RESUMEN
On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥â 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Receptor ErbB-2 , Trastuzumab , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptor ErbB-2/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Femenino , Trastuzumab/uso terapéutico , Trastuzumab/farmacología , Masculino , Persona de Mediana Edad , Estados Unidos , United States Food and Drug Administration , Aprobación de Drogas , Anciano , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacología , Inmunoconjugados/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/farmacología , Camptotecina/efectos adversos , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacologíaRESUMEN
On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.
Asunto(s)
Inmunoconjugados , Neoplasias Ováricas , Adulto , Humanos , Femenino , Neuropatía Óptica Tóxica/tratamiento farmacológico , Resistencia a Antineoplásicos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Inmunoconjugados/efectos adversos , Receptor 1 de FolatoRESUMEN
On September 17, 2021, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-refractory or ineligible. This is the first approval for patients with RAI-refractory locally advanced or metastatic DTC who have progressed following prior therapy and the first approval in pediatric patients with DTC. The approval was based on data from COSMIC-311 (Study XL184-311, NCT03690388), an international, randomized, double-blind trial in which patients with locally advanced or metastatic RAI-refractory DTC that progressed during or following treatment with at least one VEGFR-targeting tyrosine kinase inhibitor were treated with either cabozantinib 60 mg orally once daily (N = 170) or placebo with best supportive care (N = 88). The primary efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review per RECIST 1.1. The median PFS was 11.0 months [95% confidence interval (CI), 7.4-13.8] in the cabozantinib arm compared with 1.9 months (95% CI, 1.9-3.7) in the control arm, with an HR of 0.22 (95% CI, 0.15-0.31). The endpoint of ORR was not met. No new safety signals were identified with the exception of hypocalcemia, which was added as a warning in the product labeling.
Asunto(s)
Adenocarcinoma , Anilidas , Piridinas , Neoplasias de la Tiroides , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Inhibidores de la Angiogénesis/uso terapéutico , Anilidas/efectos adversos , Niño , Humanos , Radioisótopos de Yodo/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/efectos adversos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patologíaRESUMEN
On June 29, 2020, the FDA approved pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. Patients should be selected for therapy based on an FDA-approved companion diagnostic test. Approval was primarily based on the FeDeriCa trial, a randomized, open-label, multicenter comparability study of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection compared with intravenous pertuzumab and intravenous trastuzumab administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of patients with early breast cancer. The pharmacokinetic endpoints were, first, to demonstrate that the exposure of subcutaneous pertuzumab was not inferior to that of intravenous pertuzumab, and then to demonstrate that the exposure of subcutaneous trastuzumab was not inferior to that of intravenous trastuzumab. The primary endpoints were met with the observed lower limit of the two-sided 90% confidence intervals above the prespecified noninferiority margins. The most common adverse reactions were alopecia, nausea, diarrhea, anemia, and asthenia. The totality of the evidence demonstrated comparability of the subcutaneous product to intravenous, allowing for extrapolation and approval of all breast cancer indications for which intravenous trastuzumab and pertuzumab are approved.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/terapia , Terapia Neoadyuvante/métodos , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Esquema de Medicación , Aprobación de Drogas , Femenino , Humanos , Hialuronoglucosaminidasa/administración & dosificación , Hialuronoglucosaminidasa/efectos adversos , Inyecciones Subcutáneas , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Terapia Neoadyuvante/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor ErbB-2/análisis , Receptor ErbB-2/metabolismo , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversos , Resultado del Tratamiento , Estados Unidos , United States Food and Drug AdministrationRESUMEN
The aim of the study was to evaluate the quantitative relationship between duration of severe neutropenia (DSN, the efficacy endpoint) and area under effect curve of absolute neutrophil counts (ANC-AUEC, the pharmacodynamic endpoint), based on data from filgrastim products, a human granulocyte colony-stimulating factor (G-CSF). Clinical data from filgrastim product comparator and test arms of two randomized, parallel-group, phase III studies in breast cancer patients treated with myelosuppressive chemotherapy were utilized. A zero-inflated Poisson regression model best described the negative correlation between DSN and ANC-AUEC. The models predicted that with 10 × 109 day/L of increase in ANC-AUEC, the mean DSN would decrease from 1.1 days to 0.93 day in Trial 1 and from 1.2 days to 1.0 day in Trial 2. The findings of the analysis provide useful information regarding the relationship between ANC and DSN that can be used for dose selection and optimization of clinical trial design for G-CSF.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Filgrastim/uso terapéutico , Fármacos Hematológicos/uso terapéutico , Neutropenia/tratamiento farmacológico , Neutrófilos/efectos de los fármacos , Adulto , Área Bajo la Curva , Ensayos Clínicos Fase III como Asunto , Simulación por Computador , Femenino , Filgrastim/efectos adversos , Fármacos Hematológicos/efectos adversos , Humanos , Recuento de Leucocitos , Persona de Mediana Edad , Modelos Biológicos , Estudios Multicéntricos como Asunto , Neutropenia/inducido químicamente , Neutropenia/diagnóstico , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Determinación de la Elegibilidad/tendencias , Neoplasias/tratamiento farmacológico , Selección de Paciente , Proyectos de Investigación/tendencias , Antineoplásicos/efectos adversos , Humanos , Seguridad del Paciente , Medición de RiesgoRESUMEN
The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.