatment with docetaxel plus trastuzumab plus pertuzumab0.875--
      PFS without treatment0.99--
      Postprogression under treatment with trastuzumab emtansine0.603--
      PFS indicates progression-free survival.
      Costs are expressed as US dollars.
      All patients entered the model in a PFP. On admission, all underwent extended mastectomy with nodal resection.
      Mastectomy costs included surgeon, anesthesiologist, operating room fees, surgical supplies, and postsurgical hospitalization. The cost of breast reconstruction was not included, given the perspective used in this evaluation. According to the health benefit plan at this evaluation, this is a cosmetic procedure.
      The patients underwent 25 sessions of intensity-modulated or 3D conformal external beam radiation therapy 1 month later. They received the chemotherapy schedules described previously. For each chemotherapy cycle, laboratory costs were calculated (ie, cell blood count, creatinine, blood urea nitrogen, alkaline phosphatase, alanine aminotransaminase, and aspartate aminotransaminase). The costs of chemotherapy administration and supervision by clinical oncology were also included.
      After completing the chemotherapy sessions, the patients continued being followed up with clinical oncology. Follow-up included annual mammography and tamoxifen for 5 years if the patient has positive estrogen receptors. Visits were made twice a year for the first 5 years. After that, they have performed annually for the entire time horizon.
      Patients entered the PPP if they presented the first radiological evidence of progression according to the Response Evaluation Criteria in Solid Tumors. In this case, patients received chemotherapy with trastuzumab emtansine at a 3.6 mg/kg dose with an average of 4.5 cycles per patient according to the TH3RESA and EMILIA trials.
      • Krop I.E.
      • Kim S.B.
      • González-Martín A.
      • et al.
      Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial.
      ,
      • Verma S.
      • Miles D.
      • Gianni L.
      • et al.
      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      Furthermore, this scheme is recommended by the national guidelines for breast cancer management.
      Ministerio de Salud de Colombia
      Guía de práctica clínica (GPC) para la detección temprana, tratamiento integral, seguimiento y rehabilitación del cáncer de mama.
      In this state, chemotherapy and palliative care costs were included. Palliative care costs included monthly consultations for oncology psychologists, palliative physicians, and clinical oncologists. Costs for analgesics (ie, morphine, tramadol, and acetaminophen) and home oxygen were also included. A group of palliative physicians was consulted to quantify the resources in the PPP.
      The resources included in the model were valued using the national tariffs and circulars. Procedures (eg, mastectomy and chemotherapy administration) and diagnostic aids were valued using the Social Security Tariff Manual (Manual Tarifario del Seguro Social).
      Instituto de Seguros Sociales
      Acuerdo 256 del 2001. Manual de tarifas de la Entidad Promotora de Salud del Seguro Social-EPS-ISS.
      Docetaxel, trastuzumab, pertuzumab, and trastuzumab emtansine were valued according to circular 12 of 2021.
      Comisión Nacional de precios de medicamentos y dispositivos médicos
      Circular número 12 de 2021.
      This circular is the official document issued by the Colombian Ministry of Health where the value per milligram for these drugs is established. The drugs other than chemotherapy were obtained from the Drug Price Information System (Sistema de Información de Precios del Medicamento). In this platform, the Ministry of Health shows the value of nonregulated drugs.
      The following assumptions were made: (1) All patients received the complete chemotherapy regimen in both states. (2) All patients without progression received clinical follow-up by oncology in the PFP period. (3) Febrile neutropenia was the only adverse effect incorporated into the model because of its impact on cost. Although other adverse effects were more frequent than febrile neutropenia (eg, diarrhea), they do not significantly affect the costs. (4) Febrile neutropenia was only considered after cycles 1 and 2. The chances of having febrile neutropenia after cycle 3 are less than 1%.
      • Swain S.M.
      • Miles D.
      • Kim S.B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (Cleopatra): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      (5) Costs of treating febrile neutropenia are the same for the 2 alternatives assessed.
      The PSM was evaluated with TreeAge Health Pro® 2021 software (TreeAge Software, LLC, Williamstown, Massachusetts).

      Extrapolation of the Curves

      The CLEOPATRA study obtained data up to 10 years of follow-up. To assess the probability of remaining in each state in the long-term (ie, 30 years), the survival function that best fitted the KM curves of that study was calculated. The parametric survival models evaluated were exponential, Weibull, Gompertz, log-normal, log-logistic, and gamma.
      For this purpose, the ordered pairs were entered into the SurvHE package in R studio (package developed by Gianluca Baio).
      • Baio G.
      survHE: Survival Analysis fo Health Economic Evaluation and Cost-Effectiveness Modeling.
      This package estimated the individual data at the patient level. From these data, the goodness of fit of the models mentioned earlier was evaluated using the Akaike information criteria. The model with the lowest Akaike information criteria was selected. Visual validation was performed by contrasting the survival values obtained from the curve and those calculated with the model (Appendix in Supplemental Materials found at https://doi.org/10.1016/j.vhri.2022.08.002).
      The following equations represent the survival functions used in the model:
      OSTH=1t1.643.517411.64+t1.64


      PFSTH=1t1.491.1441.49+t1.49


      OSPTH=1ΦLnt1.6561.1263


      PFSPTH=1Φ(Ln(t)0.6170.192)


      where φ represents the cumulative standard normal distribution

      Currency, Price Date, and Conversion

      The costs were expressed in US dollars at the current exchange rate ($1 US dollar = 3844 Colombian pesos). The exchange rate date was October 2021, according to Banco de la República.

      Incremental Analysis

      The incremental cost-effectiveness ratio (ICER) was calculated as represented in the following equation:
      ICER=CostPTHCostTHQALYPTHQALYTH


      The comparator was considered cost-effective if ICER < $5180. According to a recent study, this value was proposed as the willingness-to-pay (WTP) threshold in Colombia.
      • Espinosa O.
      • Rodríguez-Lesmes P.
      • Orozco L.
      • et al.
      Estimating cost-effectiveness thresholds under a managed healthcare system: experiences from Colombia.
      In addition, a net monetary benefit (NMB) for each alternative was calculated. This metric is represented in the following equation:
      NMB=(QALY×λ)Cost


      where λ represents the WTP in our country.
      Under this framework, an alternative is considered cost-effective if NMB ≥ 0.

      Uncertainty

      This type of model cannot evaluate patient heterogeneity and structural uncertainty.
      Parameter uncertainty was evaluated with univariate and stochastic analysis. In the univariate analysis, the ICER was calculated for the different values of the variables presented in Table 1
      • Swain S.M.
      • Miles D.
      • Kim S.B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (Cleopatra): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      ,
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      • et al.
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      • Hassett M.J.
      • Li H.
      • Burstein H.J.
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      Neoadjuvant treatment strategies for HER2-positive breast cancer: cost-effectiveness and quality of life outcomes.
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      • et al.
      Partitioned survival and state transition models for healthcare decision making in oncology: where are we now?.
      ,
      Instituto de Seguros Sociales
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      Comisión Nacional de precios de medicamentos y dispositivos médicos
      Circular número 12 de 2021.
      • León Guzmán E.
      • Gamboa Garay O.A.
      • Gamboa Garay C.A.
      • et al.
      Análisis de impacto presupuestal de la radioterapia para el tratamiento de cáncer de mama en Colombia.
      • Aristizábal J.C.
      • Giraldo A.
      Comparison of three bioimpedance techniques with hydrodensitometry for assessment of body composition in young adult women.
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      • Estrada-Restrepo A.
      • García A.G.
      Development and validation of anthropometric equations to estimate body composition in adult women.
      • Montoya-Restrepo M.E.
      • Gómez Wolff L.R.
      • Sánchez Jiménez A.V.
      • García García H.I.
      Características y supervivencia de pacientes con cáncer de seno metastásico HER2-positivo en la era post-trastuzumab.
      • Yi M.
      • Huo L.
      • Koenig K.B.
      • et al.
      Which threshold for ER positivity? a retrospective study based on 9639 patients.
      • Lema M
      • Preciado B
      • Quiceno D
      • et al.
      Management costs of febrile neutropenia in oncology patients in Colombia.
      A sensitivity analysis was performed for the cost of pertuzumab, trastuzumab, and trastuzumab emtansine equal to 0; this means that the health system payer would not absorb the costs of these drugs. Tornado diagrams were plotted for the variables that most modified the ICER.
      A second-order Monte Carlo simulation with 10 000 iterations was performed for the stochastic analysis. Different probability distributions were used for the simulation according to the variable to be modeled. The probabilities of clinical events other than progression or death (eg, probability of febrile neutropenia) and the utilities of each health state and events were modeled with beta distribution, the resource quantities were modeled with Poisson distribution, and the physiological variables (eg, body surface area) were modeled with normal distribution. Costs were modeled with uniform distribution. Although this last type of distribution is not recommended, it was used because the costs are obtained from a tariff that does not show dispersion values. The distributions and their parameters used in the simulation are presented in the Appendix in Supplemental Materials found at https://doi.org/10.1016/j.vhri.2022.08.002.

      Results

      Base Case Analysis 10 Years

      The expected life-years gained, costs, and QALY for each alternative are presented in Table 2. According to the model, the addition of pertuzumab to the TH scheme adds 1.17 life-years and 0.75 QALYs. The expected discounted incremental cost would be $31 894. Thus, the ICER would be $42 525 per additional QALY.
      Table 2Incremental analysis.
      VariableClinical trial (10 years)Extrapolated (30 years)
      THPTHTHPTH
      Mean years per state
       PFS life-years2.213.092.343.59
       Postprogression life-years2.272.563.444.79
       Total4.485.655.788.38
       Life-years gained1.172.6
      Discounted cost
       Progression-free survival14 86548 59714 59749 042
       Postprogression73135475951211 804
       Total22 17854 07224 10960 846
       Discounted incremental cost31 89436 737
      Discounted QALY
       PFS1.792.441.802.67
       Postprogression1.141.241.481.84
       Total2.933.683.284.51
       Discounted incremental QALY0.751.23
      NMB (WTP: $5180)−7000−35 009−7118−37 484
      Discounted ICER42 52529 867
      ICER indicates incremental cost-effectiveness ratio; NMB, net monetary benefit; PFS, progression-free survival; PTH, docetaxel plus trastuzumab plus pertuzumab; TH, docetaxel plus trastuzumab; QALY, quality-adjusted life-year; WTP, willingness to pay.
      With a WTP of $5180, the NMB for TH and PTH was −$7000 and −$35 009, respectively. Thus, none of the alternatives generate benefit for the country-defined WTP in monetary terms.

      Base Case Analysis 30 Years

      The incremental analysis with a temporal horizon of 30 years also is presented in Table 2. PTH provides 8.38 years and 4.51 QALY. In contrast, TH provides 5.78 years and 3.28 QALY. Nevertheless, the cost of PTH was significantly greater in comparison with TH ($60 846 vs $24 109), with an incremental cost of $36 737.
      Using a WTP of $5180, the NMB provided by TH and PTH is −$7118 and −$37 484, respectively.

      Deterministic Sensitivity Analysis

      The ICER of the model was mainly sensitive to the cost of pertuzumab. If the cost per milligram of pertuzumab ranges from $0 to $6, the ICER ranges from $857 to $50 266/QALY. The threshold analysis reveals that PTH becomes a cost-effective alternative (ICER < $5180/QALY) if the milligram of pertuzumab costs $0.12.
      Similar behavior was presented with the 30-year time horizon. If the cost of pertuzumab fluctuates from $0 to $6, the ICER ranges from $4202 to $35 144. Tornado diagrams are presented in the Appendix in Supplemental Materials found at https://doi.org/10.1016/j.vhri.2022.08.002.

      Probabilistic Sensitivity Analysis

      The probabilistic sensitivity analysis results for both temporal horizons are presented in Table 3. When a 10-year temporal horizon was used, the mean total cost and standard deviation of TH and PTH were $16 404 ± 3651 and $37 273 ± 11 681, respectively. The mean and standard deviation of the QALY for these alternatives were 2.92 ± 0.68 and 3.68 ± 0.76, respectively.
      Table 3Probabilistic sensitivity analysis.
      ParameterDocetaxel plus trastuzumabDocetaxel plus trastuzumab plus pertuzumab
      10 years
      Mean95% lower bound95% upper boundMean95% lower bound95% upper bound
       Costs ($)16 40416 33216 47537 27337 0443702
       QALY2.922.912.943.683.673.70
       NMB ($)−1251−1351−1151−18 184−18 425−17 942
      30 years
      Mean95% lower bound95% upper boundMean95% lower bound95% upper bound
       Costs ($)17 59117 513176940 15139 95440 426
       QALY3.273.263.304.54.484.52
       NMB ($)−608−727−488−16 836−17 098−16 574
      Note. Costs and NMB are expressed as US dollars.
      NMB indicates net monetary benefit; QALY, quality-adjusted life-year.
      For the 30-year case, the mean and standard deviation of the cost of TH and PTH are 17 591 ± 3976 and 40 151 ± 12 034, respectively. QALYs are 3.27 ± 0.88 and 4.5 ± 1.089 for these alternatives.
      The incremental cost-effectiveness plane for 30 years is presented in Figure 2. The highest proportion of iterations is above the WTP line in quadrant I (92.74%). The probability that the addition of pertuzumab is cost-effective (ie, the number of iterations below the WTP line in quadrant I) was 0.0724.
      Figure thumbnail gr2
      Figure 2Incremental cost-effectiveness scatterplot.
      Most iterations (94.94%) overpassed the WTP line for the 10-year case, whereas only 5.06% were cost-effective. The Appendix in Supplemental Materials found at https://doi.org/10.1016/j.vhri.2022.08.002 can find the incremental cost-effectiveness scatterplot for 10 years.
      The acceptability curve for 30 years (Fig. 3) shows how the TH scheme is more likely to be cost-effective than PTH up to a WTP of $18 500 per QALY.
      The probability of NMB being equal or greater to 0 is different for the schemes using a WTP of $5180. The TH scheme has a probability of a positive NMB of 0.4791. In contrast, the addition of pertuzumab to this scheme decreases that probability to 0.1117.
      The relationship between NMB and WTP (Appendix in Supplemental Materials found at https://doi.org/10.1016/j.vhri.2022.08.002) shows that if WTP is $5180, none of the alternatives provides NMB greater than 0. If the WTP is $5460, the NMB is positive for TH but not for the addition of pertuzumab. The latter scheme only provides positive NMB from a WTP of $8920. If the WTP reaches $18 400, the PTH scheme provides more significant benefits than its counterpart.

      Discussion

      Historically, the treatment of MBC has represented high costs for health systems in general and the Colombian one in particular. The advent of monoclonal antibodies represented a change in the treatment paradigm of this condition and improved survival for these patients. Nevertheless, there is concern that the increasing use of chemotherapy schemes that combine several antibodies could represent a drastic increase in costs. Accordingly, our model shows that a dual immunotherapy scheme provides more gained life-years and QALY but dramatically increases healthcare costs.
      Our results are similar to other studies conducted in other countries and model types. Two PSM-based analyses evaluated the same alternatives in Singapore and Japan. They concluded that adding pertuzumab to TH is not cost-effective using their corresponding WTP.
      • Cheng L.J.
      • Loke L.
      • Lim E.H.
      • et al.
      Cost-effectiveness of pertuzumab and trastuzumab biosimilar combination therapy as initial treatment for HER2-positive metastatic breast cancer in Singapore.
      ,
      • Moriwaki K.
      • Uechi S.
      • Fujiwara T.
      • et al.
      Economic evaluation of first-line pertuzumab therapy in patients with HER2-positive metastatic breast cancer in Japan.
      Durkee et al
      • Durkee B.Y.
      • Qian Y.
      • Pollom E.L.
      • et al.
      Cost-effectiveness of pertuzumab in human epidermal growth factor receptor 2-positive metastatic breast cancer.
      evaluated the same schemes through a Markov model in the United States. Their model predicted a 0% chance of cost-effectiveness at a WTP $100 000 per QALY gained. Finally, a recent study in Canada using real-world data comparing the addition of pertuzumab plus trastuzumab with chemotherapy schedules in this population revealed that the probability of being cost-effective is less than 1%.
      • Dai W.F.
      • Beca J.M.
      • Nagamuthu C.
      • et al.
      Real-world cost-effectiveness of pertuzumab (P) with trastuzumab + chemo (T+Chemo) in patients (pts) with metastatic breast cancer (MBC): a population-based retrospective cohort study by the Canadian real-world evidence for value in cancer drugs (CanREValue) collaboration.
      These results are in line with our study.
      Different strategies can remedy the apparent low efficiency of pertuzumab addition. Ventola
      • Ventola C.L.
      Cancer immunotherapy, part 3: challenges and future trends.
      proposes that this coordination and cooperation between pharmaceutical corporations, economists, and the medical community should include the use of biomarkers with improved precision to select patients with a higher probability of response and the design and implementation of value-based reimbursement mechanisms for these drugs and the incorporation of immunoprevention strategies. Our model shows that reducing the cost per milligram of pertuzumab could become cost-effective. Univariate sensitivity analysis showed that a 98% discount in the cost per milligram of pertuzumab (ie, reducing its cost from $6 to $0.12) could reduce the ICER to less than $5180 per additional QALY. An alternative in our country is to evaluate the added value provided by these schemes using methodologies that include criteria (eg, access and equity, impact on caregivers, cultural acceptability, and technical and training requirements) beyond efficiency.
      The need to use higher or differential WTP for these patients has also been proposed. Among the reasons put forward are as follows: These treatments are indicated in a small population with a short life expectancy (24 months or less) where QALY in this population might be considered more valuable than other diseases. Society might consider paying more for end-of-life treatments, especially for reducing the suffering and physical and psychological pain.
      • Shah K.
      Does society place special value on end of life treatments?.
      • Morrell L.
      • Wordsworth S.
      • Rees S.
      • et al.
      Does the public prefer health gain for cancer patients? A systematic review of public views on cancer and its characteristics.
      • Jones-Lee M.W.
      • Hammerton M.
      • Philips P.R.
      The value of safety: results of a national sample survey.
      Other studies have shown that cancer stage, type of cancer, time since diagnosis, educational level, individual or national income, functional status, even political system, and cancer mortality rate might influence individuals to adopt different WTP.
      • Oh D.Y.
      • Crawford B.
      • Kim S.B.
      • et al.
      Evaluation of the willingness-to-pay for cancer treatment in Korean metastatic breast cancer patients: a multicenter, cross-sectional study.
      • Iwatani T.
      • Hara F.
      • Shien T.
      • et al.
      Prospective observational study estimating willingness-to-pay for breast cancer treatments through contingent valuation method in Japanese breast cancer patients (JCOG1709A).
      • Chaikumbung M.
      Democracy, culture and cancer patients’ willingness to pay for healthcare services: a meta-analysis.
      In this regard, our model showed that increasing the WTP to $8920 could produce positive NMB. Nevertheless, it is crucial to evaluate other clinical and nonclinical variables’ effects on efficacy and costs. This effect and benefit of these factors could be evaluated in a study with real-world data or multicriteria decision analysis.
      • Guevara-Cuellar C.A.
      • Rengifo-Mosquera M.P.
      • Mejía G.I.S.
      • et al.
      Value in oncology from multi-criteria decision analysis: a systematic review.
      • Camps C.
      • Badia X.
      • García-Campelo R.
      • et al.
      Development of a multicriteria decision analysis framework for evaluating and positioning oncologic treatments in clinical practice.
      • Adunlin G.
      • Diaby V.
      • Montero A.J.
      • Xiao H.
      Multicriteria decision analysis in oncology.
      Our study has several limitations. First, the PSMs did not consider patient heterogeneity. Several studies have established that multiple factors influence progression and survival in these patients.
      • Lee A.
      • Jo S.
      • Lee C.
      • et al.
      Diabetes as a prognostic factor in HER-2 positive breast cancer patients treated with targeted therapy.
      • Karakaya S.
      • Karadag I.
      • Ates O.
      • et al.
      Clinical outcomes and prognostic factors in HER-2 positive breast cancer with brain metastasis: a single-centre experience.
      • Tataroglu Ozyukseler D.
      • Basak M.
      • Ay S.
      • et al.
      Prognostic factors of ado-trastuzumab emtansine treatment in patients with metastatic HER-2 positive breast cancer.
      Second, the model assumes that there is full access to immunotherapy. Although there are no data on access to these drugs in our setting, some studies have reported access difficulties even in high-income countries.
      • Osarogiagbon R.U.
      • Sineshaw H.M.
      • Unger J.M.
      • et al.
      Immune-based cancer treatment: addressing disparities in access and outcomes.
      ,
      • De Martino M.
      • Vanpouille-Box C.
      • Galluzzi L.
      Immunological barriers to immunotherapy in primary and metastatic breast cancer.
      Third, the model was populated with data from a controlled clinical trial. Although the CLEOPATRA study is a well-designed, long-term study, it has the inherent limitations of external validity, especially in our country.
      Similarly, the utilities were obtained from a repository that could not represent our country’s actual valuation of health states. Another limitation is the absence of data about the uncertainty in the OS and PFS curves used in the model. Last but not least, the behavior of progression and survival based on extrapolated curves represents an often unrealistic assumption.
      • Guyot P.
      • Ades A.E.
      • Beasley M.
      • Lueza B.
      • Pignon J.P.
      • Welton N.J.
      Extrapolation of survival curves from cancer trials using external information.
      ,
      • Latimer N.R.
      Survival analysis for economic evaluations alongside clinical trials—extrapolation with patient-level data: inconsistencies, limitations, and a practical guide.

      Conclusion

      The addition of pertuzumab to the TH regimen in patients with HER2-positive MBC has a low probability of being cost-effective from the payer’s perspective in the Colombian health system.

      Article and Author Information

      Author Contributions: Concept and design: Guevara-Cuellar, Parody-Rúa, Conde-Crespo, Nuñez-Castro
      Acquisition of data: Guevara-Cuellar, Parody-Rúa, Rengifo-Mosquera, Conde-Crespo, Nuñez-Castro
      Analysis and interpretation of data: Guevara-Cuellar, Parody-Rúa, Rengifo-Mosquera, Conde-Crespo, Nuñez-Castro
      Drafting of the manuscript: Guevara-Cuellar, Parody-Rúa, Rengifo-Mosquera, Conde-Crespo, Nuñez-Castro
      Critical revision of paper for important intellectual content: Guevara-Cuellar, Parody-Rúa
      Statistical analysis: Guevara-Cuellar
      Administrative, technical, or logistic support: Guevara-Cuellar
      Supervision: Guevara-Cuellar
      Conflict of Interest Disclosures: The authors reported no conflicts of interest.
      Funding/Support: This study did not receive any funding from any governmental or nongovernmental organization.

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