Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer.

PURPOSE: Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities. METHODS: Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy. RESULTS: NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518 day µg/mL for white (n = 461), Asian (n = 68), and others (n = 57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n = 671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n = 42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population. CONCLUSIONS: These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.

Safety Profile and Costs of Related Adverse Events of Trastuzumab Emtansine for the Treatment of HER2-Positive Locally Advanced or Metastatic Breast Cancer Compared to Capecitabine Plus Lapatinib from the Perspective of the Canadian Health-Care System.

BACKGROUND AND OBJECTIVES: Trastuzumab emtansine (T-DM1, KADCYLA(®)) is an antibody-drug conjugate comprised of the cytotoxic agent DM1 and trastuzumab (HERCEPTIN(®)). The safety profile of T-DM1 in human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane was investigated in the phase III EMILIA trial. The trial demonstrated clinically and statistically meaningful differences in the safety profile between T-DM1 and capecitabine plus lapatinib (CAP + LAP). The objective of this study was to estimate the costs of managing treatment-related grade ≥ 3 adverse events (AEs) that occurred in ≥ 2% of patients and grade 2 AEs that occurred in ≥ 5% of patients taking T-DM1 compared with patients taking CAP + LAP based on the EMILIA trial, from the perspective of Canadian public payers. METHODS: An Excel-based model was utilized to estimate the relevant costs. Clinical data were obtained from the EMILIA trial. Cost information was obtained from the literature, clinical experts, and standard cost sources. The analysis was conducted from the Canadian public-payer perspective and reported in 2014 Canadian dollars (CAD). RESULTS: The management of included treatment-related AEs resulted in higher estimated per-patient costs of CAD6901 for CAP + LAP versus CAD3380 for T-DM1, resulting in savings of CAD3521. CONCLUSIONS: From a Canadian perspective, this analysis demonstrated that utilizing T-DM1 for the management of HER2-positive metastatic breast cancer results in substantial savings to the public health-care system when considering the costs of treatment-related AEs, due to fewer amount of toxicities compared with CAP + LAP. Results of various sensitivity analyses investigating changes in number and costs of AEs confirmed the findings; however, the magnitude of cost savings varied. Further analyses are necessary to determine whether these cost savings would occur in other countries and health-care systems.

Trastuzumab emtansine in locally advanced or metastatic HER2 positive breast cancer; GENESIS-SEFH drug evaluation report.

Trastuzumab emtansina (T-DM1) is an antibody-drug conjugate directed against the HER2 for the treatment of HER2+ mestastatic breast cancer (MBC), who has previously received trastuzumab plus a taxane. According to the results of the EMILIA trial versus lapatinib plus capecitabine T-DM1 shows an improvement in progression-free survival (PFS) and the overall survival (OS). It has a favorable profile reducing the incidence of grade 3-4 adverse reactions such as hand-foot syndrome and diarrhea. On the contrary increases significantly severe thrombocytopenia; bleeding risk and liver function should also be monitored. With the current import price T-DM1 has a cost per QALY of over 120,000 €. The price of the drug for the Spanish NHS has not yet been established. Drug cost would be the key factor in the sensitivity analysis and a 50% reduction in the price of the drug would place it close to the threshold of cost-effectiveness usually considered in our midst. According to the budget impact model used, a maximum of 1,218 patients / year and the budgetary impact throughout the Spanish state would be at € 70,490,850. In the initial analysis no advantage was found for T-DM1 in those patients without visceral involvement. Although a subsequent re-analysis of the results of PFS in which the definition of visceral involvement was specified a significant benefit was shown in this subgroup. We believe that this approach introduces a high degree of uncertainty, which does not guarantee the benefit achieved for this subgroup of patients.

T-DM1 es un conjugado anticuerpo-farmaco dirigido contra el HER2 para el tratamiento del cancer de mama metastasico (CMM) HER2 +, que ha recibido previamente trastuzumab mas un taxano. De acuerdo con los resultados del ensayo EMILIA frente a lapatinib mas capecitabina T-DM1 muestra una mejora en la supervivencia libre de progresion (SLP) y la supervivencia global (SG). Tiene un perfil favorable reducir la incidencia de reacciones adversas grado 3-4 tales como el sindrome mano- pie y la diarrea. Sin embargo, aumenta significativamente el riesgo de trombocitopenia grave y debe monitorizarse el riesgo de hemorragia y la funcion hepatica. Con el precio de importacion actual T-DM1 tiene un coste por AVAC de mas de 120.000 €. El precio del farmaco para el Sistema Nacional de Salud en Espana aun no ha sido establecido. El precio del farmaco seria el factor clave en el analisis de sensibilidad y una reduccion del 50% en el precio lo situaria cerca del umbral de coste-efectividad generalmente considerada en nuestro medio como aceptable. De acuerdo con el modelo de impacto presupuestario utilizado, se trataria un maximo de 1.218 pacientes / ano y el impacto presupuestario de todo el estado espanol estaria entorno a 70.490.850 € para este volumen de pacientes. En el analisis inicial no se encontro ninguna ventaja para T-DM1 en aquellos pacientes sin afectacion visceral. Aunque un re-analisis posterior de los resultados de SLP en el que se especifica la definicion de la afectacion visceral se muestra un beneficio significativo en este subgrupo. Creemos que este enfoque presenta un alto grado de incertidumbre, y no garantiza el beneficio logrado para este subgrupo de pacientes.

Ado-trastuzumab emtansine for the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: An update on completed and ongoing clinical trials of ado-trastuzumab emtansine for the treatment of metastatic breast cancer (MBC) is presented. SUMMARY: Ado-trastuzumab emtansine (Kadcyla, Genentech), the first U.S.-approved antibody-drug conjugate for MBC, is indicated for use as a single-agent therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive MBC who have received prior treatment with unconjugated trastuzumab and a taxane-based regimen. The standard dosage of ado-trastuzumab is 3.6 mg/kg i.v. every three weeks. In completed Phase II or III clinical trials, ado-trastuzumab was found to confer significant survival and quality-of-life benefits. The largest of those trials (the EMILIA study, n = 991) showed that ado-trastuzumab was superior to a regimen of lapatinib plus capecitabine in terms of progression-free survival (9.6 months versus 6.4 months, p < 0.001) and overall survival (30.9 months versus 25.1 months, p < 0.001); it also had a more favorable tolerability profile, with lower rates of treatment-limiting adverse effects. The most common adverse effects of ado-trastuzumab are thrombocytopenia (reported in about 12% of clinical trial participants overall) and increased transaminase levels. Two ongoing Phase III trials-the TH3RESA study (slated for completion in June 2015) and the MARIANNE study (estimated completion in 2016)-may help determine the optimal role of ado-trastuzumab relative to other HER2-targeted agents and its potential use as a front-line therapy for both heavily pretreated and treatment-naive patients with MBC. CONCLUSION: With a novel targeted mechanism of action, ado-trastuzumab is an effective treatment option for HER2-positive MBC in previously treated patient populations.