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Técnicas de Diagnóstico Molecular/métodos , Pruebas de Farmacogenómica/métodos , Medicina de Precisión/métodos , Biomarcadores , Sistemas de Apoyo a Decisiones Clínicas , Unión Europea , Humanos , Medicina Molecular/métodos , Terapia Molecular Dirigida , Proteínas de Neoplasias/análisis , Seguridad del Paciente , Receptor ErbB-2/análisis , Trastuzumab/uso terapéutico , Estados UnidosRESUMEN
INTRODUCTION: The 'one biomarker/one drug' scenario is unsustainable because cancer is a complex disorder that involves a number of molecular defects. In the past decade, major technological advances have lowered the overall cost and increased the efficiency of next-generation sequencing (NGS). AREAS COVERED: We review recent regulations on NGS and complementary diagnostics in Japan, mainly focusing on high-quality studies that utilized these new diagnostic modalities and were published within the last 5 years. We highlight significant changes in regulation, and explain the direction of efforts to translate the results of NGS and complementary diagnostics into clinical practice. EXPERT OPINION: NGS holds a number of advantages over conventional companion and complementary diagnostics that enable simultaneous analyzes of multiple cancer genes to detect actionable mutations. Parallel technological developments and regulatory changes have led to the rapid adoption of NGS into clinical practice. NGS-based genomic data have been leveraged to better understand the characteristics of a disease that affects its patient's response to a given therapy. As NGS-based tests become more widespread, however, Japanese authorities will face significant challenges particularly with respect to the complexity of genomic data, which will have to be managed if NGS is to benefit patients.
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Secuenciación de Nucleótidos de Alto Rendimiento/tendencias , Legislación de Dispositivos Médicos , Técnicas de Diagnóstico Molecular/tendencias , Neoplasias/tratamiento farmacológico , Medicina de Precisión/métodos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Análisis Mutacional de ADN/economía , Análisis Mutacional de ADN/métodos , Análisis Mutacional de ADN/tendencias , Bases de Datos de Ácidos Nucleicos , Aprobación de Recursos/legislación & jurisprudencia , Pruebas Dirigidas al Consumidor/economía , Pruebas Dirigidas al Consumidor/legislación & jurisprudencia , Farmacorresistencia Microbiana/genética , Equipos y Suministros/clasificación , Enfermedades Genéticas Congénitas/tratamiento farmacológico , Enfermedades Genéticas Congénitas/genética , Agencias Gubernamentales/organización & administración , Necesidades y Demandas de Servicios de Salud , Secuenciación de Nucleótidos de Alto Rendimiento/economía , Secuenciación de Nucleótidos de Alto Rendimiento/instrumentación , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Japón , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Técnicas de Diagnóstico Molecular/economía , Técnicas de Diagnóstico Molecular/métodos , Terapia Molecular Dirigida , Mutación , Programas Nacionales de Salud , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Neoplasias/genéticaRESUMEN
Targeted therapies continue to be key components of cancer treatment. New approaches to detection of acquired resistance at the genomic level, in combination with new therapies, help to overcome the challenges that are seen frequently, rapidly and broadly across tumor pathologies, and provide opportunities for cancer management. In the last several years, a new breed of modalities called immune checkpoint inhibitors have come to the forefront of clinically effective treatments. A plethora of rapid approvals and early access initiatives have seen anti-cytotoxic T-lymphocyte-associated antigen-4, and particularly anti-programmed death receptor-1 therapies, deployed in a number of tumor indications of high unmet need. With the rise of immune checkpoint inhibition, and the broader resurgence in the immuno-oncology field, we are facing challenges in the prediction of response.
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Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Terapia Molecular Dirigida/métodos , Animales , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/farmacología , Biomarcadores de Tumor/inmunología , Antígeno CTLA-4/uso terapéutico , Humanos , Inmunoterapia/métodos , Neoplasias/diagnóstico , Medicina de Precisión/métodos , Receptor de Muerte Celular Programada 1/uso terapéuticoRESUMEN
OBJECTIVES: The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples. METHODS: BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials. RESULTS: The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient [ICC] = 0.86-0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18-0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78-0.85). CONCLUSION: BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.
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Antígeno B7-H1/inmunología , Inmunohistoquímica/métodos , HumanosAsunto(s)
Crisis Blástica , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-mdm2/biosíntesis , Pirrolidinas/administración & dosificación , para-Aminobenzoatos/administración & dosificación , Crisis Blástica/sangre , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/mortalidad , Femenino , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Masculino , Pirrolidinas/efectos adversos , para-Aminobenzoatos/efectos adversosRESUMEN
Four challenges to the adoption of personalized medicine were identified in the mid-2000s - adherence to the blockbuster model, the lack of a supportive regulatory environment, the dysfunctional payment system and physician barriers. In this article, we report on our study findings based on interviews with 24 senior executives from leading drug and diagnostics companies to assess progress made in addressing those challenges over the last decade. Overall, we found that even with payer pushback and adjusting to new business models, the majority of developers expected their business to increase over the next 5 years. Several factors that unexpectedly helped to shape the personalized medicine landscape, such as the growth of support in genomic medicine from the public sector, are also discussed.
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Nearly 20 years ago, the US Food and Drug Administration (FDA) approved the first companion diagnostic assay and, today, this type of test governs the use of 18 different drugs. With the appearance of PD-L1 immunohistochemistry (IHC) assays linked to the use of different PD-1/PD-L1 immune checkpoint inhibitors, a new class of predictive biomarker assays has emerged; the complementary diagnostics. These are predictive biomarker assays that aid the therapeutic decision process but are not a prerequisite for receiving a specific drug, as is the case with companion diagnostics. Both types of assay have the individual patient as a point of reference and they will be decisive for the move toward a more individualized pharmacotherapy. They are also considered important elements in the realization of precision medicine. Here, I discuss both companion and complementary diagnostics.
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Bioensayo , Neoplasias/diagnóstico , Biomarcadores/metabolismo , Humanos , Neoplasias/metabolismo , Medicina de PrecisiónRESUMEN
The immune checkpoint inhibitors pembrolizumab and nivolumab together with their diagnostic assays have recently been granted market authorization for treatment of advanced non-small-cell lung cancer in the USA. The two assays, PD-L1 IHC 22C3 pharmDx and PD-L1 IHC 28-8 pharmDx (both by Dako, Glostrup, Denmark), are the first PD-L1 IHC assays to obtain regulatory approval through the Premarket Approval process. This approval is supported by recent clinical studies that have shown a positive correlation between PD-L1 expression and the outcome following treatment with different PD-1/PD-L1 checkpoint inhibitors. These diagnostic assays are able to identify the group of non-small-cell lung cancer patients who will benefit most from treatment with the immune checkpoint inhibitors. However, so far, it is only the PD-L1 IHC 22C3 pharmDx assay, which is linked to the use of pembrolizumab, that has obtained regulatory status as a companion diagnostic.
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Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Medicina de Precisión/métodos , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
The variability of pharmacotherapy can be of a significant magnitude, and the main reason for this is often diseases heterogeneity. Patients who have similar diagnoses very often respond differently to the same pharmacological intervention, with great variability in both efficacy and safety outcome. Despite having discussed personalized medicine for more than a decade, we still see that most drug prescriptions for severe chronic diseases are largely based on 'trial and error' and not on solid biomarker data. However, with the advance of molecular diagnostics and a subsequent increased understanding of disease mechanisms, things are slowly changing. Within the last few years, we have seen an increasing number of predictive biomarker assays being developed to guide the use of targeted cancer drugs. This type of assay is called companion diagnostics and is developed in parallel to the drug using the drug-diagnostic co-development model. The development of companion diagnostics is a relatively new discipline and in this review, different aspects will be discussed including clinical and regulatory issues. Furthermore, examples of drugs, such as the ALK and PD-1/PD-L1 inhibitors, that have been approved recently together with a companion or complimentary diagnostic will be given.
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There have been several major problems that have plagued biopharmaceutical development since the end of the 1990s, but two in particular have reached the point where they are impacting the economic viability of the industry: the lack of efficacy of new drugs and increasing competition among therapeutics that broadly attack certain common diseases and disease areas. The US FDA has noted that the era of one-size-fits-all treatment may well be reaching its end days as companies increasingly adopt approaches that involve biomarkers (there are now commercial databases that purport to track over 11,000 of them). Pharmacogenomic biomarkers in particular are used to create diagnostics that help to differentiate or stratify the likely outcomes a patient will experience with a drug, which can now be said to be targeted or tailored to patients with particular traits (i.e., personalized), leading to an era of so-called precision medicine. As more is understood about diseases and the why and how of their effects on people through advances in biomarkers and genomics, personalized medicine is becoming a natural result of biomedical science and a natural trajectory for the innovation-based biopharmaceutical industry. The focus of this article is to examine an apparent divergence in that trajectory engendered by a growing differentiation in the approaches to personalized medicines in terms of their accompanying diagnostics: companion diagnostics are typically linked to a specific drug within its approved label, while complementary diagnostics are associated more broadly, usually not with a specific drug but with a class of drugs, and not confined to specific uses by labeling, with consequent ramifications for economic, regulatory and strategic considerations.