RESUMO
BACKGROUND: Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported. METHODS: In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point. RESULTS: The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group. CONCLUSIONS: Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.).
Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/efeitos adversos , Idoso , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Método Duplo-Cego , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
BACKGROUND: Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC). METHODS: Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety. RESULTS: The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C. CONCLUSION: We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases. TRIAL REGISTRATION: EudraCT Number: 2013-003894-87; registered 09-September-2013.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Capecitabina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Resultado do Tratamento , Vinorelbina/administração & dosagem , Vinorelbina/efeitos adversos , Vinorelbina/uso terapêuticoRESUMO
OBJECTIVE: Research biopsies are increasingly incorporated into phase I oncology trials resulting in ethical and logistical challenges for patients and clinicians. Patients' understanding and willingness to undergo these biopsies are crucial. METHODS: Over 12 months, we administered a questionnaire comprising three sections: demographics and previous cancer therapy, understanding of phase I trials and personalized medicine, and understanding of biopsies and associated risks. RESULTS: Out of 56 patients approached, 47 patients completed the questionnaire. Overall, the patients were well informed about the concepts of personalized medicine and 89% (n = 42) were aware that early phase clinical trials aim to define a dose and explore side effects of new drugs. Interestingly, 76% (n = 36) expected early phase trials to improve symptoms, quality of life and survival. Offering hope and feeling in control of their treatment were important components for 80% (n = 38) and 57% (n = 27), respectively. The majority of this highly selective patient cohort understood the concept of research biopsies, with 59% (n = 28) willing to have a fresh research biopsy for trial participation. Although 72% (n = 34) felt that research biopsies should be optional, only 19% (n = 9) would not participate in a clinical trial with mandatory biopsies. Compared to diagnostic biopsies, the patients were less likely to accept associated risks with research biopsies. CONCLUSION: As research biopsies are crucial to many components of the drug development process, our study provides evidence for patients' overall willingness to undergo research biopsies for trial purposes. A consent process tailored to the biopsy site may help patients weigh up the associated risks versus benefits.
Assuntos
Biópsia , Ensaios Clínicos Fase I como Assunto , Neoplasias/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Percepção , Medicina de Precisão , Inquéritos e QuestionáriosRESUMO
The LAURA trial (NCT03521154) will evaluate the efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable, epidermal growth factor receptor mutation-positive (EGFRm), stage III non-small-cell lung cancer (NSCLC) without disease progression during/following definitive platinum-based chemoradiation therapy (CRT). Eligible patients include adults aged ≥ 18 years (≥ 20 years in Japan) with locally advanced, unresectable, stage III NSCLC with local/central confirmation of an EGFR exon 19 deletion/L858R mutation. Patients must have received ≥ 2 cycles of concurrent/sequential platinum-based CRT, have no investigator-assessed progression, and have creatinine < 1.5 × upper limit of normal and creatinine clearance ≥ 30 mL/min. In this phase III trial, patients will be randomized 2:1 to once-daily osimertinib 80 mg or placebo, until objective radiological disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, confirmed by blinded independent central review (BICR). The primary objective is to assess the efficacy of osimertinib per BICR-confirmed progression-free survival (PFS). Secondary objectives include central nervous system PFS, overall survival, PFS by mutation status and safety. Patients with BICR-confirmed disease progression (or investigator-confirmed progression if after primary PFS analysis) may be unblinded and receive open-label osimertinib; all will have post-progression follow-up. Serious adverse events and adverse events of special interest will be collected throughout the trial and survival follow-up. The first patient was enrolled in July 2018, with results expected in late 2022.
Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Acrilamidas/efeitos adversos , Compostos de Anilina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiorradioterapia , Método Duplo-Cego , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/patologia , Mutação , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Taxa de SobrevidaRESUMO
BACKGROUND: In the global FLAURA study, first-line osimertinib, a third-generation irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), significantly improved progression-free survival (PFS) and overall survival (OS) versus comparator EGFR TKIs in patients with EGFR mutation-positive (EGFRm) advanced non-small-cell lung cancer (NSCLC). OBJECTIVE: The FLAURA China study assessed first-line osimertinib in Chinese patients with EGFRm advanced NSCLC (NCT02296125). METHODS: FLAURA China was a double-blind, randomized, phase III study. Adults from mainland China with previously untreated EGFRm (Exon 19 deletion or L858R) advanced NSCLC were enrolled in the global study or a China-only study under the same protocol; 136 patients were randomized to osimertinib (80 mg once daily [od]; n = 71) or comparator EGFR TKI (gefitinib or erlotinib; all sites selected gefitinib 250 mg od; n = 65). Patients were randomized and allocated to treatment groups by a central computer system. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint. RESULTS: All 136 randomized patients were analyzed. Osimertinib extended median PFS by 8.0 months versus comparator EGFR TKI (17.8 vs. 9.8 months; hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37-0.85). Median OS was 33.1 months in the osimertinib group versus 25.7 months in the comparator group (HR 0.85; 95% CI 0.56-1.29). At 3 years, 20% of patients on osimertinib and 8% on the comparator remained on randomized treatment. Grade 3 or higher adverse events (AEs) were reported in 54 and 28% of patients in the osimertinib and comparator groups, respectively, driven by increased local reporting of laboratory- and disease-related AEs. No new safety signals were identified. CONCLUSIONS: First-line osimertinib treatment resulted in a clinically meaningful PFS and OS benefit versus comparator EGFR TKI in Chinese patients with EGFRm advanced NSCLC. Safety data were consistent with the known safety profile of osimertinib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02296125, registered 20 November 2014.
Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/farmacologia , China , Método Duplo-Cego , Receptores ErbB/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologiaRESUMO
INTRODUCTION: EGFR mutated (EGFRm) NSCLC tumors occasionally express programmed cell death ligand 1 (PD-L1), although frequency and clinical relevance are not fully characterized. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following treatment with osimertinib or comparator EGFR tyrosine kinase inhibitors in the FLAURA trial (phase III, NCT02296125). METHODS: Of 231 tissue blocks available from the screened population (including EGFRm-positive and -negative samples), 197 had sufficient tissue for PD-L1 testing using the SP263 (Ventana, Tucson, Arizona) immunohistochemical assay. Tumor cell (TC) staining thresholds of PD-L1 TC greater than or equal to 1%, TC greater than or equal to 25%, and TC greater than or equal to 50% were applied. Progression-free survival (PFS) was investigator-assessed, per Response Evaluation Criteria in Solid Tumor, version 1.1, according to PD-L1 expressors (TC ≥ 1%) or negatives (TC < 1%) in randomized patients. RESULTS: PD-L1 staining was successful in 193 of 197 patient formalin-fixed paraffin-embedded blocks; of these, 128 of 193 were EGFRm-positive and 106 of 128 patients were randomized to treatment (osimertinib: 54; comparator: 52). At the PD-L1 TC greater than or equal to 25% threshold, 8% (10 of 128) of EGFRm-positive tumors expressed PD-L1 versus 35% (23 of 65) of EGFRm-negative tumors. With the TC greater than or equal to 1% threshold, 51% (65 of 128) versus 68% (44 of 65) were mutation-positive and -negative, respectively, and with the TC greater than or equal to 50% threshold, 5% (7 of 128) versus 28% (18 of 65), were mutation-positive and -negative, respectively. For PD-L1 expressors (TC ≥ 1%), median PFS was 18.4 months with osimertinib and 6.9 months with comparator (hazard ratio = 0.30; 95% confidence interval: 0.15-0.60). For PD-L1-negative patients (TC < 1%), median PFS was 18.9 months with osimertinib and 10.9 months with comparator (hazard ratio = 0.37; 95% confidence interval: 0.17-0.74). CONCLUSIONS: Clinical benefit with osimertinib was unaffected by PD-L1 expression status.
Assuntos
Antineoplásicos , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina , Antineoplásicos/uso terapêutico , Apoptose , Antígeno B7-H1/genética , Antígeno B7-H1/uso terapêutico , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MutaçãoRESUMO
INTRODUCTION: Here we report efficacy and safety data of an Asian subset of the phase III FLAURA trial (NCT02296125), which compares osimertinib with standard of care (SoC) EGFR tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced NSCLC with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR TKI-sensitizing mutations. METHODS: Eligible Asian patients (enrolled at Asian sites) who were at least 18 years of age (≥20 years in Japan) and had untreated EGFR-mutated advanced NSCLC were randomized 1:1 to receive osimertinib (80 mg, orally once daily) or an SoC EGFR TKI (gefitinib, 250 mg, or erlotinib, 150 mg, orally once daily). The primary end point was investigator-assessed progression-free survival (PFS). The key secondary end points were overall survival, objective response rate, central nervous system efficacy, and safety. RESULTS: The median PFS was 16.5 versus 11.0 months for the osimertinib and SoC EGFR TKI groups, respectively (hazard ratio = 0.54, 95% confidence interval: 0.41-0.72, p < 0.0001). The overall survival data were immature (24% maturity). The objective response rates were 80% for osimertinib and 75% for an SoC EGFR TKI. The median central nervous system PFS was not calculable for the osimertinib group and was 13.8 months for the SoC EGFR TKI group (hazard ratio = 0.55, 95% confidence interval: 0.25-1.17, p = 0.118). Fewer adverse events of grade 3 or higher (40% versus 48%) and fewer adverse events leading to treatment discontinuation (15% versus 21%) were reported with osimertinib versus with an SoC EGFR TKI, respectively. CONCLUSION: In this Asian population, first-line osimertinib demonstrated a clinically meaningful improvement in PFS over an SoC EGFR TKI, with a safety profile consistent with that for the overall FLAURA study population.
Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/farmacologia , Adulto , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Povo Asiático , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Adulto JovemRESUMO
PURPOSE: To assess the utility of the cobas EGFR Mutation Test, with tissue and plasma, for first-line osimertinib therapy for patients with EGFR-mutated (EGFRm; Ex19del and/or L858R) advanced or metastatic non-small cell lung cancer (NSCLC) from the FLAURA study (NCT02296125). EXPERIMENTAL DESIGN: Tumor tissue EGFRm status was determined at screening using the central cobas tissue test or a local tissue test. Baseline circulating tumor (ct)DNA EGFRm status was retrospectively determined with the central cobas plasma test. RESULTS: Of 994 patients screened, 556 were randomized (289 and 267 with central and local EGFR test results, respectively) and 438 failed screening. Of those randomized from local EGFR test results, 217 patients had available central test results; 211/217 (97%) were retrospectively confirmed EGFRm positive by central cobas tissue test. Using reference central cobas tissue test results, positive percent agreements with cobas plasma test results for Ex19del and L858R detection were 79% [95% confidence interval (CI), 74-84] and 68% (95% CI, 61-75), respectively. Progression-free survival (PFS) superiority with osimertinib over comparator EGFR-TKI remained consistent irrespective of randomization route (central/local EGFRm-positive tissue test). In both treatment arms, PFS was prolonged in plasma ctDNA EGFRm-negative (23.5 and 15.0 months) versus -positive patients (15.2 and 9.7 months). CONCLUSIONS: Our results support utility of cobas tissue and plasma testing to aid selection of patients with EGFRm advanced NSCLC for first-line osimertinib treatment. Lack of EGFRm detection in plasma was associated with prolonged PFS versus patients plasma EGFRm positive, potentially due to patients having lower tumor burden.
Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/administração & dosagem , Acrilamidas/efeitos adversos , Alelos , Substituição de Aminoácidos , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Tomada de Decisão Clínica , Ensaios Clínicos Fase III como Assunto , Gerenciamento Clínico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Lung cancer continues to be the leading cause of cancer death in Western countries. The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor and chemotherapy is the treatment of choice for most patients with metastatic NSCLC. Platinum-based chemotherapy has long been the standard of care for advanced NSCLC. The formation of new blood vessels (angiogenesis) is needed for the growth and invasiveness of primary tumours, and plays an important role in metastatic growth. Vascular endothelial growth factor (VEGF) has emerged as a key potential target for the pharmacological inhibition of tumour angiogenesis. This review discusses current data and the future potential of bevacizumab, a recombinant humanized monoclonal antibody that binds VEGF, in the treatment of NSCLC. Results from a phase II study showed that the addition of bevacizumab to the first-line chemotherapy with paclitaxel and carboplatin (CP) may increase the overall survival (OS) and the time to progression in advanced NSCLC. Based on these promising results, a randomized phase III trial compared the combination of bevacizumab with CP versus CP alone in the treatment of advanced non-squamous NSCLC. The combination of CP plus bevacizumab led to a statistically significant increase in median OS and progression-free survival (PFS) compared with CP alone, with a response rate (RR) in the CP arm of 15% compared with 35% in the bevacizumab plus CP arm (p < 0.001). More recently, the randomized AVAIL (Avastin in Lung Cancer) study, which evaluated cisplatin with gemcitabine plus bevacizumab in two different dosages versus chemotherapy alone in 1043 patients with recurrent or advanced non-squamous NSCLC, reported a significant increase of PFS, RR and duration of response for both of the bevacizumab-containing arms. Bevacizumab has also been investigated in combination with erlitonib as second-line treatment in two small early phase trials, with interesting results. Bevacizumab was generally well tolerated in clinical trials; the main treatment-associated adverse events were neutropenia and haemorrhage, especially in the lung, but also at other sites. Several trials that incorporate bevacizumab in combination with new active drugs in NSCLC are ongoing and should further help to define the place of bevacizumab in the therapy of NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: Urothelial cancers (UC) are the fourth most common tumours worldwide after prostate (or breast), lung and colorectal cancer. Despite recent improvements in their management, UC remain an aggressive disease associated with a poor outcome. Following disease progression on first-line platinum-based chemotherapy, very few effective treatment options are available and none of them have shown significant improvement in overall survival. Alterations of the fibroblast growth factor receptor (FGFR) pathway including amplification, mutations and overexpression are common in UC. Pre-clinical data suggest that the presence of such dysregulations may confer sensitivity to FGFR inhibitors. MATERIALS AND METHODS: We present here the case of a patient with a metastatic UC of the renal pelvis with lymph node metastases treated with the selective FGFR inhibitor AZD4547. RESULTS: To date, the patient has been on a study drug for 32 months with acceptable tolerance and maintained radiological partial response as per RECIST 1.1 criteria. Exploratory biomarker analysis showed FGFR3, FGFR1, FGF-ligand and fibroblast growth factor receptor substrate 2 (FRS2) expression in the patient's tumour, together with the presence of a germ-line mutation in the FGFR3 extracellular binding domain. This is not a known hotspot mutation, and the functional significance remains unclear. CONCLUSIONS: The FGFR inhibitor AZD4547 exhibits antitumour activity in a metastatic urothelial cancer displaying FGFR1, FGFR3, FGF-ligand and FRS2 expression. This lends support to the further exploration of FGFR inhibitors in urothelial cancer. Further studies are required to determinate the most effective way to select those patients most likely to respond.
Assuntos
Receptores ErbB/genética , Transdução de Sinais/genética , Neoplasias Ureterais/genética , Neoplasias da Bexiga Urinária/genética , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pelve Renal/metabolismo , Pelve Renal/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Piperazinas/uso terapêutico , Pirazóis/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Ureterais/tratamento farmacológico , Neoplasias Ureterais/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismoRESUMO
The Personalized Medicine approach in oncology is a direct result of an improved understanding of complex tumor biology and advances in diagnostic technologies. In recent years, there has been an increased demand for archival and fresh tumor analysis in early clinical trials to foster proof-of-concept biomarker development, to understand resistance mechanisms, and ultimately to assess biological response. Although phase I studies are aimed at defining drug safety, pharmacokinetics, and to recommend a phase II dose for further testing, there is now increasing evidence of mandatory tumor biopsies even at the earliest dose-finding stages of drug development. The increasing demand for fresh tumor biopsies adds to the complexity of novel phase I studies and results in different challenges, ranging from logistical support to ethical concerns. This paper investigates key issues, including patients' perceptions of research biopsies, the need for accurate informed consent, and alternative strategies that may guide the drug development process.
RESUMO
Gastric cancer and cancer of the gastro-oesophageal junction (GOJ) are the 4th most common cancer diagnoses worldwide with regional differences in incidence rates. The treatment of gastric and GOJ cancers is complex and requires multimodality treatment including chemotherapy treatment, surgery, and radiotherapy. During the past decade considerable improvements were achieved by advanced surgical techniques, tailored chemotherapies/radiotherapy and technical innovations in clinical diagnostics. In patients with advanced or metastatic gastric/GOJ cancer systemic chemotherapy with fluoropyrimidine/platinum-based regimens (+/-human epidermal growth factor receptor-2 antibody) is the mainstay of treatment. Despite these improvements, the clinical outcome for patients with advanced or metastatic disease is generally poor with 5-year survival rates ranging between 5%-15%. These poor survival rates may to some extent be related that standard therapies beyond first-line therapies have never been defined. Considering that this patient population is often not fit enough to receive further treatments there is an increasing body of evidence from phase-2 studies that in fact second-line therapies may have a positive impact in terms of overall survival. Moreover two recently published phase-3 studies support the use of second-line chemotherapy. A South Korean study compared either, irinotecan or docetaxel with best supportive care and a German study compared irinotecan with best supportive care-both studies met their primary endpoint overall survival. In this "Field of Vision" article, we review these recently published phase-3 studies and put them into the context of clinical prognostic factors helping to guide treatment decisions in patients who most likely benefit.
Assuntos
Oncologia/normas , Neoplasias Gástricas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Medicina Baseada em Evidências/normas , Gastrectomia/normas , Humanos , Oncologia/métodos , Terapia de Alvo Molecular/normas , Terapia Neoadjuvante/normas , Radioterapia Adjuvante , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
The molecular determinants of spleen organogenesis and the etiology of isolated congenital asplenia (ICA), a life-threatening human condition, are unknown. We previously reported that Pbx1 deficiency causes organ growth defects including asplenia. Here, we show that mice with splenic mesenchyme-specific Pbx1 inactivation exhibit hyposplenia. Moreover, the loss of Pbx causes downregulation of Nkx2-5 and derepression of p15Ink4b in spleen mesenchymal progenitors, perturbing the cell cycle. Removal of p15Ink4b in Pbx1 spleen-specific mutants partially rescues spleen growth. By whole-exome sequencing of a multiplex kindred with ICA, we identify a heterozygous missense mutation (P236H) in NKX2-5 showing reduced transactivation in vitro. This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development.
Assuntos
Proteínas de Homeodomínio/genética , Baço/anormalidades , Esplenopatias/genética , Fatores de Transcrição/genética , Adolescente , Sequência de Aminoácidos , Animais , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Proteínas de Ligação a DNA/deficiência , Exoma , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/metabolismo , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Fator de Transcrição 1 de Leucemia de Células Pré-B , Proteínas Proto-Oncogênicas/deficiência , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismoRESUMO
Production of interleukin (IL)-10, a major immunoregulatory cytokine, by phagocytes during clearance of apoptotic cells is critical to ensuring cellular homeostasis and suppression of autoimmunity. Little is known about the regulatory mechanisms in this fundamental process. We report that IL-10 production stimulated by apoptotic cells was regulated at the point of transcription in a manner dependent on p38 mitogen-activated protein kinase, partially on the scavenger receptor CD36, and required cell-cell contact but not phagocytosis. By using a reporter assay, we mapped the apoptotic-cell-response element (ACRE) in the human IL10 promoter and provide biochemical and physiological evidence that ACRE mediates the transcriptional activation of IL10 by pre-B cell leukemia transcription factor-1b and another Hox cofactor Pbx-regulating protein 1 in response to apoptotic cells. This study establishes a role of two developmentally critical factors (Pbx1 and Prep-1) in the regulation of homeostasis in the immune system.