trastuzumab emtansine
Fuentes regulatorias consultadas
Indicaciones aprobadas
- En monoterapia, cáncer de mama metastásico HER2+ previamente tratado con trastuzumab y un taxano, con tratamiento previo para enfermedad metastásica o recaída durante o en los 6 meses posteriores a la adyuvancia.
- Tratamiento adyuvante del cáncer de mama temprano HER2+ con enfermedad invasiva residual tras tratamiento neoadyuvante basado en taxano y trastuzumab.
Advertencias clínicas
- Advertencia destacada (boxed warning) · Puede causar hepatotoxicidad grave, fallo hepático y muerte. Controla transaminasas y bilirrubina antes de iniciar y antes de cada dosis; ajusta o suspende según los resultados. — FDA SPL, KADCYLA set_id 23f3c1f4-0fc8-4804-a9e3-04cf25dd302e
- Advertencia destacada (boxed warning) · Puede reducir la FEVI y causar cardiotoxicidad. Evalúa la función ventricular izquierda antes y durante el tratamiento y retén o suspende según los criterios de la etiqueta. — FDA SPL, KADCYLA set_id 23f3c1f4-0fc8-4804-a9e3-04cf25dd302e
- Advertencia destacada (boxed warning) · Puede causar daño embriofetal; verifica el embarazo antes de iniciar y usa anticoncepción eficaz. — FDA SPL, KADCYLA set_id 23f3c1f4-0fc8-4804-a9e3-04cf25dd302e
- Advertencia mayor · Vigila la enfermedad pulmonar intersticial/neumonitis, las reacciones a la perfusión o la hipersensibilidad, las hemorragias potencialmente mortales, la trombocitopenia, la neuropatía periférica y la extravasación. Suspende o ajusta según el evento. — FDA SPL, KADCYLA set_id 23f3c1f4-0fc8-4804-a9e3-04cf25dd302e
Interacciones medicamentosas
- SeveraInhibidores potentes de CYP3A4
Mecanismo: Pueden aumentar la exposición al componente DM1 y su toxicidad.
Recomendación: Evita la combinación. Si es inevitable, retrasa KADCYLA aproximadamente 3 semividas del inhibidor cuando sea posible o vigila estrechamente la toxicidad.
FDA SPL, KADCYLA set_id 23f3c1f4-0fc8-4804-a9e3-04cf25dd302e
- SeveraAnticoagulantes y antiagregantes plaquetarios
Mecanismo: La trombocitopenia y el efecto hemorrágico de KADCYLA pueden aumentar el riesgo de hemorragia grave o mortal.
Recomendación: Si el uso concomitante es necesario, extrema la precaución y añade monitorización.
FDA SPL, KADCYLA set_id 23f3c1f4-0fc8-4804-a9e3-04cf25dd302e
Eventos adversos
Comunes (≥1%)
fatiga · náuseas · dolor musculoesquelético · hemorragia · trombocitopenia · cefalea · elevación de transaminasas · estreñimiento · epistaxis · neuropatía periférica · artralgia
Raros pero graves
insuficiencia hepática mortal · insuficiencia cardiaca · enfermedad pulmonar intersticial · hemorragia mortal · reacción a la perfusión potencialmente mortal
Embarazo y lactancia
Puede causar daño fetal. Verifica el embarazo antes de iniciar. Las mujeres deben usar anticoncepción durante el tratamiento y durante 7 meses después; los hombres con pareja con capacidad reproductiva deben usar anticoncepción durante el tratamiento y durante 4 meses después. No amamantes durante el tratamiento ni durante 7 meses después.
Bibliografía reciente (PubMed)
Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane. We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety. Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the
An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab
Patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer with residual invasive disease after neoadjuvant systemic therapy have a high risk of recurrence and death. The primary analysis of KATHERINE, a phase 3, open-label trial, showed that the risk of invasive breast cancer or death was 50% lower with adjuvant trastuzumab emtansine (T-DM1) than with trastuzumab alone. We randomly assigned patients with HER2-positive early breast cancer with residual invasive disease in the breast or axilla after neoadjuvant systemic treatment with taxane-based chemotherapy and trastuzumab to receive T-DM1 or trastuzumab for 14 cycles. Here, we report the prespecified final analysis of invasive disease-free survival and the second interim analysis of overall survival. With a median follow-up of 8.4 years, T-DM1 sustained the improvement in invasive disease-free survival over trastuzumab (unstratified hazard ratio for invasive disease or death, 0.54; 95% confidence interval [CI], 0.44 to 0.66). Seven-year invasive disease-free survival was 80.8% with T-DM1 and 67.1% with trastuzumab (difference, 13.7 percentage points). T-DM1 also led to a significantly lower risk of death than trastuzumab (unstratified hazard ratio, 0.66; 95% CI, 0.51 to 0.87; P = 0.003). Seven-year overall survival was 89.1% with T-DM1 and 84.4% with trastuzumab (difference, 4.7 percentage points). Adverse events of grade 3 or higher were noted in 26.1% of the patients in the T-DM1 group and 15.7% of those in the trastuzumab group. As compared with trastuzumab, T-DM1 improved overall survival with sustained improvement in invasive disease-free survival among patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472.).
Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24-0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56-0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 .
The treatment of cancer patients has dramatically changed over the past decades with the advent of monoclonal antibodies, immune-checkpoint inhibitors, bispecific antibodies, and innovative T-cell therapy. Antibody-drug conjugates (ADCs) have also revolutionized the treatment of cancer. Several ADCs have already been approved in hematology and clinical oncology, such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) for the treatment of metastatic breast cancer, and enfortumab vedotin (EV) for the treatment of urothelial carcinoma. The efficacy of ADCs is limited by the emergence of resistance due to different mechanisms, such as antigen-related resistance, failure of internalization, impaired lysosomal function, and other mechanisms. In this review, we summarize the clinical data that contributed to the approval of T-DM1, T-DXd, SG, and EV. We also discuss the different mechanisms of resistance to ADCs, as well as the ways to overcome this resistance, such as bispecific ADCs and the combination of ADCs with immune-checkpoint inhibitors or tyrosine-kinase inhibitors.