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1.
Gastric Cancer ; 25(4): 741-750, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35661944

RESUMEN

BACKGROUND: Immune checkpoint inhibitors (ICI) are now standard-of-care treatment for patients with metastatic gastric cancer (GC). To guide patient selection for ICI therapy, programmed death ligand-1 (PD-L1) biomarker expression is routinely assessed via immunohistochemistry (IHC). However, with an increasing number of approved ICIs, each paired with a different PD-L1 antibody IHC assay used in their respective landmark trials, there is an unmet clinical and logistical need for harmonization. We investigated the interchangeability between the Dako 22C3, Dako 28-8 and Ventana SP-142 assays in GC PD-L1 IHC. METHODS: In this cross-sectional study, we scored 362 GC samples for PD-L1 combined positive score (CPS), tumor proportion score (TPS) and immune cells (IC) using a multiplex immunohistochemistry/immunofluorescence technique. Samples were obtained via biopsy or resection of gastric cancer. RESULTS: The percentage of PD-L1-positive samples at clinically relevant CPS ≥ 1, ≥ 5 and ≥ 10 cut-offs for the 28-8 assay were approximately two-fold higher than that of the 22C3 (CPS ≥ 1: 70.3 vs 49.4%, p < 0.001; CPS ≥ 5: 29.1 vs 13.4%, p < 0.001; CPS ≥ 10: 13.7 vs 7.0%, p = 0.004). The mean CPS score on 28-8 assay was nearly double that of the 22C3 (6.39 ± 14.5 vs 3.46 ± 8.98, p < 0.001). At the clinically important CPS ≥ 5 cut-off, there was only moderate concordance between the 22C3 and 28-8 assays. CONCLUSION: Our findings suggest that scoring PD-L1 CPS with the 28-8 assay may result in higher PD-L1 scores and higher proportion of PD-L1 positivity compared to 22C3 and other assays. Until stronger evidence of inter-assay concordance is found, we urge caution in treating the assays as equivalent.


Asunto(s)
Antígeno B7-H1 , Inmunoterapia , Neoplasias Gástricas , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Estudios Transversales , Humanos , Inmunohistoquímica , Neoplasias Gástricas/tratamiento farmacológico
2.
Mol Cancer ; 17(1): 29, 2018 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-29455654

RESUMEN

Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care.


Asunto(s)
Inhibidores de Proteínas Quinasas/uso terapéutico , Acrilamidas , Compuestos de Anilina , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Mutación/genética , Piperazinas/uso terapéutico
3.
Expert Rev Anticancer Ther ; 20(4): 233-240, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32186215

RESUMEN

Introduction: The treatment of lung cancer has changed dramatically with the development of tyrosine kinase inhibitors (TKIs) that target sensitizing somatic (gene) activations including anaplastic lymphoma kinase (ALK)-rearrangements. Despite remarkable initial responses, patients develop progressive disease via various resistance mechanisms, some of which are ALK dependent. Various next-generation ALK TKIs have been developed to improve on central nervous system (CNS) activity and also target the multitude of acquired resistance mechanisms. Of these, lorlatinib has the greatest spectrum of clinical activity against multiple ALK resistance mutations and has also demonstrated promising efficacy in patients with known brain metastases.Areas covered: We discuss the structure, pharmacology and efficacy of lorlatinib and also provide future perspectives in the management of patients with ALK-rearranged non-small cell lung cancer (NSCLC).Expert opinion: Patients invariably develop resistance during treatment with lorlatinib. Unique combinations of ALK resistance mutations may confer sensitivity to alternate ALK TKIs. There is a move toward individualized biomarker-driven treatment strategies to identify the select group of candidates that can benefit from existing therapies.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Lactamas Macrocíclicas/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Aminopiridinas , Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/genética , Reordenamiento Génico , Humanos , Lactamas , Lactamas Macrocíclicas/farmacología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles
4.
Expert Opin Drug Metab Toxicol ; 14(11): 1123-1138, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30360668

RESUMEN

INTRODUCTION: Aberrant cellular proliferation due to dysregulation of the cyclin-dependent kinase (CDK) retinoblastoma (Rb)-pathway occurs in several cancers. Selective inhibition of CDK4/6 is an attractive target particularly in hormone-receptor positive (HR+) metastatic breast cancer (MBC), where it has transformed the treatment of these cancers in recent years. Three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved for the treatment of HR+, HER2 negative (HER2-) MBC. Areas covered: We reviewed and compared the pharmacology, clinical efficacy, and toxicity profiles of the three CDK4/6 inhibitors and discussed several challenges in the use of these drugs, particularly in identifying biomarkers, optimizing dosing strategies, and finding best combinations with other therapies. Expert opinion: All three CDK4/6 inhibitors have shown remarkable efficacy when added to endocrine therapy in the treatment of HR+/HER2- MBC with consistent improvements in progression-free survival across all phase III trials. As efficacy appears similar between the drugs, differences in toxicities, dosing schedule, and monitoring requirements may influence the choice of CDK4/6 inhibitor. There is a paucity of predictive biomarkers that have been identified thus far, but a few promising biomarkers have been studied in the preclinical setting and results of ongoing clinical studies are awaited to validate their utility.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Aminopiridinas/administración & dosificación , Aminopiridinas/efectos adversos , Aminopiridinas/farmacología , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Femenino , Humanos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piperazinas/farmacología , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Purinas/administración & dosificación , Purinas/efectos adversos , Purinas/farmacología , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacología
5.
Target Oncol ; 13(2): 141-156, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29423594

RESUMEN

The treatment of lung cancer has changed dramatically with the development of tyrosine kinase inhibitors (TKIs) that target sensitizing somatic mutations of the epidermal growth factor receptor (EGFR). Despite remarkable initial responses, patients eventually develop progressive disease, with the most common cause of resistance to first-line EGFR TKIs being the acquired T790M mutation. Various third-generation EGFR TKIs have been developed to specifically target this acquired mutation, of which osimertinib is currently the only approved agent. In addition, the eagerly anticipated data from the FLAURA study recently found improved efficacy with increased progression-free survival (PFS) with osimertinib compared to standard of care first-generation EGFR TKIs in the first-line setting. Of note, osimertinib has also demonstrated promising efficacy in patients with known brain metastases. However, as patients invariably develop resistance during treatment with osimertinib, most commonly with the development of triple mutated EGFR (sensitizing mutations/T790M/C797S), which is resistant to all existing EGFR TKIs, efforts are currently ongoing to develop new strategies or novel compounds to specifically target this resistance mechanism.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores ErbB/farmacología , Receptores ErbB/uso terapéutico , Humanos , Inhibidores de Proteínas Quinasas/farmacología
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