RESUMO
BACKGROUND: Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. METHODS: In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. RESULTS: A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. CONCLUSIONS: In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.).
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Célula de Merkel/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma de Célula de Merkel/patologia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Recidiva , Neoplasias Cutâneas/patologiaRESUMO
OBJECTIVE: To evaluate the humoral immune response to pneumococcal and influenza vaccination in adults with rheumatoid arthritis (RA) receiving certolizumab pegol (CZP). METHODS: In this 6-week, single-blind, placebo-controlled trial with optional 6-month open-label extension (NCT00993668), patients were stratified by concomitant methotrexate (MTX) use and randomized to receive CZP 400 mg (loading dose; according to CZP label) or placebo at weeks 0, 2, and 4. Pneumococcal (polysaccharide 23) and influenza vaccines were administered at Week 2. Satisfactory humoral immune response, defined as ≥2-fold titer increase in ≥3 of 6 pneumococcal antigens and ≥4-fold titer increase in ≥2 of 3 influenza antigens, were assessed independently 4 weeks after vaccination. RESULTS: Following pneumococcal vaccination, 62.5% of placebo patients and 54.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions was -8.0 percentage points; 95% CI -22.5 to 6.6%). Following influenza vaccination, 61.4% of placebo and 53.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions: -8.0 percentage points; 95% CI -22.9 to 7.0%). In all patients, including those with effective titers at baseline, 58.2% of placebo and 53.3% of CZP patients developed satisfactory pneumococcal titers, and 54.1% of placebo and 50.5% of CZP patients developed satisfactory influenza antibody titers. Vaccine responses to pneumococcal and influenza antigens were reduced similarly in both treatment groups with concomitant MTX use. CONCLUSION: Humoral immune responses to pneumococcal and influenza vaccination are not impaired when given during the loading phase of CZP treatment in patients with RA. (ClinicalTrials.gov NCT00993668).
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Imunossupressores/administração & dosagem , Vacinas contra Influenza/administração & dosagem , Vacinas Pneumocócicas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Fatores Etários , Anticorpos Monoclonais Humanizados/efeitos adversos , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Artrite Reumatoide/diagnóstico , Certolizumab Pegol , Intervalos de Confiança , Feminino , Seguimentos , Humanos , Imunidade Humoral/efeitos dos fármacos , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Imunossupressores/efeitos adversos , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Vacinas Pneumocócicas/efeitos adversos , Polietilenoglicóis/efeitos adversos , Valores de Referência , Medição de Risco , Fatores Sexuais , Método Simples-Cego , Resultado do Tratamento , Vacinação/métodosRESUMO
OBJECTIVE: Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). METHODS: In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). RESULTS: At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. CONCLUSION: In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/administração & dosagem , Atividades Cotidianas , Adalimumab , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Placebos , Qualidade de Vida , Radiografia , Recuperação de Função Fisiológica , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Because traditional therapies for rheumatoid arthritis (RA) such as methotrexate (MTX) do not produce an adequate response in many patients, newer therapies that block the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are increasingly being used in combination with MTX. OBJECTIVE: This study evaluated the efficacy, pharmacokinetics, and safety profile of adalimumab, a fully human anti-TNF alpha monoclonal antibody, when added to continuing MTX therapy. METHODS: This Phase I, randomized, dose-titration study consisted of a 4-week, double-blind, placebo-controlled treatment phase and a 26-month, open-label continuation phase. Patients with RA who had been taking stable doses of MTX (mean dose, 17 mg/wk) for > or =3 months before enrollment with an inadequate response were randomly assigned to receive 2 single doses of either adalimumab 0.25, 0.5, 1, 3, or 5 mg/kg i.v. or placebo in the double-blind phase. In the open-label phase, patients received treatment with 1 of the doses of adalimumab every other week or monthly for 18 months; patients were then switched to adalimumab 40 mg i.v. or SC every other week or monthly. The main efficacy end point was 20% improvement in American College of Rheumatology response criteria (ACR20). Other efficacy end points included 50% (ACR50) and 70% improvements in ACR response criteria. Pharmacokinetic parameters were analyzed for adalimumab and MTX during both phases of the study. Serum adalimumab concentrations were analyzed using a validated enzyme-linked immunosorbent assay relying on the double-antigen principle. Peak and trough concentrations were determined from observed concentration-time data, and a modeling approach was used to estimate total serum clearance, mean apparent terminal half-life, apparent volume of distribution at steady state, and area under the concentration-time curve. RESULTS: Sixty patients entered the double-blind phase, 45 receiving adalimumab and 15 receiving placebo; 1 placebo recipient chose not to continue into the open-label phase. Overall, the study population included 47 (78.3%) women and 13 (21.7%) men. The mean age was 52.9 years (range, 24-73 years), and the mean body weight was 69.7 kg (range, 43-98 kg). ACR20 and ACR50 responses were achieved on at least 1 assessment during the 4-week double-blind phase by a respective 29 (64.4%) and 11 (24.4%) of 45 patients receiving active treatment and by 4 (26.7%) and none of the 15 patients receiving placebo. Responses to adalimumab were rapid, with 10 (22.2%) of 45 patients achieving an ACR20 response within 24 hours of dosing. Of 29 adalimumab recipients who had an ACR20 response, 18 (62.1%) had a duration of response (time from first occurrence of a response to first occurrence of a nonresponse) of 1 to 2 weeks, and 11 (37.9%) had a duration of response of 3 to 13 weeks. The pharmacokinetic properties of adalimumab appeared to be linear. The mean apparent terminal half-life after a single intravenous dose of adalimumab ranged from 15 to 19 days in the 5 dose groups. Repeated administration of adalimumab had no statistically significant effect on the pharmacokinetics of MTX, indicating that dose adjustment of MTX is not necessary. Adalimumab was well tolerated, and there were no dose-related adverse events. CONCLUSIONS: Among patients with active RA who had not had an adequate response to MTX, addition of adalimumab to MTX achieved statistically significant, long-term improvement compared with placebo plus MTX (P < or = 0.05), as indicated by ACR responses at 26 months. The combination was well tolerated. Adalimumab exhibited linear pharmacokinetics. In this selected patient population, adalimumab's long half-life of 15 to 19 days supports every-other-week dosing. Coadministration of adalimumab did not alter serum levels of MTX.
Assuntos
Anticorpos Monoclonais/farmacocinética , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Fator de Necrose Tumoral alfa/imunologia , Adalimumab , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Meia-Vida , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX. METHODS: In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks. RESULTS: An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events. CONCLUSION: The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/administração & dosagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Colagenases/sangue , Terapia Combinada , Precursores Enzimáticos/sangue , Fadiga/tratamento farmacológico , Feminino , Humanos , Masculino , Metaloproteinase 1 da Matriz , Metaloendopeptidases/sangue , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologiaRESUMO
OBJECTIVE: This study, known as STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis), evaluated the safety and efficacy of adalimumab (Humira), a fully human monoclonal tumor necrosis factor-alpha (TNF-a) antibody, when given with standard antirheumatic therapy in patients with active rheumatoid arthritis (RA) not adequately responding to such therapies. Standard antirheumatic therapy included traditional disease modifying antirheumatic drugs (DMARD), low dose corticosteroids, nonsteroidal antiinflammatory drugs (NSAID), and/or analgesics. METHODS: In this 24-week, double-blind, placebo-controlled study, 636 patients with RA were randomly assigned to receive adalimumab 40 mg subcutaneously (sc) every other week (n = 318) or placebo (n = 318) while continuing standard antirheumatic therapy. The frequencies of adverse events, serious adverse events, severe or life-threatening adverse events, adverse events leading to withdrawal, infection, or serious infection were the primary endpoints. Secondary endpoints were determined by American College of Rheumatology (ACR) response criteria. RESULTS: During the study, the majority of patients received concomitant traditional DMARD (83.5%) and/or corticosteroids, NSAID, and/or analgesics (97.3%). Overall, 56.0% of patients continued treatment with one, 23.6% with 2, and 3.9% with > or = 3 traditional DMARD. At 24 weeks, there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events (86.5% vs 82.7%), serious adverse events (5.3% vs 6.9%), severe or life-threatening adverse events (11.9% vs 15.4%), or those leading to withdrawal (2.8% vs 2.2%). There were also no statistically significant differences in the rates of infections (52.2% vs 49.4%) or serious infections (1.3% vs 1.9%) between the groups. The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD (0, 1, or 2). Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 (52.8% vs 34.9%), ACR50 (28.9% vs 11.3%), and ACR70 (14.8% vs 3.5%) response rates at Week 24 (p < or = 0.001). CONCLUSION: This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant standard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA. The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to standard antirheumatic therapy, including one or more traditional DMARD, corticosteroids, NSAID, and analgesics.