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Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While induction chemotherapy leads to remission in most patients, a significant number will experience relapse. Therefore, there is a need for novel therapies that can improve remission rates in patients with relapsed and refractory AML. CD70 is the natural ligand for CD27 (a member of the TNF superfamily) and appears to be a promising therapeutic target. Consequently, there is considerable interest in developing chimeric antigen receptor (CAR) T-cell therapy products that can specifically target CD70 in various neoplasms, including AML. In this study, we employed routine diagnostic techniques, such as immunohistochemistry and flow cytometry, to investigate the expression of CD70 in bone marrow samples from treatment-naïve and relapsed AML patients after hypomethylating agents (HMA). Also, we evaluated the impact of HMA on CD70 expression and examined CD70 expression in various leukemic cell subsets and normal hematopoietic progenitors.
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BACKGROUND: The authors report results from the thyroid carcinoma cohort of the multicohort phase 2 KEYNOTE-158 study (NCT02628067), which evaluated pembrolizumab monotherapy in patients with previously treated cancers. METHODS: Eligible patients had histologically and/or cytologically confirmed papillary or follicular thyroid carcinoma, failure of or intolerance to prior therapy, and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients received pembrolizumab (200 mg) every 3 weeks for up to 35 cycles. The primary end point was objective response rate (ORR) per RECIST v1.1 by independent central review. RESULTS: A total of 103 patients were enrolled and received pembrolizumab. Median duration from first dose to data cutoff (October 5, 2020) was 49.4 (range, 43.9-54.9) months. ORR was 6.8% (95% confidence interval [CI], 2.8%-13.5%), and median duration of response was 18.4 (range, 4.2-47.2+) months. ORR was 8.7% (95% CI, 2.4%-20.8%) among patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 (n = 46) and 5.7% (95% CI, 1.2%-15.7%) among patients with PD-L1 CPS <1 (n = 53). Median overall survival and progression-free survival were 34.5 (95% CI, 21.2 to not reached) and 4.2 (95% CI, 3.9-6.2) months, respectively. Treatment-related adverse events occurred in 69.9% of patients (grade 3-5, 14.6%). CONCLUSIONS: Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in a small subset of patients with advanced thyroid cancer. These results provide evidence of modest antitumor activity in this setting regardless of tumor PD-L1 expression. Future studies evaluating immune checkpoint inhibitors in patients with differentiated thyroid cancer should focus on biomarker-driven patient selection or combination of immune checkpoint inhibitors with other agents, in order to achieve higher response rates than observed in this study.
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Adenocarcinoma Folicular , Antineoplásicos Imunológicos , Neoplasias da Glândula Tireoide , Humanos , Inibidores de Checkpoint Imunológico , Antígeno B7-H1 , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adenocarcinoma Folicular/tratamento farmacológicoRESUMO
AIM: We evaluated pembrolizumab monotherapy in patients with advanced salivary gland carcinoma on the phase 2 KEYNOTE-158 study (NCT02628067). METHODS: Eligible patients had histologically/cytologically confirmed advanced salivary gland carcinoma with prior failure or intolerance to standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1., and ECOG performance status 0-1. Patients were enrolled irrespective of tumour PD-L1 expression. Patients received pembrolizumab 200 mg Q3W for up to 35 cycles (â¼2 years). Radiographic imaging occurred every 9 weeks through month 12, then every 12 weeks. PD-L1 positivity was defined as combined positive score ≥1 (evaluated using PD-L1 IHC 22C3 pharmDx). The primary endpoint was objective response rate per RECIST v1.1. RESULTS: In total, 109 patients were enrolled (PD-L1-positive, 25.7%). At the data cutoff (October 5, 2020), median follow-up was 53.3 (range, 50.8-56.3) months. Objective response rate was 4.6% (95% CI, 1.5-10.4%) among all patients (complete response, n = 1; partial response, n = 4) and was 10.7% (95% CI, 2.3-28.2%) in patients with PD-L1-positive disease and 2.6% (95% CI, 0.3-9.1%) in patients with PD-L1-negative disease. Duration of response was ≥24 months for all 5 responders; median duration of response was not reached (range, 25.1-49.8+ months). Median progression-free survival and overall survival were 4.0 (95% CI, 2.6-4.2) and 21.1 (95% CI, 15.9-25.5) months, respectively. Treatment-related adverse events occurred in 75.2% (grade 3-4, 15.6%; grade 5, 0%) of patients. Immune-mediated adverse events occurred in 22.0% of patients (grade 3, 5.5%; grade 4-5, 0). CONCLUSIONS: A small subset of patients with advanced salivary gland carcinoma treated with pembrolizumab had a response; all had response duration ≥2 years. The safety profile of pembrolizumab was manageable.
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Carcinoma , Neoplasias das Glândulas Salivares , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/metabolismo , Humanos , Neoplasias das Glândulas Salivares/tratamento farmacológico , Glândulas Salivares/metabolismoRESUMO
BACKGROUND: In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability-high (MSI-H)/mismatch repairâdeficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K). PATIENTS AND METHODS: Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score. RESULTS: At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19-5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36-15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91-9.25]), role (9.88 [3.80-15.97]), emotional (5.62 [1.56-9.68]), and social (8.33 [2.70-13.97]) functioning, and stable cognitive functioning (1.74 [-1.45 to 4.94]). CONCLUSIONS: Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours.
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Neoplasias , Qualidade de Vida , Anticorpos Monoclonais Humanizados , Reparo de Erro de Pareamento de DNA , Humanos , Instabilidade de Microssatélites , Neoplasias/tratamento farmacológico , Neoplasias/genética , Qualidade de Vida/psicologiaRESUMO
OBJECTIVE: Treatment options for advanced vulvar cancer are limited. We evaluated pembrolizumab monotherapy in patients with advanced vulvar squamous cell carcinoma (SCC) enrolled in the phase 2 multicohort, open-label KEYNOTE-158 study (NCT02628067). METHODS: Eligible patients had histologically or cytologically documented advanced vulvar SCC with prior treatment failure, measurable disease per RECIST v1.1, ECOG performance status 0-1, and a tumor sample available for biomarker analysis. Pembrolizumab 200â¯mg was administered intravenously Q3W for up to 35â¯cycles (approximately 2â¯years). The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central radiologic review in all patients and subgroups based on PD-L1 combined positive score (≥1 [PD-L1-positive] versus <1 [PD-L1-negative]). RESULTS: 101 patients were enrolled. Median time from first dose to data cutoff was 36.0â¯months. The ORR (95% CI) was 10.9% (5.6%-18.7%) among all patients, 9.5% (4.2%-17.9%) among the 84 patients with PD-L1-positive tumors, and 28.6% (3.7%-71.0%) among the 7 patients with PD-L1-negative tumors. Among patients with a response, median DOR was 20.4 (range, 2.1+ to 28.0) months. Median (95% CI) PFS and OS were 2.1 (2.0-2.1) and 6.2 (4.9-9.4) months, respectively. Treatment-related AEs occurred in 50.5% of patients (grade 3-5, 11.9%) and led to discontinuation of treatment in 5.0% of patients. Two deaths were considered treatment-related (hepatitis, nâ¯=â¯2). CONCLUSIONS: Pembrolizumab monotherapy was associated with durable responses in a subset of patients with vulvar SCC. Responses occurred regardless of tumor PD-L1 status. No new safety signals emerged; overall, pembrolizumab was well tolerated.
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Carcinoma de Células Escamosas , Neoplasias Vulvares , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Feminino , Humanos , Neoplasias Vulvares/tratamento farmacológicoRESUMO
BACKGROUND: Outcomes in advanced anal squamous cell carcinoma are poor, with few treatment options and controlled clinical trials. We evaluated the efficacy and safety of pembrolizumab in patients with advanced anal squamous cell carcinoma (cohort A) from the phase 2 KEYNOTE-158 study. METHODS: Eligible patients enrolled in the ongoing non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study, which was done across 38 centres worldwide, were aged 18 years or older; had histologically or cytologically confirmed advanced or metastatic anal squamous cell carcinoma; had previous failure of or intolerance to standard therapy or no standard therapy options; and had a PD-L1-evaluable tissue sample. Patients received pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or until disease progression, unacceptable toxicity, investigator's decision to withdraw the patient from the study, or withdrawal of patient consent. The primary endpoint was objective response, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy and safety analyses included all patients who received at least one dose of pembrolizumab. The trial is registered with ClinicalTrials.gov, NCT02628067. FINDINGS: Between March 3, 2016, and July 23, 2018, 163 patients were screened, of whom 112 were enrolled and treated in the anal cancer cohort. 91 (81%) patients were female, 104 (93%) had M1 disease, and 75 (67%) had PD-L1-positive tumours. The median time from first dose to data cutoff (June 27, 2019) was 34·7 months (IQR 32·5-36·4). 12 (11%, 95% CI 6-18) patients had an objective response, including 11 (15%, 8-25) of 75 patients with PD-L1-positive tumours and one (3%; 0-17) of 30 patients with PD-L1-negative tumours. 68 (61%) patients had treatment-related adverse events (20 [18%] patients had grade 3-4 adverse events), the most common of which were fatigue (17 patients), diarrhoea (13), hypothyroidism (13), and nausea (13). Serious treatment-related adverse events occurred in 12 (11%) patients. 25 (22%) patients had immune-mediated adverse events, and one (1%) had an infusion reaction. There were no treatment-related deaths. INTERPRETATION: Pembrolizumab monotherapy is a possible treatment option with a favourable benefit-risk ratio for patients with previously treated advanced anal squamous cell carcinoma who have no alternative satisfactory treatment options. FUNDING: Merck Sharp & Dohme.
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Anticorpos Monoclonais Humanizados , Neoplasias do Ânus , Carcinoma de Células Escamosas , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias do Ânus/tratamento farmacológico , Antígeno B7-H1 , Carcinoma de Células Escamosas/tratamento farmacológico , Feminino , Humanos , MasculinoRESUMO
PURPOSE: Pembrolizumab demonstrated durable antitumor activity in patients with previously treated, advanced microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) tumors, including endometrial cancer, in the nonrandomized, open-label, multicohort, phase II KEYNOTE-158 study (NCT02628067). We report efficacy and safety outcomes for patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158. METHODS: Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumor, except colorectal) with previously treated, advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles. The primary end point was objective response rate per RECIST version 1.1 by independent central radiologic review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. RESULTS: As of October 5, 2020, 18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment. In the efficacy population (patients who received ≥ 1 dose of pembrolizumab and had ≥ 26 weeks of follow-up; N = 79), the median time from first dose to data cutoff was 42.6 (range, 6.4-56.1) months. The objective response rate was 48% (95% CI, 37 to 60), and median duration of response was not reached (2.9-49.7+ months). Median progression-free survival was 13.1 (95% CI, 4.3 to 34.4) months, and median overall survival was not reached (95% CI, 27.2 months to not reached). Among all treated patients, 76% had ≥ 1 treatment-related adverse event (grades 3-4, 12%). There were no fatal treatment-related events. Immune-mediated adverse events or infusion reactions occurred in 28% of patients (grades 3-4, 7%; no fatal events). CONCLUSION: Pembrolizumab demonstrated robust and durable antitumor activity and encouraging survival outcomes with manageable toxicity in patients with previously treated, advanced MSI-H/dMMR endometrial cancer.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/tratamento farmacológico , Instabilidade de Microssatélites , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study. METHODS: The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067. FINDINGS: Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation. INTERPRETATION: Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Mesotelioma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. METHODS: In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance toâone or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. FINDINGS: Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0-38·3). Objective responses were observed in 30 (29%; 95% CI 21-39) of 102 patients in the tTMB-high group and 43 (6%; 5-8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3-5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related. INTERPRETATION: tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Biomarcadores Tumorais/genética , Neoplasias/terapia , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Neoplasias/patologia , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Análise de SobrevidaRESUMO
We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Idoso , Antígeno B7-H1/metabolismo , Neoplasias do Sistema Biliar/metabolismo , Feminino , Humanos , Masculino , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
PURPOSE: KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET). PATIENTS AND METHODS: Pembrolizumab 200 mg was administered every 3 weeks for 2 years or until progression, intolerable toxicity, or physician/patient decision. Tumor imaging was performed every 9 weeks for the first year and then every 12 weeks. Endpoints included objective response rate (ORR) per RECIST v1.1 by independent central radiologic review (primary) and duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (secondary). RESULTS: A total of 107 patients with NETs of the lung, appendix, small intestine, colon, rectum, or pancreas were treated. Median age was 59.0 years (range, 29-80), 44.9% had ECOG performance status 1, 40.2% had received ≥3 prior therapies for advanced disease, and 15.9% had PD-L1-positive tumors (combined positive score ≥1). Median follow-up was 24.2 months (range, 0.6-33.4). ORR was 3.7% (95% CI, 1.0-9.3), with zero complete responses and four partial responses (three pancreatic and one rectal) all in patients with PD-L1-negative tumors. Median DOR was not reached, with one of four responses ongoing after ≥21 months follow-up. Median PFS was 4.1 months (95% CI, 3.5-5.4); the 6-month PFS rate was 39.3%. Median OS was 24.2 months (95% CI, 15.8-32.5). Treatment-related adverse events (AE) occurred in 75.7% of patients, 21.5% of whom had grade 3-5 AEs. CONCLUSIONS: Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in patients with previously treated advanced well-differentiated NETs.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Tumores Neuroendócrinos/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/imunologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Receptor de Morte Celular Programada 1/imunologia , Taxa de SobrevidaRESUMO
INTRODUCTION: Pembrolizumab has shown clinical benefit in patients with previously treated recurrent or metastatic SCLC in the phase 1b multicohort study KEYNOTE-028 (NCT02054806) and the phase 2 multicohort study KEYNOTE-158 (NCT02628067). We present a pooled analysis of patients from KEYNOTE-028 and KEYNOTE-158 who had received two or more lines of previous therapy for SCLC. METHODS: Eligible patients were aged 18 years and above, had histologically or cytologically confirmed incurable recurrent or metastatic SCLC, had an Eastern Cooperative Oncology Group performance status of 1 and below, and had received two or more lines of previous therapy. Patients in KEYNOTE-028 were required to have a programmed death ligand 1 (PD-L1)-positive tumor. Patients received pembrolizumab (10 mg/kg every 2 weeks in KEYNOTE-028 or 200 mg every 3 weeks in KEYNOTE-158) for up to 2 years. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1, which is presented here per independent review. RESULTS: Eighty-three patients who had received two or more lines of previous therapy (KEYNOTE-028, n = 19; KEYNOTE-158, n = 64) were included. Median follow-up duration was 7.7 (range, 0.5-48.7) months. Objective response rate was 19.3% (95% confidence interval: 11.4-29.4); two patients had complete response (one with a PD-L1-positive tumor), and 14 patients had partial response (13 with PD-L1-positive tumors). The median duration of response was not reached (range, 4.1â35.8+ mo; plus sign indicates ongoing response); 61% of responders had responses lasting 18 months or longer. Fifty-one patients (61.4%) experienced any-grade treatment-related adverse events; eight patients (9.6%) had grade 3 or higher events. CONCLUSIONS: Pembrolizumab exhibited durable antitumor activity in a subset of patients with recurrent or metastatic SCLC who had undergone two or more previous lines of therapy, regardless of PD-L1 expression. Pembrolizumab was well tolerated.
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Neoplasias Pulmonares , Adolescente , Anticorpos Monoclonais Humanizados , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
INTRODUCTION: A 13-year-old African-American female presented to her primary care physician's office with fatigue, syncope, and hematemesis. After initial evaluation, the patient was referred to pediatric gastroenterology clinic for further evaluation. MAIN CONCERNS, IMPORTANT FINDINGS: An upper gastrointestinal endoscopy was performed to evaluate the source of her bleeding. Endoscopy revealed a 3-cm mass in the lesser curvature of the stomach, and a biopsy of the mass revealed a concern for carcinoid (neuroendocrine) features. DIAGNOSIS: She underwent an open gastrectomy. Post-surgical pathology reports confirmed a well-differentiated neuroendocrine tumor of the stomach. CONCLUSION: Neuroendocrine tumors of the stomach in children are rare and we presently do not have pediatric-specific diagnostic and treatment guidelines. Although adult-based The North American Neuroendocrine Tumor Society (NANETS) guidelines are helpful, they are clearly not geared toward pediatric patients. To establish pediatric guidelines and to assess effectiveness of treatments, multicenter data collection is essential. In the long run, accumulation of clinically useful treatment information and long-term follow-up guidelines should enable clinicians to improve standard of care given to children with neuroendocrine tumors.
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Tumor Carcinoide/patologia , Neoplasias Gástricas/patologia , Adolescente , Tumor Carcinoide/cirurgia , Diagnóstico Diferencial , Feminino , Gastrectomia , Humanos , Estômago/patologia , Neoplasias Gástricas/cirurgiaRESUMO
Hematopoietic stem cells (HSCs) maintain tissue homeostasis by rapidly responding to environmental changes. Although this function is well understood, the molecular mechanisms governing this characteristic are largely unknown. We used a sequenced-based strategy to explore the role of both transcriptional and post-transcriptional regulation in HSC biology. We characterized the gene expression differences between HSCs, both quiescent and proliferating, and their differentiated progeny. This analysis revealed a large fraction of sequence tags aligned to intronic sequences, which we showed were derived from unspliced transcripts. A comparison of the biological properties of the observed spliced versus unspliced transcripts in HSCs showed that the unspliced transcripts were enriched in genes involved in DNA binding and RNA processing. In addition, levels of unspliced message decreased in a transcript-specific fashion after HSC activation in vivo. This change in unspliced transcript level coordinated with increases in gene expression of splicing machinery components. Combined, these results suggest that post-transcriptional regulation is important in HSC activation in vivo.
Assuntos
Diferenciação Celular/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Splicing de RNA/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Animais , Proliferação de Células , Células Cultivadas , Senescência Celular/fisiologia , Perfilação da Expressão Gênica/métodos , Células-Tronco Hematopoéticas/citologia , Homeostase/fisiologia , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
Analyzing the regenerative compartment in the blast cell population of patients with acute myeloid leukemia (AML) may yield important insights into the mechanisms of disease progression. Here we present findings with a human AML cell line (AML-SP1), initiated from leukemic precursor cells and consecutively propagated by serial xenotransplantation in vivo. AML-SP1 maintained the characteristics of a human AML, consistently exhibiting a small leukemic side population (SP) of blast cells with high Hoechst 33342 exclusion. In the AML-SP1 line, an increased expression of the ABC transporters MDR1, MRP, ABCG2 and ABCA3 was found in the SP cells. The detection of ABCA3 in leukemic progenitor cells merits further investigation with regard to intracellular drug transport in AML blast cells. In vivo propagation of leukemias, such as AML-SP1 is a model system of maintaining the populational heterogeneity of AML disease, especially the unique characteristics of leukemic SP cells.
Assuntos
Transportadores de Cassetes de Ligação de ATP/biossíntese , Leucemia Mielomonocítica Aguda/patologia , Proteínas de Neoplasias/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Animais , Transporte Biológico , Transplante de Medula Óssea , Linhagem Celular Tumoral/citologia , Linhagem Celular Tumoral/metabolismo , Linhagem Celular Tumoral/transplante , Feminino , Humanos , Leucemia Mielomonocítica Aguda/metabolismo , Leucemia Mielomonocítica Aguda/terapia , Camundongos , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia , Transplante de NeoplasiasRESUMO
OBJECTIVE: Skeletal muscle-derived cells have the potential to repopulate the major peripheral blood lineages of lethally irradiated mice and thus behave like hematopoietic stem cells (HSC). We have recently shown that muscle cells with HSC activity (ms-HSC) express CD45 and Sca-1, suggesting a hematopoietic origin. Here we sought to clarify contradictions in the literature regarding the phenotype of ms-HSC and precisely define the hematopoietic origin of these cells. METHODS: Skeletal muscle-derived cells fractionated based on the expression of CD45 and c-kit and efflux of Hoechst 33342 and were examined for HSC activity in vivo. WBM HSC expressing beta-galactosidase were transplanted into lethally irradiated recipients, whose ms-HSC compartment was later analyzed for beta-galactosidase activity to determine if ms-HSC were derived from WBM HSC. RESULTS: Muscle-derived HSC fall exclusively in the c-kit(dim)CD45(pos) compartment of the muscle side population (msSP). Furthermore, the CD45(pos) msSP compartment of skeletal muscle is derived from WBM HSC. CD45(pos)c-kit(dim) msSP are about 22-fold less potent in HSC activity than WBM HSC cells in competitive repopulation assays and express low levels of c-kit relative to WBM HSC. CONCLUSIONS: In our transplantation experiments, WBM HSC gave rise to ms-HSC, suggesting that WBM HSC and ms-HSC likely represent the same stem cell population in distinct environments. However, these two related populations are both functionally distinct in their ability to repopulate the peripheral blood of irradiated mice and phenotypically distinct.