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1.
Ann Oncol ; 29(8): 1869-1876, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29912274

RESUMO

Background: Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Patients and methods: Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly. Results: LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved. Conclusions: These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Neuroendócrino/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Neoplasias Encefálicas/secundário , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Estudo de Prova de Conceito , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/farmacologia , Piridinas/farmacologia , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Clin Endocrinol Metab ; 94(11): 4171-9, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19850694

RESUMO

BACKGROUND: We previously demonstrated comparable thyroid remnant ablation rates in postoperative low-risk thyroid cancer patients prepared for administration of 3.7GBq (131)I (100 mCi) after recombinant human (rh) TSH during T(4) (L-T4) therapy vs. withholding L-T4 (euthyroid vs. hypothyroid groups). We now compared the outcomes of these patients 3.7 yr later. PATIENTS AND METHODS: Fifty-one of the 63 original patients (28 euthyroid, 23 hypothyroid) participated. Forty-eight received rhTSH and serum thyroglobulin (Tg) sampling. A (131)I whole-body scan was performed in 43 patients, and successful ablation was defined by criteria from the previous study. Based on the criterion of uptake less than 0.1% in thyroid bed, 100% (43 of 43) remained ablated. When no visible uptake instead was used, five patients (four euthyroid, one hypothyroid) had minimal visible activity. When the TSH-stimulated Tg criterion was used, only two of 45 (one euthyroid, one hypothyroid) had a stimulated Tg level greater than 2 ng/ml. RESULTS: No patient in either group died, and no patient declared disease free had sustained tumor recurrence. Nine (four euthyroid, five hypothyroid) had received additional (131)I between the original and current studies due to detectable Tg or imaging evidence of disease; with follow-up, all now had a negative rhTSH-stimulated whole-body scan and seven (three euthyroid, four hypothyroid) had a stimulated serum Tg less than 2 ng/ml. CONCLUSIONS: In conclusion, after a median 3.7 yr, low-risk thyroid cancer patients prepared for postoperative remnant ablation either with rhTSH or after L-T4 withdrawal were confirmed to have had their thyroid remnants ablated and to have comparable rates of tumor recurrence and persistence.


Assuntos
Radioisótopos do Iodo/uso terapêutico , Hormônios Tireóideos/administração & dosagem , Neoplasias da Glândula Tireoide/radioterapia , Tireotropina/uso terapêutico , Adenocarcinoma Folicular/tratamento farmacológico , Adenocarcinoma Folicular/radioterapia , Adenocarcinoma Folicular/cirurgia , Adulto , Idoso , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/radioterapia , Carcinoma Papilar/cirurgia , Terapia Combinada , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Tireoglobulina/sangue , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Resultado do Tratamento
3.
J Clin Endocrinol Metab ; 94(4): 1310-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19158200

RESUMO

PURPOSE: The purpose of the study was to assess prospectively the impact of recombinant human TSH (rhTSH) administration on positron emission tomography (PET)/computed tomography (CT) imaging in differentiated thyroid cancer patients who, after primary treatment, had a suppressed or stimulated serum thyroglobulin greater than 10 ng/ml and no radioactive iodine uptake consistent with thyroid cancer on a whole body scan. PATIENTS AND METHODS: PET/CT was performed before (basal PET) and 24-48 h after rhTSH administration (rhTSH-PET) in 63 patients (52 papillary and 11 follicular thyroid cancers). Images were blindly analyzed by two readers. The proposed treatment plan was prospectively assessed before basal PET, after basal PET, and again after rhTSH-PET. RESULTS: A total of 108 lesions were detected in 48 organs in 30 patients. rhTSH-PET was significantly more sensitive than basal PET for the detection of lesions (95 vs. 81%; P = 0.001) and tended to be more sensitive for the detection of involved organs (94 vs. 79%; P = 0.054). However, basal PET and rhTSH-PET did not have significantly different sensitivity for detecting patients with any lesions (49 vs. 54%; P = 0.42). Changes in treatment management plan occurred in 19% of the patients after basal PET. Lesions found only by rhTSH-PET contributed to an altered therapeutic plan in eight patients, among whom only four were true-positive on pathology (6%). CONCLUSION: The use of rhTSH for 2-[18F]-fluoro-2-deoxy-D-glucose-PET/CT significantly increased the number of lesions detected, but the numbers of patients in whom any lesion was detected were no different between basal and rhTSH-stimulated PET/CT scans. Treatment changes due to true positive lesions occurred in 6% of cases.


Assuntos
Adenocarcinoma Folicular/diagnóstico por imagem , Fluordesoxiglucose F18 , Neoplasia Residual/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Tireotropina , Adenocarcinoma Folicular/patologia , Adenocarcinoma Folicular/cirurgia , Adulto , Idoso , Variação Genética , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Metástase Neoplásica/patologia , Projetos Piloto , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Proteínas Recombinantes , Sensibilidade e Especificidade , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Tomografia Computadorizada por Raios X
4.
J Clin Endocrinol Metab ; 91(3): 926-32, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16384850

RESUMO

CONTEXT: After surgery for differentiated thyroid carcinoma, many patients are treated with radioiodine to ablate remnant thyroid tissue. This procedure has been performed with the patient in the hypothyroid state to promote endogenous TSH stimulation and is often associated with hypothyroid symptoms and impaired quality of life. OBJECTIVE AND INTERVENTION: This international, randomized, controlled, multicenter trial aimed to compare the efficacy and safety of recombinant human TSH (rhTSH) to prepare euthyroid patients on L-thyroxine therapy (euthyroid group) to ablate remnant thyroid tissue with 3.7 GBq (100 mCi) 131I, compared with that with conventional remnant ablation performed in the hypothyroid state (hypothyroid group). Quality of life was determined at the time of randomization and ablation. After the administration of the 131-I dose, the rate of radiation clearance from blood, thyroid remnant, and whole body was measured. RESULTS: The predefined primary criterion for successful ablation was "no visible uptake in the thyroid bed, or if visible, fractional uptake less than 0.1%" on neck scans performed 8 months after therapy and was satisfied in 100% of patients in both groups. A secondary criterion for ablation, an rhTSH-stimulated serum thyroglobulin concentration less than 2 ng/ml, was fulfilled by 23 of 24 (96%) euthyroid patients and 18 of 21 (86%) hypothyroid patients (P = 0.2341). Quality of life was well preserved in the euthyroid group, compared with the hypothyroid group, as demonstrated by their lower pretreatment scores on the Billewicz scale for hypothyroid signs and symptoms, 27 +/- 7 vs. 18 +/- 4 (P < 0.0001) and their significantly higher Short Form-36 Health Assessment Scale scores in five of eight categories. Euthyroid patients had a statistically significant one third lower radiation dose to the blood, compared with patients in the hypothyroid group. CONCLUSIONS: This study demonstrates comparable remnant ablation rates in patients prepared for 131I remnant ablation with 3.7 GBq by either administering rhTSH or withholding thyroid hormone. rhTSH-prepared patients maintained a higher quality of life and received less radiation exposure to the blood.


Assuntos
Radioisótopos do Iodo/uso terapêutico , Neoplasias da Glândula Tireoide/radioterapia , Tireotropina/uso terapêutico , Adolescente , Adulto , Carcinoma/patologia , Carcinoma/radioterapia , Carcinoma/reabilitação , Feminino , Humanos , Radioisótopos do Iodo/farmacocinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Qualidade de Vida , Proteínas Recombinantes/uso terapêutico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/reabilitação , Resultado do Tratamento
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