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1.
Anticancer Res ; 41(4): 2093-2100, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813419

RESUMO

BACKGROUND/AIM: The Renin-Angiotensin system (RAS) induces immunosuppression in the tumor microenvironment, and RAS inhibitors (RASi) improve the tumor immune microenvironment. We evaluated the impact of RASi on the efficacy anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies. PATIENTS AND METHODS: This retrospective study analyzed non-small cell lung cancer (NSCLC) patients who received anti-PD-1/PD-L1 antibodies monotherapy as second- or later-line treatment. We classified patients into those with or without use of RASi. RESULTS: A total of 256 NSCLC patients were included and 37 patients used RASi. The median PFS of patients treated with RASi was significantly longer than that of patients treated without (HR=0.59, 95%CI=0.40-0.88). The median OS of patients treated with RASi tended to be longer than that of patients treated without (HR=0.71, 95%CI=0.45-1.11). CONCLUSION: The use of RASi was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibodies. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibodies.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Sinergismo Farmacológico , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Japão/epidemiologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
2.
Ciudad Autónoma de Buenos Aires; Comisión Nacional de Evaluación de Tecnologías de Salud; Marzo 2021. 30 p. (Informe de Evaluación de Tecnologías Sanitarias N°10, 10).
Monografia em Espanhol | LILACS, BINACIS, ARGMSAL | ID: biblio-1151681

RESUMO

El presente informe es producto del trabajo colaborativo de la Comisión Nacional de Evaluación de Tecnologías de Salud (CONETEC), dependiente del Ministerio de Salud de la Nación y creada por RM N° 623/2018. La CONETEC realiza evaluaciones y emite recomendaciones a la autoridad sanitaria sobre la incorporación, forma de uso, financiamiento y políticas de cobertura de las tecnologías sanitarias desde una perspectiva global del sistema de salud argentino. En sus evaluaciones y recomendaciones, la CONETEC tiene en cuenta criterios de calidad, seguridad, efectividad, eficiencia y equidad, evaluados bajo dimensiones éticas, médicas, económicas y sociales. Sus resultados son consensuados mediante discusiones públicas y ponderados a través de un marco de valor explícito, con la participación de todos los actores involucrados en el proceso de toma de decisiones en salud. Los informes y recomendaciones de esta comisión surgen de este proceso público, transparente y colaborativo, siendo de libre consulta y acceso para toda la sociedad.


Assuntos
Nivolumabe , Neoplasias Pulmonares , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/epidemiologia
3.
Ciudad Autónoma de Buenos Aires; Comisión Nacional de Evaluación de Tecnologías de Salud; Marzo 2021. 28 p. (Informe de Evaluación de Tecnologías Sanitarias N°13, 13).
Monografia em Espanhol | LILACS, BINACIS, ARGMSAL | ID: biblio-1151676

RESUMO

El presente informe es producto del trabajo colaborativo de la Comisión Nacional de Evaluación de Tecnologías de Salud (CONETEC), dependiente del Ministerio de Salud de la Nación y creada por RM N° 623/2018. La CONETEC realiza evaluaciones y emite recomendaciones a la autoridad sanitaria sobre la incorporación, forma de uso, financiamiento y políticas de cobertura de las tecnologías sanitarias desde una perspectiva global del sistema de salud argentino. En sus evaluaciones y recomendaciones, la CONETEC tiene en cuenta criterios de calidad, seguridad, efectividad, eficiencia y equidad, evaluados bajo dimensiones éticas, médicas, económicas y sociales. Sus resultados son consensuados mediante discusiones públicas y ponderados a través de un marco de valor explícito, con la participación de todos los actores involucrados en el proceso de toma de decisiones en salud. Los informes y recomendaciones de esta comisión surgen de este proceso público, transparente y colaborativo, siendo de libre consulta y acceso para toda la sociedad


Assuntos
Nivolumabe , Melanoma , Melanoma/diagnóstico , Melanoma/epidemiologia
6.
Nat Commun ; 12(1): 1402, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658501

RESUMO

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1+CD8+ T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8+ T cells. Furthermore, an increase in the frequency of the CX3CR1+ subset in circulating CD8+ T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy.


Assuntos
Biomarcadores Farmacológicos/sangue , Receptor 1 de Quimiocina CX3C/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/fisiologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Feminino , Humanos , Antígeno Ki-67/sangue , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Nivolumabe/farmacologia , Receptores de Antígenos de Linfócitos T/metabolismo , Taxa de Sobrevida , Resultado do Tratamento
7.
N Engl J Med ; 384(9): 829-841, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33657295

RESUMO

BACKGROUND: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known. METHODS: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point. RESULTS: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib. CONCLUSIONS: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).


Assuntos
Anilidas/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/administração & dosagem , Piridinas/administração & dosagem , Sunitinibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Análise de Intenção de Tratamento , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Piridinas/efeitos adversos , Qualidade de Vida , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sunitinibe/efeitos adversos , Análise de Sobrevida
8.
Drugs Today (Barc) ; 57(3): 187-197, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33729216

RESUMO

The use of monoclonal antibodies directed against programmed cell death protein 1 (PD-1) and its ligand, programmed cell death 1 ligand 1 (PD-L1), widely extends to a large number of tumors such as melanoma, non-small cell lung, renal or lymphomas, among others. Some of them are already approved as first- or second-line treatment, as pembrolizumab, nivolumab or cemiplimab. Dostarlimab is an investigational humanized anti-PD-1 that is being developed both in monotherapy and as combination therapy, for gynecological tumors but also for lung cancer or melanoma. The preliminary results, particularly in endometrial cancer, show a high affinity against PD-1 with encouraging clinical activity. Here we summarize the development of this compound as well as the current preclinical and clinical data and potential future development.


Assuntos
Antineoplásicos Imunológicos , Neoplasias do Endométrio , Neoplasias Pulmonares , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1 , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico
9.
Anticancer Res ; 41(3): 1539-1545, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788747

RESUMO

BACKGROUND/AIM: Nivolumab monotherapy for advanced/metastatic renal cell carcinoma (RCC) shows a survival benefit. The purpose of this study was to evaluate tumor responses to nivolumab in various metastatic and primary sites in patients with RCC. PATIENTS AND METHODS: We retrospectively reviewed 68 patients who underwent nivolumab monotherapy after one or more regimens of targeted therapy for advanced/metastatic RCC. The site-specific response was evaluated and progression-free survival was estimated. RESULTS: The site-specific overall response rates (ORRs) were as follows: lung (36%), bone (5%), lymph node (33%), liver (50%), adrenal gland (29%), pancreas (33%), and brain (0%). The ORR of bone metastasis was significantly worse in comparison to lung and liver metastases (p=0.017, 0.008). The site-specific median progression-free survival times were as follows: lung (5.1 months), bone (not reached), lymph node (not reached), and liver (17.5 months). CONCLUSION: Responses to nivolumab may vary depending on metastasized organs.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Carga Tumoral
10.
s.l; CONETEC; mar. 2021.
Não convencional em Espanhol | BRISA/RedTESA | ID: biblio-1150457

RESUMO

INTRODUCCIÓN: El cáncer de pulmón de células no pequeñas (CPCNP) comprende entre el 85 y 90% de los cánceres de pulmón, siendo el tumor maligno más frecuente para esta patología. Constituye la primera causa de muerte por cáncer a nivel mundial y la mayoría de estos cánceres se diagnostican en estadios avanzados. El tratamiento en estos estadios y para segunda línea puede incluir quimioterapia, antiangiogénicos, terapia dirigida en caso de pacientes que presentan mutaciones activantes, e inmunoterapia. El nivolumab es un anticuerpo monoclonal humano de tipo inmunoglobulina G4 que se une al receptor de muerte programada 1 (PD-1) y bloquea su acción. De este modo, el nivolumab potenciaría las respuestas antitumorales de los linfocitos T. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las guías de práctica clínica, políticas de cobertura y económicos del uso de nivolumab para CPCNP avanzado o metastásico, escamoso o no escamoso en estadio III/IV recurrente, que hayan progresado a una primera línea de tratamiento basada en doble terapia con platino. METODOLOGÍA: Para responder a la pregunta, se realizó una búsqueda sensible en Pubmed, Lilacs, CRD, Cochrane, EPISTEMONIKOS y buscadores genéricos de Internet. Se buscó además en agencias de ETS (NICE; PBAC/ MSAC; CADTH, CONITEC) y se consultó con expertos en Oncología. Se seleccionaron ensayos clínicos aleatorizados que comparan de manera directa la tecnología con los comparadores propuestos. RESULTADOS: Como resultado, se incluyeron siete estudios que cumplían estos criterios. Se valoró el riesgo de sesgo de los ensayos mediante la herramienta RoB2, y la confianza del cuerpo de la evidencia para cada desenlace a través del enfoque GRADE. Para CPCNP escamoso, nivolumab mostró mejoras significativas para la sobrevida al año y la sobrevida libre de progresión al año, con una calidad de la evidencia de confianza moderada, como para la calidad de vida, aunque con una baja confianza frente a docetaxel. Para esta población, tanto los eventos adversos de cualquier tipo como los serios fueron más frecuentes en el grupo docetaxel que en el grupo nivolumab, con una confianza moderada. En CPCNP no escamoso, nivolumab también mostró ser significativamente mejor para la sobrevida al año, pero no fue así para la sobrevida libre de progresión al año, con una calidad de la evidencia de confianza moderada para ambos desenlaces. Para la calidad de vida, nivolumab también se mostró mejor que docetaxel, aunque con baja confianza. Los eventos adversos reportados para esta población fueron similares entre los comparadores, sin embargo, los eventos adversos serios fueron más frecuentes con docetaxel con una confianza clasificada como moderada. En los estudios de seguimiento a dos, tres y cinco años las diferencias para cada desenlace para ambos tipos histológicos parecen mantenerse, aunque estos resultados deben interpretarse con precaución. CONCLUSIÓN: Las evaluaciones económicas provenientes de países de altos ingresos relevadas encuentran a nivolumab en la indicación evaluada como no costo-efectiva, y recomiendan acuerdos especiales para dar acceso. El análisis de impacto presupuestario de elaboración propia concluye que la inclusión de esta tecnología tendría un impacto incremental significativo en el gasto de salud. Todas las guías de práctica clínica y evaluaciones de tecnologías relevadas recomiendan la utilización de la tecnología como una opción en la indicación evaluada. Algunas de las políticas de cobertura en Latinoamérica relevadas brindan acceso, pero consideran que el costo del tratamiento es una limitante de gran relevancia. Todas las políticas de cobertura de países de altos ingresos relevadas mencionan la tecnología en la indicación evaluada. Completando el proceso de evaluación de la evidencia científica y económica, la votación sobre los atributos del marco de valor realizado por la Mesa Técnica y el análisis final de la Mesa de Recomendaciones, el presente informe de la CONETEC sugiere una COBERTURA CONDICIONAL de esta tecnología, sujeta a la aplicación conjunta de distintos ítems prestacionales y de acceso.(AU)


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Nivolumabe/uso terapêutico , Avaliação da Tecnologia Biomédica , Análise Custo-Benefício
11.
Am J Clin Oncol ; 44(3): 121-125, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33617179

RESUMO

OBJECTIVES: The aim of our study was to collect data about of the outcome of metastatic renal cell carcinoma patients who progressed after immune checkpoint inhibitors in order to enhance data about efficacy and safety of treatment beyond immune-oncology (IO). MATERIALS AND METHODS: A total of 162 eligible patients, progressing to IO, were enrolled from 16 Italian referral centers adhering to the Meet-Uro association. Baseline characteristics, outcome data and toxicities were retrospectively collected. Descriptive analysis was made using median values and ranges. Kaplan-Meier method and Mantel-Haenszel log-rank test were performed to compare differences between groups. RESULTS: A total of 111 patients (68.5%) were treated after IO progression. In all, 51 patients (31.5%) did not receive further treatment for clinical deterioration. Median IO progression free survival (PFS) was 4 months (95% confidence interval [CI]: 3.1-4.8). IO-PFS tends to be longer in patients reporting adverse events (AE) of any grade (5.03 [95% CI: 3.8-6.1] vs. 2.99 [95% CI: 2.4-3.5] months P=0.004). Subsequent therapies included cabozantinib (n=79, 48%), everolimus (n=11, 6.7%), and others (n=21, 12.9%).Median PFS post-IO was 6.5 months (95% CI: 5.1-7.8). Cabozantinib showed longer PFS compared with everolimus (7.6 mo [95% CI: 5.2-10.1] vs. 3.2 mo [95% CI: 1.8-4.5]) (hazard ratio: 0.2; 95% CI: 0.1026-0.7968) and other drugs (4.3 mo [95% CI: 1.3-7.4]) (hazard ratio: 0.6; 95% CI: 0.35-1.23). All grade AE were reported in 83 patients (74%) and G3 to G4 AE in 39 patients (35%). Target therapies post-IO showed median overall survival of 14.7 months (95% CI: 0.3-21.4). CONCLUSIONS: In our real world experience after progression to IO, vascular endotelial groth factor-tyrosine kinase inhibitors, given to patients, proved to be active and safe choices. Cabozantinib was associated with a better outcome in terms of median PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Idoso , Anilidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Progressão da Doença , Everolimo/administração & dosagem , Feminino , Humanos , Itália , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Piridinas/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
12.
J Med Econ ; 24(1): 291-298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33538203

RESUMO

BACKGROUND: Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. METHODS: Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. RESULTS: Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,773,865 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,773,865 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. CONCLUSION: At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.


Assuntos
Antineoplásicos Imunológicos/economia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/economia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe/economia , Axitinibe/uso terapêutico , Brasil , Carcinoma de Células Renais/patologia , Análise Custo-Benefício , Feminino , Gastos em Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Humanos , Ipilimumab/economia , Ipilimumab/uso terapêutico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Modelos Econômicos , Nivolumabe/economia , Nivolumabe/uso terapêutico , Intervalo Livre de Progressão , Índice de Gravidade de Doença , Sunitinibe/economia , Sunitinibe/uso terapêutico , Adulto Jovem
13.
Nat Med ; 27(2): 256-263, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33558721

RESUMO

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/efeitos adversos , Interferon gama/genética , Ipilimumab/efeitos adversos , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Mutação/genética , Terapia Neoadjuvante/efeitos adversos , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Recidiva
14.
Nat Med ; 27(2): 301-309, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33558722

RESUMO

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.


Assuntos
Melanoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/efeitos adversos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Terapia Neoadjuvante/efeitos adversos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Adulto Jovem
15.
BMJ Case Rep ; 14(2)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526518

RESUMO

Immune checkpoint inhibitors (ICIs) are increasingly used to treat certain malignancies due to their higher efficacy compared with conventional chemotherapy. As familiarity with these agents increases, it is becoming apparent that a significant number of patients treated with ICIs experience adverse events. With time, more immune-related adverse events (IRAEs) are being recognised. It is important to be vigilant for IRAEs and recognise that a patient may have multiple IRAEs affecting multiple organ systems. Common cardiovascular adverse events associated with ICIs include myocarditis, arrhythmias and pericarditis. This case report identifies a patient presenting with takotsubo syndrome followed by ketoacidosis (associated with sodium-glucose transport protein 2 (SGLT2) inhibitor) in the setting of combination ipilimumab and nivolumab therapy for metastatic melanoma.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cetoacidose Diabética/induzido quimicamente , Melanoma/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Cardiomiopatia de Takotsubo/induzido quimicamente , Idoso , Compostos Benzidrílicos/efeitos adversos , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/secundário , Angiografia Coronária , Diabetes Mellitus Tipo 2/complicações , Cetoacidose Diabética/complicações , Ecocardiografia , Glucosídeos/efeitos adversos , Humanos , Ipilimumab/efeitos adversos , Imagem por Ressonância Magnética , Masculino , Melanoma/complicações , Melanoma/secundário , Nivolumabe/efeitos adversos , Cardiomiopatia de Takotsubo/complicações , Cardiomiopatia de Takotsubo/diagnóstico por imagem
16.
JAMA Netw Open ; 4(2): e2036741, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33630085

RESUMO

Importance: In clinical trials supporting the regulatory approval of oncology drugs, solid tumor response is assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Calculation of RECIST-based responses requires sequential, timed imaging data, which presents challenges to the method's application in real-world evidence research. Objective: To evaluate the feasibility and validity of a novel real-world RECIST method in assessing tumor burden associated with therapy for a large heterogeneous patient population undergoing treatment in routine clinical practice. Design, Setting, and Participants: This cohort study used physician-abstracted data pooled from retrospective, multisite electronic health record (EHR) review studies of patients treated with anticancer drugs at US oncology practices from 2014 through 2017. Included patients were receiving first-line treatment for thyroid cancer, breast cancer, or metastatic melanoma. Data were analyzed from March through August 2020. Exposures: Undergoing treatment with immunotherapy or targeted therapy. Main Outcomes and Measures: Tumor response was classified according to RECIST guidelines (ie, change in sum diameter of target lesions) post hoc with measurements derived from imaging scans and reports. Results: Among 1308 completed electronic case report forms, 956 forms (73.1%) had adequate data to classify real-world RECIST response. The greatest difference between physician-recorded responses and real-world RECIST-based responses was found in the proportion of complete responses: 118 responses (12.3%) vs 46 responses (4.8%) (P < .001). Among 609 patients in the metastatic melanoma population, complete responses were reported in 112 physician-recorded responses (18.4%) vs 44 real-world RECIST-based responses (7.2%) (P < .001), compared with 11 of 247 responses (4.5%) to 31 of 192 responses (16.1%) across pivotal trials of the same melanoma therapies. Conclusions and Relevance: These findings suggest that comparing tumor lesion sizes and categorizing treatment response according to RECIST guidelines may be feasible using real-world data. This study found that physician-recorded assessments were associated with overestimation of treatment response, with the largest overestimation among complete responses. Real-world RECIST-based assessments were associated with better approximations of tumor response reported in clinical trials compared with those reported in EHRs.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Melanoma/tratamento farmacológico , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma/diagnóstico por imagem , Carcinoma/secundário , Ensaios Clínicos como Assunto , Estudos de Viabilidade , Feminino , Humanos , Masculino , Melanoma/diagnóstico por imagem , Melanoma/secundário , Terapia de Alvo Molecular , Nivolumabe/uso terapêutico , Variações Dependentes do Observador , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento , Carga Tumoral
17.
Front Immunol ; 12: 627186, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33613575

RESUMO

After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Linfócitos B/imunologia , Carcinoma de Células Renais/diagnóstico , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Neoplasias Renais/diagnóstico , Nivolumabe/uso terapêutico , Linfócitos T/imunologia , Anticorpos Antivirais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Células Cultivadas , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Neoplasias Renais/tratamento farmacológico , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
18.
Gan To Kagaku Ryoho ; 48(2): 211-213, 2021 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-33597361

RESUMO

For immune checkpoint inhibitor(ICI)-pretreated patients, docetaxel and ramucirumab(DTX plus RAM)combination therapy can be more effective than no treatment. Herein, we present the case of a patient who had been treated with ICIs and was thereafter successfully treated with DTX plus RAM. A 62-year-old man with primary pulmonary squamous cell carcinoma( PDL-1 tumor proportion score<1%)at clinical stage ⅠA2(cT1bN0M0)was treated as follows: 1)right upper lobectomy ND2a-2(pT1bN0M0, stage ⅠA2); 2)surgery for a solitary pleural metastasis 20 months later; 3)cisplatin plus vinorelbine for multiple pleural metastases as a first-line treatment 24 months after the initial surgery; and 4)nivolumab as a second-line treatment. However, progressive disease and an adverse event occurred after 5 courses of nivolumab, and DTX plus RAM were introduced as a third-line treatment. A complete response to 12 courses of combination therapy(41 months after surgery/29 months after recurrence)was determined. Unfortunately, the DTX plus RAM regimen had to be withdrawn because the patient developed drug-induced acute pneumonitis. The patient has been in remission since drug discontinuation and is receiving steroid and home-oxygen therapy.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Docetaxel/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Nivolumabe/uso terapêutico
19.
BMJ Case Rep ; 14(2)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558380

RESUMO

Cancers can develop the ability to evade immune recognition and destruction. Immune checkpoint inhibitors (ICIs) are drugs targeting these immune evasion mechanisms. ICIs have significantly improved outcomes in several cancers including metastatic melanoma. However, data on toxicities associated with allograft transplant recipients receiving ICI is limited. We describe a case of a 71-year-old woman who was diagnosed with metastatic melanoma 13 years after renal transplantation. She was commenced on the ICI nivolumab. She developed acute renal transplant rejection 15 days after administration of the first dose. She continues on haemodialysis but has demonstrated complete oncological response. This case demonstrates the risk of acute renal transplant rejection versus improved oncological outcomes. Patients and clinicians must consider this balance when initiating ICI therapy in allograft transplant recipients. Patients should be fully consented of the potential consequences of acute renal transplant rejection including lifelong dialysis.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Rejeição de Enxerto/induzido quimicamente , Transplante de Rim , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Feminino , Humanos , Falência Renal Crônica/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Metástase Linfática , Melanoma/patologia , Couro Cabeludo/patologia , Neoplasias Cutâneas/patologia , Fatores de Tempo , Transplante Homólogo
20.
Ann Hematol ; 100(3): 691-698, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33528609

RESUMO

Immune checkpoint inhibitors (ICI) have demonstrated high therapeutic efficacy in relapsed or refractory classical Hodgkin lymphoma (r/r cHL). Nevertheless, despite the accumulated data, the question of the ICI therapy duration and efficacy of nivolumab retreatment remains unresolved. In this retrospective study, in a cohort of 23 adult patients with r/r cHL who discontinued nivolumab in complete response (CR), the possibility of durable remission achievement (2-year PFS was 55.1%) was demonstrated. Retreatment with nivolumab has demonstrated efficacy with high overall response rate (ORR) and CR (67% and 33.3% respectively). At the final analysis, all patients were alive with median PFS of 16.5 months. Grade 3-4 adverse events (AEs) were reported in 36% of patients, and there was no deterioration in terms of nivolumab retreatment-associated complications.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Nivolumabe/administração & dosagem , Adulto , Estudos de Coortes , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nivolumabe/efeitos adversos , Recidiva , Retratamento , Estudos Retrospectivos , Resultado do Tratamento , Suspensão de Tratamento , Adulto Jovem
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