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1.
Anticancer Res ; 39(9): 5149-5156, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519627

RESUMO

BACKGROUND: Factors associated with response to lenvatinib have not been clarified in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This study retrospectively analyzed 50 patients treated with lenvatinib as first-line therapy between March 2018 and March 2019. Patients were divided into two groups by the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) (responders and non-responders, whose best overall responses were complete (CR)/partial response (PR) and stable (SD)/progressive disease (PD), respectively). Factors associated with response were assessed, including the relative dose intensity 8 weeks after lenvatinib induction (8W-RDI). RESULTS: The best overall responses were 0/22/14/14 of CR/PR/SD/PD. Multivariate analysis revealed that only 8W-RDI was significantly associated with response. The receiver operating characteristic curve for 8W-RDI in differentiating responders from non-responders revealed a cut-off value of 75%. Patients with 8W-RDI ≥75% experienced a higher response rate and longer progression-free survival than patients with 8W-RDI <75%. CONCLUSION: Our results suggest that maintaining an RDI ≥75% during the initial 8 weeks of lenvatinib treatment has a favorable impact on response.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento
3.
Expert Opin Drug Metab Toxicol ; 15(9): 767-774, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31478386

RESUMO

Introduction: The phosphatidylinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway has emerged as an important target in cancer therapy. Numerous PI3K/AKT/mTOR pathway inhibitors are extensively studied; some are used clinically, but most of these drugs are undergoing clinical trials. Potential adverse effects, such as severe hepatotoxicity and pneumonitis, have largely restricted the application and clinical significance of these inhibitors. A summary of mechanisms underlying the adverse effects is not only significant for the development of novel PI3K/AKT/mTOR inhibitors but also beneficial for the optimal use of existing drugs. Areas covered: We report a profile of the adverse effects, which we consider the class effects of PI3K/AKT/mTOR inhibitors. This review also discusses potential molecular toxicological mechanisms of these agents, which might drive future drug discovery. Expert opinion: Severe toxicities associated with PI3K/AKT/mTOR inhibitors hinder their approval and limit long-term clinical application of these drugs. A better understanding regarding PI3K/AKT/mTOR inhibitor-induced toxicities is needed. However, the mechanisms underlying these toxicities remain unclear. Future research should focus on developing strategies to reduce toxicities of approved inhibitors as well as accelerating new drug development. This review will be useful to clinical, pharmaceutical, and toxicological researchers.


Assuntos
Antineoplásicos/efeitos adversos , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/efeitos adversos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Humanos , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores
4.
Expert Rev Clin Pharmacol ; 12(9): 841-849, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31454267

RESUMO

Introduction: The receptor tyrosine kinase FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). FLT3-internal tandem duplication mutations are associated with an increased risk of relapse, and a number of small molecule inhibitors of FLT3 have been developed. The highly potent and selective FLT3 kinase inhibitor gilteritinib is the first tyrosine kinase inhibitor approved as monotherapy for the treatment of relapsed and/or refractory FLT3-mutated AML. Areas covered: We review the biology and prognostic significance of FLT3 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of gilteritinib. We also summarize important differences among the various FLT3 inhibitors that are currently approved or under development and highlight areas of ongoing research. Expert opinion: Gilteritinib has been shown to improve survival compared to salvage chemotherapy in relapsed and/or refractory FLT3-mutated AML. Gilteritinib is orally available with a favorable toxicity profile and as such is quickly becoming the standard of care for this patient population. Ongoing clinical trials are evaluating gilteritinib in combination with frontline chemotherapy, in combination with other agents such as venetoclax and azacitidine for patients who are ineligible for standard induction therapy, and as a maintenance agent.


Assuntos
Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Pirazinas/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Recidiva , Sobrevida , Tirosina Quinase 3 Semelhante a fms/genética
5.
J Cancer Res Clin Oncol ; 145(10): 2613-2624, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31463717

RESUMO

PURPOSE: To determine the frequency of co-occurring genes in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and the predictive effect of co-mutations on the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). METHODS: 54 patients with advanced NSCLC were tested for 422 clinically relevant genes by next-generation sequencing (NGS) before treatment. Among them, patients with EGFR mutation received first-line treatment of EGFR-TKIs. Progression-free survival (PFS) and objective response rate (ORR) were evaluated using Kaplan-Meier methods and compared between two groups using log-rank test. RESULTS: Among 24 EGFR mutant and 30 EGFR wild-type patients, co-mutation rate was lower in patients with EGFR mutation (62.5% [15/24] vs 93.3% [28/30], p = 0.005). There was lower frequency for co-alterations in BRAF (0% [0/24] vs 20% [7/30], p = 0.033), NF1 (4.2% [1/24] vs 30% [9/30], p = 0.038) and RAS-RAF-MAPK pathway genes (16.6% [4/24] vs 56.7% [17/30], p = 0.003) in EGFR mutation group. 24 patients with EGFR mutation received first-line treatment of gefitinib or erlotinib, with an ORR of 83.3% and a median PFS of 12.3 months (95% CI 10.00-14.60). Co-mutation was associated with shorter median PFS (10.2 months [95% CI 5.20-15.20] vs 15.3 months [95% CI 12.09-15.81]; HR 0.29 [95% CI 0.10-0.82]; p = 0.014) in EGFR mutation cohort. Among patients with EGFR mutation and distant metastasis, median PFS was decreased in those with co-mutations (6.3 months [95% CI 3.25-9.35] vs 22.0 months[95% CI 12.10-31.90]; HR 0.12 [95% CI 0.00-5.87]; p = 0.007) and frequency of PIK3CA (0% [0/12] vs 41.7% [5/12], p = 0.037) and PI3K/AKT/mTOR pathway genes (0% [0/12] vs 50% [6/12], p = 0.014) was lower. CONCLUSION: The presence of co-mutations was lower in the EGFR mutation patients and reduces the efficacy of EGFR-TKI, especially in patients with distant metastases. Lower frequency of co-mutation in PIK3CA and PI3K/AKT/mTOR pathway genes may be responsible for promoting metastasis and limiting the efficacy of EGFR-TKIs.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
6.
Medicine (Baltimore) ; 98(35): e16919, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464927

RESUMO

Antiangiogenic therapy has shown clinical benefit in metastatic colorectal cancer (mCRC). We aimed to evaluate the efficacy and safety of apatinib in patients who failed standard treatment and to explore potential factors related to its efficacy.A total of 47 patients were enrolled in this retrospective study. Patients who received apatinib therapy after failure of standard therapy from December 2014 and February 2018 were included. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events were recorded and evaluated.The median PFS was 3.717 months (95% confidence interval [CI], 3.198-4.235), and the median OS was 7.335 months (95% CI, 6.738-7.932). The disease control rate was 72.34%, and the ORR was 8.51%. The most common grade 3 to 4 adverse reactions were hypertension, proteinuria, hand-foot syndrome, and diarrhea. Multivariate analysis indicated previous antiangiogenic therapy and baseline elevated neutrophil-to-lymphocyte ratio (NLR) as independent prognostic factors.Apatinib might be a reasonable treatment option with a controlled safety profile for patients with mCRC who have failed standard therapy. Patients who previously received antiangiogenic therapy and who have baseline elevated NLR are more likely to benefit from apatinib.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Administração Oral , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Análise Multivariada , Prognóstico , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
7.
Cancer Sci ; 110(9): 2884-2893, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31265163

RESUMO

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard of care for non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression-free survival (PFS) over platinum-doublet chemotherapy in patients with T790M-positive NSCLC who had progressed on previous EGFR-TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre-planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all-cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1-2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.


Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Acrilamidas/efeitos adversos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Exantema/induzido quimicamente , Exantema/epidemiologia , Humanos , Japão/epidemiologia , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Paroniquia/induzido quimicamente , Paroniquia/epidemiologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Análise de Sobrevida , Taxa de Sobrevida
8.
Cancer Invest ; 37(6): 253-264, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31303065

RESUMO

We fully investigate the skin toxicities of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in cancer patients. The studies about randomized controlled trials in cancer treatment with EGFR-TKIs were retrieved and the systematic evaluation was conducted. The results suggest that EGFR-TKIs significantly increase the risk of skin toxicities including all-grade rash, pruritus, dry skin, and high-grade rash, pruritus. However, the risk of high-grade dry skin did not increase. Rash was the most common toxicity. Physicians should be aware of skin toxicities and should monitor cancer patients when receiving EGFR-TKIs.


Assuntos
Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pele/efeitos dos fármacos , Exantema/induzido quimicamente , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Cancer Treat Rev ; 77: 57-66, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31279169

RESUMO

One of the major complications that patients experience during pharmacological treatment is the occurrence of adverse drug reactions (ADRs). The most affected organs are the liver, kidney, heart and the gastrointestinal-immune system. In comparison to the other organs, less progress has been made on human-relevant prediction of drug-induced intestinal toxicity, evidencing current large data gaps. The most widely used drugs that are associated with intestinal damage include chemotherapeutics, such as 5-Fluorouracil or Tyrosine Kinase Inhibitors (TKIs), as well as non-steroidal anti-inflammatory drugs (NSAIDs). Chemotherapeutics are regarded as inducers of acute intestinal toxicity whereas NSAIDs are associated with chronic inflammation of the intestine. In view of the fact that only a few studies have been dedicated to studying cellular and genomic responses in relation to drug-induced intestinal ADRs, little is known about how intestinal toxicity develops after exposure to such drugs or which molecular mechanisms are involved. Therefore, new models and experiments are required to establish transcriptomic responses and alterations of molecular markers induced by different medicines. This review summarizes the available information about transcriptomic responses and biomarkers of toxicity induced by 5-FU, NSAIDS or TKIs in different experimental models. Future investigation should address the challenges in predicting intestinal toxicity induced by drugs and unveil specific gene expression profiles that can be applied in the development of safer drugs.


Assuntos
Enteropatias/induzido quimicamente , Enteropatias/genética , Transcriptoma/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/efeitos adversos , Fluoruracila/efeitos adversos , Humanos , Inibidores de Proteínas Quinases/efeitos adversos
10.
Anticancer Res ; 39(7): 3871-3878, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262915

RESUMO

BACKGROUND: Lenvatinib has become an important treatment option for advanced thyroid cancer. Fistula and tumor-related bleeding are life-threatening adverse effects that are triggered by tumor shrinkage. The aim of this study was to evaluate basic parameters, such as time and tumor shrinkage level, and analyze patient characteristics that might be related to onset of complications. PATIENTS AND METHODS: A retrospective study of 16 patients who received lenvatinib for thyroid cancer treatment was performed. RESULTS: Fistula was observed in two patients (12.5%), while tumor-related bleeding was observed in one (6.3%). Complications were found to appear at 10.4 weeks from initiation and with tumor decrease of 19.2%. Risk factors for complications were identified as anaplastic histological type, tumor invasion, and leukocytopenia induced by lenvatinib. CONCLUSION: Individual dose adjustment is needed with respect to these features in order to manage severe adverse effects induced by lenvatinib.


Assuntos
Antineoplásicos/efeitos adversos , Fístula/induzido quimicamente , Hemorragia/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/patologia
11.
Anticancer Res ; 39(7): 3955-3959, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262927

RESUMO

BACKGROUND: Spindle cell oncocytoma (SCO) is a rare non-neuroendocrine neoplasm of the pituitary gland. In general, surgical excision and radiation therapy is performed. However, local recurrences are frequently seen, requiring repeated surgical and radio-oncological interventions. Thus, mutational analysis of the tumor and targeted therapy may represent a valuable therapy option in these patients. CASE REPORT: A 38-year-old female patient with past medical history of 6 surgeries (two transsphenoidal and four transcranial), radiation therapy, and chemoradiation therapy due to several recurrences of a SCO, presented for follow-up imaging. MRI of the brain showed growth of a tumor in the right parasellar region consistent with a new local recurrence, which due to its size and location was considered to be not resectable. Molecular analysis of a previously surgically removed tumor showed a BRAF V600E mutation and thus, combined targeted inhibition of the MAPK/ERK signaling pathway using a BRAF inhibitor and a MEK inhibitor was started. Due to drug-induced panniculitis, MEK inhibitor had to be stopped and BRAF inhibitor only was continued, which was well tolerated by the patient. Subsequent imaging revealed tumor regression already four weeks after therapy initiation and no disease progression has been observed to date. CONCLUSION: A SCO patient with BRAF V600E mutation was successfully treated using targeted inhibition of the MAPK/ERK signaling pathway. Under therapy, tumor regression was observed and the patient has been free of progressive disease for more than two years now. Thus, mutational analysis and targeted inhibition may offer an effective treatment option for SCO patients, while potential side-effects to this therapy, like observed in our case, can occur and needs to be adequately treated.


Assuntos
Adenoma Oxífilo/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Paniculite/induzido quimicamente , Neoplasias Hipofisárias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Adenoma Oxífilo/genética , Adulto , Feminino , Humanos , Mutação , Paniculite/genética , Neoplasias Hipofisárias/genética
13.
Medicine (Baltimore) ; 98(26): e16065, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261514

RESUMO

BACKGROUND: Apatinib is an oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Some clinical trials have demonstrated that apatinib is efficacious against advanced nonsquamous NSCLC. OBJECTIVE: This study aimed to probe efficacy and safety of apatinib plus docetaxel, as the second or above line treatment, in advanced nonsquamous NSCLC. DESIGN: Multicenter, prospective, single arm study. SETTING: Three teaching hospitals centers in the Sichuan. PARTICIPANTS: Fourteen patients with stage IVA/B nonsquamous NSCLC had previously received at least 1 platinum-based chemotherapy regimen. INTERVENTION: Patients who were enrolled between November 2016 and January 2018 were given docetaxel (75 mg/m, i.v., d1) plus oral apatinib (250 mg/d), 4 weeks as one cycle, until disease progression or intolerance to adverse events (AE). MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival (PFS). The secondary endpoints comprised objective response rate (ORR), disease control rate (DCR), overall survival (OS), and AE incidence rate. RESULTS: All patients carried adenocarcinoma by pathological type. The median follow-up duration was 9.76 months. Out of 14 cases, 12 were evaluable, showing ORR of 33.33%, DCR of 66.67%, DCR of 50% in cases with brain metastasis, median PFS of 2.92 months (95% CI: 1.38-4.48), and 6-month OS of 80%. Primary AEs encompassed: leukopenia in 7 cases (58.33%), hand-foot skin reaction in 5 cases (41.67%), and diarrhea in 4 cases (33.33%). Among them, grade 3 AEs were: leukopenia in 4 cases (33.33%), and hand-foot skin reaction in 1 case (8.33%). No grade 4/5 AEs were reported. Univariate and multivariate analysis were conducted respectively for PFS and OS. These factors encompassed: gender, age, gene mutations, clinical stage, ECOG scores, quantity of metastatic foci, brain metastasis, and hand-foot skin reaction. Results demonstrated zero risk factors for PFS or OS. CONCLUSION: Apatinib plus docetaxel, as the second or above line treatment, is effective and safe against advanced nonsquamous NSCLC, with good tolerance profile. TRIAL REGISTRATION: NCT03416231.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Progressão da Doença , Docetaxel/efeitos adversos , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Dados Preliminares , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/efeitos adversos , Retratamento , Análise de Sobrevida , Resultado do Tratamento , Moduladores de Tubulina/efeitos adversos , Moduladores de Tubulina/uso terapêutico
14.
Gan To Kagaku Ryoho ; 46(5): 891-894, 2019 May.
Artigo em Japonês | MEDLINE | ID: mdl-31189810

RESUMO

We retrospectively investigated hypophosphatemia induced byty rosine kinase inhibitors(TKIs), in patients with chronic myeloid leukemia. Subjects evaluated were 14, 11, and 8 patients who received TKIs(imatinib, dasatinib and nilotinib), respectively, at the Department of Hematology in Ichinomiya Municipal Hospital, between 1st January 2006 and 31st Decem- ber 2016. The incidence of hypophosphatemia was 85.7%(12/14)for imatinib, 18.2%(2/11)for dasatinib, and 37.5%(3/ 8)for nilotinib, and hypophosphatemiaBgrade 3 occurred in 57.1%(8/14)of imatinib- and 9.1%(1/11)of dasatinibtreated patients. Instances of hypophosphatemiaBgrade 3 were not confirmed for nilotinib. Six patients received oral phosphate for hypophosphatemia, and all of these were patients who had been administered imatinib. We confirmed a significant improvement(p<0.05, 95%CI: 0.111-0.989)in serum phosphate levels after administration of oral phosphate, suggesting that it constitutes an effective measure against this situation.


Assuntos
Hipofosfatemia , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases/efeitos adversos , Antineoplásicos , Humanos , Hipofosfatemia/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas Tirosina Quinases , Estudos Retrospectivos
15.
Lancet ; 394(10197): 478-487, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31229240

RESUMO

BACKGROUND: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection. METHODS: This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369. FINDINGS: Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27-53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy. INTERPRETATION: Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery. FUNDING: Daiichi Sankyo.


Assuntos
Antineoplásicos/administração & dosagem , Tumor de Células Gigantes de Bainha Tendinosa/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
16.
N Engl J Med ; 381(7): 626-636, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31166680

RESUMO

BACKGROUND: Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors. METHODS: We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. RESULTS: A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. CONCLUSIONS: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/administração & dosagem , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Seguimentos , Humanos , Imidazóis/efeitos adversos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Oximas/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem
17.
Croat Med J ; 60(3): 250-254, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31187953

RESUMO

We present the case of a 33-year-old chronic myeloid leukemia (CML) female patient, in whom the occurrence of nephrotic syndrome, during the treatment with tyrosine kinase activity inhibitors (TKIs), was potentially influenced by transient phenoconversion. Seven years after the CML diagnosis in 2004 and complete response, the patient experienced pain in the mandible and extremities. After this, imatinib was replaced by nilotinib, but generalized maculopapular rash was presented and successfully treated with antihistamines. The therapy was then discontinued due to planned pregnancy, and the patient experienced a relapse of CML with BCR-ABL/ABL1 transcripts of 18.9%. Dasatinib was introduced, and CML was in remission. Two years later, urine protein levels (6.19 g/L) and erythrocyte sedimentation rate were elevated (ESR=90 mm/3.6 ks). The patient was diagnosed with nephrotic syndrome. With dasatinib dose reduction, urine protein level returned to the reference range. In order to determine the best genotype-guided therapy, the patient underwent pharmacogenomic testing, showing a homozygous CYP3A4 genotype *1/*1, associated with extensive metabolizer (EM) enzyme phenotype, typical for normal rates of drug metabolism for TKIs. However, this was inconsistent with nephrotic syndrome occurrence. A possible explanation would be CYP3A4 EM genotype coding a poor metabolizer enzyme phenotype, leading to the drug accumulation in the patient's blood. This transient phenoconversion can be explained by inflammation with elevated ESR during nephrotic syndrome. This case shows that a broader approach that recognizes genetic, clinical, and epigenomic factors is required for a quality decision on the personalized therapy regimen.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Dasatinibe/efeitos adversos , Dasatinibe/metabolismo , Síndrome Nefrótica/induzido quimicamente , Adulto , Citocromo P-450 CYP3A/genética , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Testes Farmacogenômicos , Fenótipo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/uso terapêutico
18.
N Engl J Med ; 381(4): 307-316, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31166679

RESUMO

BACKGROUND: An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival. METHODS: We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87). CONCLUSIONS: This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).


Assuntos
Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Purinas/administração & dosagem , Adulto , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Pessoa de Meia-Idade , Perimenopausa , Pré-Menopausa , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/efeitos adversos , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona , Análise de Sobrevida , Tamoxifeno/administração & dosagem
19.
Crit Rev Oncol Hematol ; 141: 23-35, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202955

RESUMO

Recently, tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICPIs) have emerged as new classes of anticancer therapies. Although generally considered less toxic than cytotoxic chemotherapy, these new drugs can cause significant unanticipated side effects including thyroid dysfunction. This review provides a literature assessment of thyroid dysfunctions induced by TKI and ICPIs. We intend to define for these two classes the frequency of thyroid involvement, the potential mechanisms that result in this toxicity, the clinical-biological impact and the therapeutic management. Detection of thyroid dysfunction requires monitoring of TSH, in combination with free T4 if needed and, depending on the clinical impact and the kinetics of biological abnormalities, starting symptomatic treatment of hyperthyroidism and/or correcting hypothyroidism.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Doenças da Glândula Tireoide/induzido quimicamente , Antineoplásicos Imunológicos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/diagnóstico , Hipotireoidismo/patologia , Hipotireoidismo/terapia , Neoplasias/fisiopatologia , Inibidores de Proteínas Quinases/uso terapêutico , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/patologia , Doenças da Glândula Tireoide/terapia , Testes de Função Tireóidea
20.
Lancet Haematol ; 6(8): e419-e428, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31208944

RESUMO

BACKGROUND: Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. We postulated that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia. METHODS: We did a multicentre, open-label, non-randomised, single-arm phase 2 trial at seven sites in the USA. We enrolled patients aged 65 years or younger with previously untreated chronic lymphocytic leukaemia. Our initial cohort (original cohort) was not restricted by prognostic marker status and included patients who had del(17p) or TP53 aberrations. After a protocol amendment (on March 21, 2017), we enrolled an additional cohort (expansion cohort) that included patients without del(17p). Ibrutinib was given orally (420 mg/day) for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine (25 mg/m2, days 1-3), cyclophosphamide (250 mg/m2, days 1-3), and rituximab (375 mg/m2 day 1 of cycle 1; 500 mg/m2 day 1 of cycles 2-6) with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR. Analyses were done per-protocol in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT02251548) and is ongoing. FINDINGS: Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years (IQR 50-58). At data cutoff, median follow-up was 16·5 months (IQR 10·6-34·1). A complete response and undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23-0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance, assessed as possibly related to ibrutinib). The most common all-grade toxic effects were haematological, including thrombocytopenia in 63 (74%) patients, neutropenia in 53 (62%), and anaemia in 41 (49%). Grade 3 or 4 non-haematological serious adverse events included grade 3 atrial fibrillation in three (4%) patients and grade 3 Pneumocystis jirovecii pneumonia in two (2%). INTERPRETATION: The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status. Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients. FUNDING: Pharmacyclics and the Leukemia & Lymphoma Society.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Rituximab/administração & dosagem , Vidarabina/análogos & derivados , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Esquema de Medicação , Feminino , Doenças Hematológicas/etiologia , Doenças Hematológicas/patologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Indução de Remissão , Rituximab/efeitos adversos , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos
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