Cost-Effectiveness Analysis of Trastuzumab Deruxtecan Versus Trastuzumab Emtansine for Patients With Human Epidermal Growth Factor Receptor 2 Positive Metastatic Breast Cancer in the United States.

OBJECTIVES: To assess the cost-effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine as second-line therapy for patients with human epidermal growth factor receptor 2 positive metastatic breast cancer from a US healthcare sector perspective. METHODS: A 3-state partitioned survival model was developed to estimate the cost-effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine. For both treatments, modeled patients were administered treatment intravenously every 3 weeks indefinitely or until disease progression. Transition parameters were principally derived from the updated DESTINY-Breast03 phase III randomized clinical trial. Costs include drug costs extracted from Centers for Medicare and Medicaid Services average sales price and administrative, adverse event, and third-line therapy costs derived from published literature, measured in 2022 US dollars. Health utilities for health states and disutilities for adverse events were sourced from published literature. Effects were measured in quality-adjusted life years (QALYs). We conducted both probabilistic sensitivity analysis and comprehensive scenario analysis to test model assumptions and robustness, while utilizing a lifetime horizon. RESULTS: In our base-case analysis, total costs for trastuzumab deruxtecan were $1 266 945, compared with $820 082 for trastuzumab emtansine. Total QALYs for trastuzumab deruxtecan were 5.09, compared with 3.15 for trastuzumab emtansine. The base-case incremental cost-effectiveness ratio was $230 285/QALY. Probabilistic sensitivity analysis indicated that trastuzumab deruxtecan had an 11.1% probability of being cost-effective at a $100 000 per QALY willingness-to-pay threshold. CONCLUSIONS: Despite the higher efficacy of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, our findings raise concern regarding its value at current prices.

Survival, treatment patterns, and costs of HER2+ metastatic breast cancer patients in Ontario between 2005 to 2020.

BACKGROUND: To enable the integration of novel therapies, it is critical to understand current long-term outcomes in HER2-positive metastatic breast cancer (mBC), including survival, treatment patterns, and costs. We sought to define these outcomes among patients with mBC in Ontario. METHODS: We conducted a retrospective population-level study in Ontario women diagnosed with breast cancer of any stage between January 1, 2005 and December 31, 2019, with follow-up until December 31, 2020. HER2-positivity was based on receipt of a HER2-targeted therapy (HER2-TT) in the first line (1L) metastatic setting. Administrative databases at ICES were used to assess outcomes. RESULTS: In Ontario, 2557 patients were diagnosed with mBC and received a HER2-TT, and of these 1606 were diagnosed with early-stage (stage I-III) that became metastatic (recurrent), while 951 were diagnosed with late stage/de novo mBC (stage IV). The average age of all patients was 54.8 years ± 12.7 years. Treatment regimens that included pertuzumab and trastuzumab (cohort name: pert_tras) were the most frequently used HER2-TT for 1L mBC (51.4%), while T-DM1 was the most frequent therapy (87.5%) in second line (2L). The median overall survival (mOS) from initiation of 1L pert_tras was not reached, whereas mOS from initiation of T-DM1 in 2L was 18.7 months. The overall mean cost per patient on pert_tras during 1L was $267,282. The main cost drivers were the cost of systemic therapy, followed by cancer clinic visits, with a mean cost per patient at $158,961 and $73,882, respectively. CONCLUSION: The baseline characteristics and treatment patterns for patients who received HER2-TT in our study align with previously reported results. However, the mOS observed for 2L T-DM1 was shorter than that found in pivotal, clinical trial literature. As expected, anti-cancer systemic therapy costs were the main contributor to the over quarter-million dollar mean cost per patient on pert_tras in 1L.

Cost-utility analysis of trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer in Chinese setting.

PURPOSE: Trastuzumab deruxtecan (T-DXd) expressed substantial improvement in the progression-free survival and overall survival contrasted with trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (mBC), becoming the second-line standard of care, promisingly. We aim to estimate the cost-utility of T-DXd versus T-DM1 in HER2-positive mBC from the Chinese healthcare perspective. METHODS: A partitioned survival model was applied to examine the cost-utility of T-DXd versus T-DM1. Clinical patients and outcome data were sourced from the DESTINY-Breast 03 trial. Costs and utilities were sourced in Chinese setting. Total costs, quality-adjusted life months (QALMs), and an incremental cost-utility ratios (ICUR) were calculated for cost-utility analysis. The willingness-to-pay threshold was set at $3188/QALM. Univariate, scenario, and probabilistic sensitivity analyses were performed. RESULTS: T-DXd group gained ∆QALM of 7.09 months and ∆Cost of $304,503 compared with T-DM1 therapy, which caused an ICUR of $42,936/QALM. The results of sensitivity analyses confirmed the base-case findings. Furthermore, T-DXd must reduce the price to enter the Chinese mainland market. At least when the cycle cost of T-DXd is reduced to $2975, T-DXd has an 83.3% chance of becoming a better choice. CONCLUSIONS: T-DXd appears to be not cost effective compared with T-DM1 for HER2-positive mBC patients previously treated with trastuzumab and a taxane.

Cost-efficiency analysis of conversion to biosimilar filgrastim for supportive cancer care and resultant expanded access analysis to supportive care and early-stage HER2+ breast cancer treatment in Saudi Arabia: simulation study.

AIMS: This study estimated, for Saudi Arabia, the cost-efficiency of converting patients from reference Neupogen and Neulastim to one of two filgrastim biosimilars (Nivestim, Zarzio); the budget-neutral expanded access to supportive care with biosimilar filgrastim and therapeutic care to ado-trastuzumab emtansine thus afforded; and the number-needed-to-convert (NNC) to provide supportive or therapeutic treatment to one patient. MATERIALS AND METHODS: Replicating prior studies, we modeled the cost-efficiencies gained from converting varying proportions of a hypothetical panel of 4,000 patients undergoing six cycles of cancer treatment from Neupogen or Neulastim to one of the two biosimilar G-CSF formulations, using national cost inputs. Cost-savings in USD were used to estimate the additional doses of biosimilar G-CSF and expanded access to ado-trastuzumab emtansine on a budget-neutral basis, and NNC to purchase one additional dose of supportive or therapeutic treatment. RESULTS: Savings from conversion from reference to a biosimilar filgrastim were $3,086,400 (Nivestim) and $3,460,800 (Zarzio). With reference pegfilgrastim, savings from conversion were $11,712,240 (Nivestim) and $12,086,640 (Zarzio). Biosimilar conversion from reference to biosimilar filgrastim enabled expanded access to ado-trastuzumab emtansine ranging from 61 patients (5 days, Nivestim) to 191 patients (14 days, Zarzio). For supportive care, biosimilar conversion enabled expanded access ranging from 8,244 patients (5 days, Nivestim) to 25,882 patients (14 days, Zarzio). For biosimilar conversion from daily filgrastim, the NNC for treatment with ado-trastuzumab emtansine decreased as days of injections increased [5 days: 395 (Nivestim), 352 (Zarzio); 14 days: 141(Nivestim), 126 (Zarzio)]. Alternately, for biosimilar conversion from single-injection pegfilgrastim to daily biosimilar filgrastim, the NNC for treatment with ado-trastuzumab emtansine rose as days of injections increased, being highest under the 14-day scenario (146, Nivestim; 130, Zarzio). CONCLUSION: This simulation study demonstrated significant potential cost-savings from biosimilar conversion. These savings provide budget-neutral increased access to supportive and therapeutic cancer care.

Trastuzumab deruxtecan versus trastuzumab emtansine for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: A cost-effectiveness analysis.

BACKGROUND: DESTINY-Breast03 (NCT03529110) was the first global phase III study to assess the antitumor activity of trastuzumab deruxtecan (T-DXd) compared to trastuzumab emtansine (T-DM1) in 2022. However, the balance between efficacy and cost of T-DXd remains unclear. As a result, the present study's goal is to investigate the cost-effectiveness of T-DXd vs T-DM1 as a second-line treatment for patients with HER2-positive MBC from the US and Chinese payer's perspectives. METHODS: A Markov model with a 20-year time horizon was developed to evaluate the overall cost of patient treatment, incremental cost-effectiveness ratio (ICER), quality-adjusted life-years (QALYs), and life-years (LYs) in the US and China at WTP levels of 150,000/QALY and 37,653/QALY, respectively (3 times GDP per capita in 2021). Key data were gathered from the US government's official website, the Xiangya Hospital of Central South University, and published literature. To determine the model's stability, a sensitivity analysis was performed. A subgroup analysis was also implemented. RESULTS: Compared with T-DM1, treatment with T-DXd generated an additional 1.672 QALYs (2.796 LYs), resulting in an ICER of $13,342/QALY (US) and $186,017/QALY (China). The cost of drugs is the most influential factor in the American and Chinese models. Subgroup analysis revealed that the T-DXd and T-DM1 regimens were more cost-effective at reducing the risk of death in the US and Chinese HER2-positive MBC patients. CONCLUSION: T-DXd as second-line treatment could gain more health benefits for HER2-positive MBC patients in comparison with T-DM1, which is considered to be cost-effective in the US but not in China.

Residual Disease Burden After Neoadjuvant Therapy Among US Patients With High-Risk HER2-positive Early-Stage Breast Cancer: A Population Effectiveness Model.

BACKGROUND: Approximately half of patients with high-risk HER2-positive early-stage breast cancer (ESBC) do not have pathologic complete response (pCR) after neoadjuvant therapy. The residual burden of disease among this population has not been previously quantified. MATERIALS AND METHODS: We used decision-modeling techniques to simulate recurrence, progression from locoregional to distant cancer, breast cancer-related mortality, and mortality from other causes over a 10-year period in a hypothetical cohort. We derived progression probabilities primarily from the KATHERINE trial of T-DM1 (ado-trastuzumab emtansine) and mortality outcomes from the published literature. Modeled outcomes included recurrences, breast cancer deaths, deaths from other causes, direct medical costs, and costs due to lost productivity. To estimate the residual disease burden, we compared outcomes from a cohort of patients treated with T-DM1 versus a hypothetical cohort with no disease recurrence. RESULTS: We estimated that 9,300 people would experience incident high-risk HER2-positive ESBC in the United States in 2021 based on cancer surveillance databases, clinical trial data, and expert opinion. We estimated that, in this group, 2,118 would experience disease recurrence, including 1,576 distant recurrences, and 1,358 would experience breast cancer deaths. This residual disease burden resulted in 6,435 life-years lost versus the recurrence-free cohort, and healthcare-related costs totaling $644 million, primarily associated with treating distant cancers. CONCLUSION: Patients with HER2-positive ESBC who do not achieve pCR after neoadjuvant therapy are at ongoing risk of recurrence despite the effectiveness of neoadjuvant treatment. There is substantial clinical and economic value in further reducing the residual disease burden in this population.

Effectiveness and cost-effectiveness of trastuzumab emtansine in women with HER2-positive locally advanced or metastatic breast cancer: A systematic review and meta-analysis.

Background: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor-2 targeted antibody-drug conjugate that contains a monoclonal antibody, trastuzumab, covalently linked to DM1, a small molecule cytotoxin. Methods: We conducted a systematic review and meta-analysis of published trials to examine the efficacy and safety of T-DM1 for patients with HER2-positive metastatic breast cancer. In addition, we systematically reviewed existing economic evaluations of T-DM1. An electronic literature search of online databases (Medline, CENTRAL, and Embase) was performed. Randomized controlled trials that compared T-DM1 with other active treatment agents were eligible for inclusion. In addition, studies that involved T-DM1 as one of the treatment comparators in an economic evaluation were included. Four trials with a total of 2462 participants were included in this meta-analysis. Results: Pooled results showed T-DM1 substantially improved overall survival (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.67-0.85; I2 = 0%) and progression-free survival (HR, 0.67; 95% CI, 0.52-0.85; I2 = 75%). In addition, T-DM1 showed greater association with severe thrombocytopenia and liver dysfunction than other regimens, but a lower rate of neutropenia, leukopenia, febrile neutropenia, asthenia, and diarrhea. All four trials included in the meta-analysis overall had a low risk of bias. Two cost-utility analyses involving T-DM1 were identified, and the overall quality was high. Conclusions: T-DM1 is effective for the treatment of patients with HER2-positive metastatic breast cancer, and it demonstrates a tolerable safety profile compared with other active controls. Little evidence was available regarding the cost-effectiveness of T-DM1 so no conclusions can be drawn.

Cost-Effectiveness Analysis of Trastuzumab Deruxtecan versus Trastuzumab Emtansine in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer in the USA.

INTRODUCTION: Based on data from the DESTINY-Breast03 trial, we performed a cost-effectiveness analysis of trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who had been previously treated with trastuzumab and a taxane from the US payer perspective. METHODS: We conducted a Markov model to assess the cost-effectiveness of T-DXd versus trastuzumab emtansine (T-DM1). The simulation time horizon for this model was the lifetime of patients. Transition probabilities were based on data from the DESTINY-Breast03 trial. Health utility data were derived from published studies. Outcome measures were costs (in 2022 US$), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses assessed the uncertainty of key model parameters and their joint impact on the base-case results. RESULTS: The base-case results found that T-DXd provided an improvement of 3.90 QALYs compared with T-DM1, and the ICER was $220,533 per QALY. The one-way sensitivity analysis demonstrated that the utility value of progression-free survival, hazard ratios of T-Dxd versus T-DM1, and cost of T-Dxd contributed substantial uncertainty to the model. Probabilistic sensitivity analysis predicted T-DXd being cost-effective compared to T-DM1 was 0, 1, 16, and 46% at willingness-to-pay of $50,000, $100,000, $150,000, and 200,000 per QALY, respectively. CONCLUSION: T-DXd was unlikely to offer a reasonable value for the money spent compared to T-DM1 in a US payer setting.

Cost-effectiveness analysis of Ado-trastuzumab emtansine for the treatment of residual invasive HER2-positive breast cancer.

OBJECTIVE: Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancer cases. Ado-trastuzumab emtansine (T-DM1) is approved to treat residual HER2-positive breast cancer after neoadjuvant therapy. The aim of this study was to determine the quality-adjusted time with symptoms or toxicity and without symptoms or toxicity (Q-TWiST) of T-DM1 compared to trastuzumab for residual invasive HER2-positive breast cancer. METHODS: The authors developed an analytical model extracting individual patient data and estimated invasive disease-free survival and overall survival over a 30-year time horizon. Only direct costs from adjuvant treatment were considered as well as relapse treatment from Brazilian and American payer perspectives. Heart events were considered for utility and cost analysis. RESULTS: The 30-year projection utilizing the Weibull method estimated a mean invasive disease-free survival of 16.4 years for T-DM1 and 10.4 for Trastuzumab, in addition to a mean overall survival of 18.1 and 15.4 years, respectively. We determined a Q-TWiST gain of 3,812 years for the T-DM1 arm when compared to trastuzumab and an Incremental cost-effectiveness ratio per Q-TWiST of US$ 11,467.65 in the United States and US$ 3,332.73 in Brazil. CONCLUSION: Ado-trastuzumab emtansine is cost-effective from both Brazilian and American perspectives.

Eficacia y seguridad de trastuzumab emtansina para el tratamiento adyuvante de pacientes adultos con cáncer de mama HER2 positivo localmente avanzado con enfermedad invasiva residual después de tratamiento neoadyuvante con trastuzumab y quimioterapia / Efficacy and safety of trastuzumab emtansine for the adjuvant treatment of adult patients with locally advanced her2-positive breast cancer with residual invasive disease after neoadjuvant treatment with trastuzumab and chemotherapy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Institución de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021, se ha elaborado el presente dictamen, el que expone la evaluación de la eficacia y seguridad de trastuzumab emtansina para el tratamiento adyuvante de pacientes adultos con cáncer de mama, HER2 positivo, localmente avanzado con enfermedad invasiva residual después de tratamiento neoadyuvante con trastuzumab y quimioterapia. Así, el Dr. Rodrigo Auqui Flores, médico especialista en Oncología del Servicio de Oncología Médica del Hospital Nacional Almanzor Aguinaga Asenjo de la Red Asistencial Lambayeque, siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, envió al Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI la solicitud de uso fuera del petitorio del producto trastuzumab emtansina. ASPECTOS GENERALES: A nivel mundial y en el Perú, el cáncer de mama es el cáncer que se diagnostica con más frecuencia entre las mujeres y es la principal causa de muerte por cáncer en las mismas (Institute for Health Metrics and Evaluation 2021). El cáncer de mama es una enfermedad heterogénea y fenotípicamente diversa, compuesta por varios subtipos biológicos que tienen un comportamiento distinto. La amplificación o sobreexpresión del oncogén del receptor 2 del factor de crecimiento epidérmico humano (HER2) está presente en aproximadamente el 15 % de los cánceres de mama invasivos primarios (Burstein 2021). Las mujeres con cáncer de mama, localmente avanzado, positivo para HER2, a menudo requieren tratamiento neoadyuvante (preoperatorio) con trastuzumab y quimioterapia. El tratamiento neoadyuvante tiene como objetivo reducir el tamaño del tumor antes de la cirugía. Si bien la mayoría de pacientes presenta una respuesta patológica completa después del tratamiento neoadyuvante, existe un grupo de pacientes que experimentan enfermedad invasiva residual. Aunque, hasta la fecha, no existe evidencia sólida que demuestre que una respuesta patológica completa prediga un efecto sobre los desenlaces finales a largo plazo, como la sobrevida global (SG) (Cortazar et al. 2014), algunos autores sugieren que la ausencia de una respuesta patológica completa estaría asociada con un peor pronóstico (von Minckwitz et al. 2019). Adicional, e independientemente a la respuesta al tratamiento neoadyuvante, en general, todas las pacientes reciben tratamiento adyuvante (posoperatorio). El tratamiento adyuvante tiene como objetivo reducir el riesgo de recurrencia después de la cirugía (Burstein 2021; NICE 2020). METODOLOGÍA: Se realizó una búsqueda sistemática utilizando las bases de datos PubMed, Cochrane Library y LILACS. Además, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), el Instituto de Evaluación Tecnológica en Salud de Colombia (IETS), la Comissáo Nacional de Incorpornáo de Tecnologias no Sistema Único de Saúde (CONITEC), entre otros. Asimismo, se revisó la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en el manejo del cáncer como la National Comprehensive Cancer Network (NCCN), la European Society for Medical Oncology (ESMO), y la American Society of Clinical Oncology (ASCO). Adicionalmente, se hizo una búsqueda en las páginas web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) y de la International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados. RESULTADOS: La búsqueda de literatura permitió identificar diez publicaciones que aportan información de relevancia para fines de la presente actualización: tres GPC realizadas por la NCCN (NCCN 2021), la ESMO (Cardoso et al. 2019), y la ASCO (Denduluri et al. 2021), cinco ETS elaboradas por el NICE de Inglaterra y Gales (NICE 2020), el SMC de Escocia (SMC 2020), la CADTH de Canadá (CADTH 2020), el IQWiG de Alemania (IQWiG 2020), y la HAS de Francia (HAS 2020), y dos publicaciones del ECA KATHERINE (von Minckwitz et al. 2019; Conte et al. 2020). CONCLUSIÓN: Por todo lo expuesto, el IETSI no aprueba el uso de trastuzumab emtansina para el tratamiento adyuvante de pacientes adultos con cáncer de mama, HER2 positivo, localmente avanzado con enfermedad invasiva residual después de tratamiento neoadyuvante con trastuzumab y quimioterapia.

Mapping the EORTC QLQ-C30 to EQ-5D-3L in patients with breast cancer.

BACKGROUND: The types of outcomes measured collected in clinical studies and those required for cost-effectiveness analysis often differ. Decision makers routinely use quality adjusted life years (QALYs) to compare the benefits and costs of treatments across different diseases and treatments using a common metric. QALYs can be calculated using preference-based measures (PBMs) such as EQ-5D-3L, but clinical studies often focus on objective clinician or laboratory measured outcomes and non-preference-based patient outcomes, such as QLQ-C30. We model the relationship between the generic, preference-based EQ-5D-3L and the cancer specific quality of life questionnaire, QLQ-C30 in patients with breast cancer. This will result in a mapping that allows users to convert QLQ-C30 scores into EQ-5D-3L scores for the purposes of cost-effectiveness analysis or economic evaluation. METHODS: We use data from a randomized trial of 602 patients with HER2-positive advanced breast cancer provided 3766 EQ-5D-3L observations. Direct mapping using adjusted, limited dependent variable mixture models (ALDVMM) is compared to a random effects linear regression and indirect mapping using seemingly unrelated ordered probit models. EQ-5D-3L was estimated as a function of the summary scales of the QLQ-C30 and other patient characteristics. RESULTS: A four component mixture model outperformed other models in terms of summary fit statistics. A close fit to the observed data was observed across the range of disease severity. Simulated data from the model closely aligned to the original data and showed that mapping did not significantly underestimate uncertainty. In the simulated data, 22.15% were equal to 1 compared to 21.93% in the original data. Variance was 0.0628 in the simulated data versus 0.0693 in the original data. The preferred mapping is provided in Excel and Stata files for the ease of users. CONCLUSION: A four component adjusted mixture model provides reliable, non-biased estimates of EQ-5D-3L from the QLQ-C30, to link clinical studies to economic evaluation of health technologies for breast cancer. This work adds to a growing body of literature demonstrating the appropriateness of mixture model based approaches in mapping.

Trastuzumab emtansina para el tratamiento de cáncer de mama metastásico HER 2 positivo / Trastuzumab emtansine for the treatment of HER 2 positive metastatic breast cancer

DESCRIPCIÓN DEL PROBLEMA DE SALUD: El cáncer de mama es un cáncer potencialmente mortal diagnosticado con frecuencia en mujeres en todo el mundo. En países menos desarrollados como el nuestro, es la principal causa de muerte por cáncer en mujeres; no obstante, en los países desarrollados, ha sido superado por el cáncer de pulmón como causa de muerte por cáncer en mujeres 1 . En los Estados Unidos, el cáncer de mama representa el 30% de todos los cánceres en las mujeres, con un estimado de 49,290 casos de carcinoma ductal de mama femenino in situ y 281,550 casos de enfermedad invasiva en 2021. Los hombres representan el 1% de los casos de cáncer de mama2 . La Agencia Internacional para la Investigación del Cáncer registró un total de 210 100 casos de cáncer de mama en la región de Latinoamérica y el Caribe, en el año 2020, esto representa el 9,3 % del total de cáncer de mama en el mundo, mientras que la mortalidad representa un 8,5 % del total de muertes por cáncer de mama en el mundo3 . En El Salvador, para el año 2018, el cáncer de mama representó el 14,4 % del total de cánceres, con una tasa de incidencia de cáncer de mama en mujeres fue de 39,9 casos por 100 000 habitantes, en comparación con el año 2020, presentado un aumento de los casos diagnosticados de cáncer de mama, por lo que paso a representar el 16,4 % del total de cánceres. TRATAMIENTO ACTUAL/ COMPARADOR: Trastuzumab o el tratamiento de elección del médico administrado según la práctica local. METODOLOGÍA: Se realizó una pesquisa de la literatura en relación a la eficacia y seguridad de trastuzumab emtansina en pacientes con diagnóstico de Cáncer HER2 positivo, que progresaron durante o dentro de los seis meses de haber finalizado el uso de trastuzumab a título adyuvante o como tratamiento de primera línea de enfermedad metastásica. Esta pesquisa se realizó utilizando los siguientes motores de búsqueda clínica: National Libary of Medicene (Pumed ­ Medline), Translating Research into Practice (TRIPDATABASE) y Healh Systems Evidencie. Al mismo tiempo se extendió la pesquisa consultando la evidencia generada por agencias internaciones de evaluación de tecnologías sanitarias, comités y grupos que realizan revisiones sistemáticas y guías de práctica clínica, entre las que se encuentran: The National Institute for Health and Care Excellence (NICE) Reino Unido, Haute Autorité de Santé (HAS) Francia, Agency for Healthcare Research and Quality (AHRQ) Alemania, The Canadian Agency for Drugs and Technologies in Health (CADTH) Canadá, y Scottish Medicines Consortium (SMC) Escocia. Asimismo, se fue atrás de la identificación de ensayos clínicos que se encuentren corriendo actualmente o que aún no han sido publicados consultando la página web www.clinicaltrials.gov. Por otro lado, de conformidad a la pregunta de investigación clínica (PICO). Los términos de búsqueda utilizados tomando en cuenta a la población de interés, la intervención y el diseño del estudio, se utilizaron términos Mesh Medical Subject Heading. Lenguaje libre y filtros específicos de cada motor de búsqueda consultado. "ado-trastuzumab emtnasine" "human epidermal growth factor receptor 2", "breast neoplasms", "breast cancer", y "metastasic breast cancer". Se indico filtró de búsqueda a Estudios Clínicos fase III, controlados randomizados, Revisiones Sistemáticas, Meta-análisis, Guías de Práctica Clínica, además se limitó la búsqueda estudios en humanos. RESULTADOS: Se seleccionaron un total de 1474 pacientes y se incluyeron 991 pacientes en el estudio. Entre los 483 pacientes seleccionados y no aleatorizados, los principales motivos de no inclusión fueron la presencia de metástasis cerebrales (139 pacientes), un estado negativo o desconocido expresión de HER2 después de la revisión por el laboratorio central independiente (153 pacientes). La población aleatorizada correspondiente a la población ITT para el análisis de eficacia fue: - 495 pacientes en el grupo T-DM1, - 496 pacientes en el grupo de control (combinación de lapatinib / capecitabina). En la fecha del primer análisis intermedio 14 de enero de 2012 (mediana de seguimiento de los pacientes de 12,9 meses en el grupo T-DM1 y 12,4 meses en el grupo control), 366 pacientes (73,9%) de El grupo T-DM1 y 316 pacientes (63,7%) en el grupo control todavía estaban en tratamiento o en el período de seguimiento. En la fecha del segundo análisis intermedio el 31 de julio de 2012 (mediana de seguimiento de los pacientes de 19,1 meses en el grupo T-DM1 y 18,6 meses en el grupo control), 308 pacientes (62,2%) en el grupo de T-DM1 y 261 pacientes (52,6%) en el grupo de control todavía estaban bajo tratamiento o en el periodo de seguimiento. La mediana de edad de los pacientes fue de 53 años. Todos los pacientes tenían una puntuación de rendimiento ECOG de 0 (61% en el grupo T-DM1 y 64% en el grupo control) o de 1 (respectivamente 39% y 36%). El 12,1% de los pacientes del grupo T-DM1 y el 11,7% del grupo control no habían recibido tratamiento para su enfermedad metastásica y corresponden a una población de pacientes llamados "recaídas tempranas", es decir, pacientes que han progresado rápidamente en durante la terapia adyuvante o dentro de los 6 meses posteriores a su finalización. CONCLUSIONES: Eficacia: Se ha encontró que Trastuzumab emtansina retrasa el empeoramiento de la enfermedad y prolonga la supervivencia en pacientes con cáncer de mama avanzado y metastásico que expresaban HER2 y que habían sido previamente tratadas con trastuzumab y un taxano. El estudio fundamental en que participaron 991 pacientes, los manejados con Trastuzumab emtansina vivieron una media de 9,6 meses sin que su enfermedad empeorara en comparación con los 6,4 meses de los pacientes que fueron tratados con otros dos medicamentos contra el cáncer, capecitabina y lapatanib. Los pacientes tratados con trastuzumab emtansina también sobrevivieron durante 31 meses en comparación con los 25 meses de los pacientes tratados con capecitabina y lapatinib. Seguridad: El perfil de seguridad de trastuzumab emtansina se ha evaluado en estudios clínicos y en la etapa de post comercialización pacientes con cáncer de mama. En esta población las reacciones adversas a medicamentos graves más frecuentes (> 0,5% de los pacientes) fueron hemorragia, fiebre, trombocitopenia, disnea, dolor abdominal, dolor musculoesquelético y vómitos. Las reacciones adversas más frecuentes ≥25% con trastuzumab emtansina fueron náuseas, fatiga, dolor musculoesquelético, hemorragias, dolor de cabeza, elevación de las transaminasas, trombocitopenia y neuropatía periférica. La mayoría de las reacciones adversas a medicamentos notificadas fueron de Grado 1 ó 2 de gravedad. Las reacciones adversas a medicamentos de Grado ≥ 3, de acuerdo con los Criterios de Terminología Común para Acontecimientos Adversos del National Cancer Institute (NCI-CTCAE), más frecuentes (> 2%) fueron trombocitopenia, transaminasas elevadas, anemia, neutropenia, fatiga e hipopotasemia e hipopotasemia. Conveniencia: En cuanto a la conveniencia para la administración del medicamento, Trastuzumab emtansina, se considera es similar a la de trastuzumab, ya que comparten características como vía de administración, tiempo de administración y régimen terapéutico. Costo: Las Evaluaciones Económicas revisadas concluyen que se trata de una terapia costoefectiva, para los países bajo sus perspectivas. No obstante, nuestro contexto como país en desarrollo es sumamente diferente por lique no es pertinente realizar una extrapolación exacta de estos datos. El costo en El Salvador por paciente/ año es de $128,478.84 USD, lo cual se encuentra por encima del umbral de impacto presupuestario asumible por el ISSS ($25,000 USD).

Cost-effectiveness Analysis of Ado-trastuzumab Emtansine (T-DM1) for the Adjuvant Treatment of Patients With Residual Invasive HER2+ Early Breast Cancer in the United States.

OBJECTIVE: Ado-trastuzumab emtansine (T-DM1) was recently approved for patients with human epidermal growth factor receptor 2 positive (HER2+) early breast cancer (eBC) with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. Cost-effectiveness analysis was conducted to compare T-DM1 versus trastuzumab in the United States. MATERIALS AND METHODS: A Markov cohort-based model tracked clinical and economic outcomes over a lifetime horizon from a US payer perspective. The model included 6 health states: invasive disease-free, nonmetastatic (locoregional) recurrence, remission, first-line and second-line metastatic BC and death. Model state transitions were based on statistical extrapolation of the head-to-head KATHERINE study and published sources. Dosing and treatment duration reflected prescribing information and trials. Costs (2019 US dollars) associated with pharmaceutical treatment (wholesale acquisition costs), health state specific care, adverse events, and end-of-life care were included. Health state utilities were obtained from KATHERINE and published literature. RESULTS: T-DM1 dominated trastuzumab, yielding lower lifetime costs (-$40,271), and higher life-years (2.980) and quality-adjusted life-years (2.336). Results were driven by patients receiving T-DM1 spending less time in more costly downstream health states, as these patients are less likely to experience a recurrence overall, despite having a higher likelihood of metastatic disease (distant recurrence) in the subset of patients who experience recurrence. Probabilistic sensitivity analysis indicated robust results, with 96.7% of 5000 stochastic simulations producing dominance for T-DM1. The most influential variables were related to treatment costs, off treatment utilities, and health state costs. Additional scenario analyses tested a range of model inputs and assumptions, and produced consistent results. CONCLUSION: Relative to trastuzumab, T-DM1 treatment for patients with HER2+ eBC who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment is likely to reduce the overall financial burden of cancer, while simultaneously improving patient outcomes.

Cost-effectiveness Analysis of Trastuzumab Emtansine as Second-line Therapy for HER2-Positive Breast Cancer in China.

BACKGROUND AND OBJECTIVE: Trastuzumab emtansine (T-DM1) is the standard second-line option for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive breast cancer for its superior clinical efficacy in prolonging progression-free survival. The objective of this study was to evaluate the cost effectiveness of T-DM1 from the Chinese healthcare perspective. Capecitabine (Cap), capecitabine + lapatinib (Cap + Lap), capecitabine + trastuzumab (Cap + Tra), capecitabine + trastuzumab + pertuzumab (Cap + Tra + Per) were selected as comparators. METHODS: A three-state Markov simulation model was performed. The state transition probabilities were estimated based on the results of a published network meta-analysis, and utilities were derived from the published literature. The costs populated in the model were acquired from the local charge or previously published studies. One-way sensitive analysis and probabilistic sensitivity analyses were performed to test the robustness of the results. RESULTS: Compared with Cap, Cap + Lap, Cap + Tra, and Cap + Tra + Per, T-DM1 was estimated to increase the cost by US$109,699.1, $106,019.1, $97,506.3, and $67,121.9, respectively, and yield a gain of 0.544 quality-adjusted life years (QALYs), 0.383 QALYs, 0.367 QALYs, 0.087 QALYs, respectively. Corresponding incremental cost-effectiveness ratios (ICERs) were $201,652.9, $276,812.5, $265,685.0, and $771,516.1 per QALY. The probabilities of T-DM1 as the dominant option were 0% at the willingness-to-pay (WTP) threshold of $31,245.1/QALY. CONCLUSIONS: T-DM1, as second-line therapy in the treatment of HER2-positive breast cancer, is not a cost-effective option in China. Given the significant clinical efficacy, an appropriate price reduction of T-DM1 is required to benefit more HER2-positive breast cancer patients.

Economic evaluation of adjuvant trastuzumab emtansine in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment in Canada.

Background: In the katherine trial, adjuvant trastuzumab emtansine [T-DM1, Kadcyla (Genentech, South San Francisco, CA, U.S.A.)], compared with trastuzumab, significantly reduced the risk of recurrence or death by 50% (unstratified hazard ratio: 0.50; 95% confidence interval: 0.39 to 0.64; p < 0.0001) in patients with her2-positive early breast cancer (ebc) and residual invasive disease after neoadjuvant systemic treatment. A cost-utility evaluation, with probabilistic analyses, was conducted to examine the incremental cost per quality-adjusted life-year (qaly) gained associated with T-DM1 relative to trastuzumab, given the higher per-cycle cost of T-DM1. Methods: A Markov model comprising a number of health states was used to examine clinical and economic outcomes over a lifetime horizon from the Canadian public payer perspective. Patients entered the model in the invasive disease-free survival (idfs) state, where they received either T-DM1 or trastuzumab. Transition probabilities between the health states were derived from the katherine trial, Canadian life tables, and published literature from other relevant clinical trials (emilia, cleopatra, and M77001). Resource use, costs, and utilities were derived from katherine, other clinical trials, published literature, provincial fee schedules, and clinical expert opinion. Sensitivity analyses were conducted for key assumptions and model parameters. Results: Compared with trastuzumab, adjuvant T-DM1 was associated with a cost savings of $8,300 per patient and a 2.16 incremental qaly gain; thus T-DM1 dominated trastuzumab. Scenario analyses yielded similar results, with T-DM1 dominating trastuzumab or producing highly favourable incremental cost-utility ratios of less than $10,000 per qaly. Conclusions: Adjuvant T-DM1 monotherapy is a cost-effective strategy compared with trastuzumab alone in the treatment of patients with her2-positive ebc and residual invasive disease after neoadjuvant systemic treatment.

Cost-Effectiveness of Neoadjuvant-Adjuvant Treatment Strategies for Women With ERBB2 (HER2)-Positive Breast Cancer.

Importance: The neoadjuvant treatment options for ERBB2-positive (also known as HER2-positive) breast cancer are associated with different rates of pathologic complete response (pCR). The KATHERINE trial showed that adjuvant trastuzumab emtansine (T-DM1) can reduce recurrence in patients with residual disease compared with patients treated with trastuzumab; however, T-DM1 and other ERBB2-targeted agents are costly, and understanding the costs and health consequences of various combinations of neoadjuvant followed by adjuvant treatments in the United States is needed. Objective: To examine the costs and disease outcomes associated with selection of various neoadjuvant followed by adjuvant treatment strategies for patients with ERBB2-positive breast cancer. Design, Setting, and Participants: In this economic evaluation, a decision-analytic model was developed to evaluate various neoadjuvant followed by adjuvant treatment strategies for women with ERBB2-positive breast cancer from a health care payer perspective in the United States. The model was informed by the KATHERINE trial, other clinical trials with different regimens from the KATHERINE trial, the Flatiron Health Database, McKesson Corporation data, and other evidence in the published literature. Starting trial median age for KATHERINE patients was 49 years (range, 24-79 years in T-DM1 arm and 23-80 years in trastuzumab arm). The model simulated patients receiving 5 different neoadjuvant followed by adjuvant treatment strategies. Data analyses were performed from March 2019 to August 2020. Exposure: There were 4 neoadjuvant regimens: (1) HP: trastuzumab (H) plus pertuzumab (P), (2) THP: paclitaxel (T) plus H plus P, (3) DDAC-THP: dose-dense anthracycline/cyclophosphamide (DDAC) plus THP, (4) TCHP: docetaxel (T) plus carboplatin (C) plus HP. All patients with pCR, regardless of neoadjuvant regimen, received adjuvant H. Patients with residual disease received different adjuvant therapies depending on the neoadjuvant regimen according to the 5 following strategies: (1) neoadjuvant DDAC-THP followed by adjuvant H, (2) neoadjuvant DDAC-THP followed by adjuvant T-DM1, (3) neoadjuvant THP followed by adjuvant DDAC plus T-DM1, (4) neoadjuvant HP followed by adjuvant DDAC/THP plus T-DM1, or (5) neoadjuvant TCHP followed by adjuvant T-DM1. Main Outcomes and Measures: Lifetime costs in 2020 US dollars and quality-adjusted life-years (QALYs) were estimated for each treatment strategy, and incremental cost-effectiveness ratios were estimated. A strategy was classified as dominated if it was associated with fewer QALYs at higher costs than the alternative. Results: In the base-case analysis, costs ranged from $415 833 (strategy 3) to $518 859 (strategy 4), and QALYs ranged from 9.67 (strategy 1) to 10.73 (strategy 3). Strategy 3 was associated with the highest health benefits (10.73 QALYs) and lowest costs ($415 833) and dominated all other strategies. Probabilistic analysis confirmed that this strategy had the highest probability of cost-effectiveness (>70% at willingness-to-pay thresholds of $0-200,000/QALY) and was associated with the highest net benefit. Conclusions and Relevance: These results suggest that neoadjuvant THP followed by adjuvant H for patients with pCR or followed by adjuvant DDAC plus T-DM1 for patients with residual disease was associated with the highest health benefits and lowest costs for women with ERBB2-positive breast cancer compared with other treatment strategies considered.

A cost-effectiveness analysis of trastuzumab-containing treatment sequences for HER-2 positive metastatic breast cancer patients in Taiwan.

OBJECTIVE: Treatment options for HER-2-positive metastatic breast cancer (mBC) patients have expanded markedly since trastuzumab approval in 1998. Several other regimens are now available, including pertuzumab plus trastuzumab plus docetaxel, T-DM1, capecitabine plus lapatinib, and trastuzumab plus lapatinib. This study assesses the cost-effectiveness of four treatment sequences for HER-2-positive mBC according to the Taiwanese National Health Insurance Administration (TNHIA). METHODS: Costs (U.S. Dollars) and effectiveness (quality-adjusted life years) of four treatment sequences for HER-2-positive mBC patients were examined using a Markov model over a lifetime horizon. Transition probabilities, disease progression, and probability of adverse events and survival were derived from clinical trial data. Costs and health utilities were estimated from TNHIA, Taipei Medical University Hospital, and the literature. Deterministic, probabilistic sensitivity analyses and a scenario analysis examined parameter uncertainty and accounted for drug wastage in dosage and cost calculations. RESULTS: Sequence 3 (1st line: trastuzumab plus docetaxel; 2nd line: T-DM1; 3rd line: trastuzumab plus lapatinib) was the most cost-effective sequence followed by sequence 1 (1st line: pertuzumab plus trastuzumab plus docetaxel; 2nd line: T-DM1; 3rd line: capecitabine plus lapatinib), and sequence 4 (1st line: trastuzumab plus docetaxel; 2nd line: trastuzumab plus lapatinib; 3rd line: trastuzumab plus capecitabine), respectively. The model was sensitive to costs and transition probabilities, but not particularly sensitive to the wastage assumption. CONCLUSIONS: From the perspective of the TNHIA, trastuzumab plus docetaxel as 1st line followed by T-DM1 and trastuzumab plus lapatinib as 2nd and 3rd line represents the most cost-effective strategy among the four sequences considered for treating HER-2-positive mBC patients.

Stability assessment of antibody-drug conjugate Trastuzumab emtansine in comparison to parent monoclonal antibody using orthogonal testing protocol.

Antibody-drug conjugates (ADC) represent an emerging, novel class of biopharmaceuticals. The heterogeneity originating from the sophisticated structure requires orthogonal analytical techniques for quality and stability assessment of ADC to ensure safety and efficacy. In this study, the stability of Trastuzumab (recombinant humanized IgG1 mAb, targeting HER2 receptor) and its ADC with DM1 (anti-tubulin anticancer drug), Trastuzumab emtansine (T-DM1) were studied. SE-HPLC was used to monitor formation of aggregates and/or fragments of the monoclonal antibodies (mAb). Correlation with the results of reducing and non-reducing sodium dodecyl sulphate - polyacrylamide gel electrophoresis (SDS-PAGE) and dynamic light scattering (DLS) were performed to interpret the obtained results. RP-HPLC was used for assessment of the stability of DM1 in ADC while spectrophotometry was employed to determine drug antibody ratio (DAR) . The studied drugs were subjected to several stress conditions including pH, temperature, mechanical agitation and repeated freeze and thaw to generate possible degradation products and ensure suitability of the assay protocol. The degradation pattern and extent were demonstrated under the indicated stress conditions. The correlation between the results of SE-HPLC and those of SDS-PAGE and DLS ensured the validity of the orthogonal assay protocol and indicated aggregates that were not detected using SE-HPLC. Results showed clearly that T-DM1 is relatively less stable than its parent mAb. This was attributed to the presence of the drug-linker part that is attached to the mAb. RP-HPLC showed that the cytotoxic drug moiety is liable for degradation under the studied conditions resulting in alteration of DAR as well as formation of degradation products. This confirmed the need for more robust coupling chemistries for production of safe and effective ADC and highlighted the importance of orthogonal testing protocols for quality assessment. The assay protocol should be applicable for quality and stability assessment of various ADC.