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Background: Immunotherapy has been shown to improve outcomes for patients with cancer. Biliary tract cancers are a group of lethal diseases, and immunotherapy is an exciting new strategy to treat patients in advanced stages. Role of immunotherapy in biliary cancers: Durvalumab, an anti-PD-L1 antibody, is a new immunotherapy option for patients with advanced biliary cancers. In a randomized phase III trial, the combination of durvalumab and chemotherapy improved disease outcomes, including overall survival, in patients with advanced biliary cancers regardless of PD-L1 expression. Future perspective: Promising new combinations with new and potent antibodies or antiangiogenics are under development. Combinations with new immunotherapy agents targeting CTLA-4 or OX40 can enhance T-cell activation and improve outcomes compared with single anti-PD-1/PD-L1 agents. Furthermore, ctDNA is being used as an alternative to tissue genomic analysis and can be used to identify actionable targets. In this review, we will discuss the most important studies involving immunotherapy in biliary cancers as well as future perspectives in the field.
New treatment strategies for advanced biliary cancers with chemoimmunotherapy combinations have been shown to lead to better tumor responses and overall survival compared with chemotherapy alone. The combination of durvalumab, cisplatin and gemcitabine may become a new standard of care for advanced disease despite the modest improvement in median overall survival of less than 2 months. Promising combinations with anti-CTLA-4 antibodies or antiangiogenics are underway with the objective of improvement in survival. Although multiple combinations are available with the potential to establish a new standard of care, concerns regarding toxicities should also be evaluated. In this review, we will discuss the most important studies involving immunotherapy in biliary cancers as well as future perspectives in the field.
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Neoplasias do Sistema Biliar , Humanos , Imunoterapia , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Due to the increasing number of trials with immune checkpoint inhibitors (ICIs) in the first-line therapy of non-small cell lung cancer (NSCLC) patients, we performed a systematic review and meta-analyses to investigate the difference between anti PD-1 and PD-L1 antibodies, used alone or in combination with chemotherapy, through adjusted indirect analysis to minimize the potential bias regarding overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3-5 adverse events (AEs). METHODS: A systematic review of studies reporting clinical outcomes and toxicity associated with first-line therapy employing anti-PD1 or anti-PD-L1 antibodies alone, or in combination with chemotherapy, to treat metastatic, treatment-naïve NSCLC patients was performed. Primary outcomes were OS, PFS, ORR and grade 3-5 AEs. We used a random-effects model to generate pooled estimates for proportions. Meta-analyses using pooled risk ratios were performed for binary outcomes from comparative studies with the random effects model. RESULTS: A total of 13 eligible studies met our eligibility criteria, including 7673 patients. In the ICI-chemotherapy combination subgroup, we observed that anti-PD1 therapy was associated with better OS (p = 0.022) and PFS (p = 0.029) compared with anti-PD-L1 therapy. In the monotherapy subgroup, there was no statistical difference between the use of anti-PD-1 and anti-PD-L1 for OS and PFS. With regard to ORR and toxicity, in the ICI-chemotherapy combination subgroup, we observed a trend of better ORR (p = 0.12) with the use of anti-PD1 therapy and less frequent grade 3-5 AEs compared to the use of anti-PD-L1 therapy (p = 0.0302). In the monotherapy subgroup, there was no statistical difference between the use of anti-PD-1 and anti-PD-L1 regarding ORR and toxicity. CONCLUSIONS: Our study suggests that PD-1 drug plus chemotherapy is superior to anti-PD-L1 plus chemotherapy for NSCLC; nevertheless, as monotherapy, both strategies appear to be similar.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
ABSTRACT Programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand-1 (PD-L1), play key roles in the suppression of the cytotoxic activity of T cells. PD-L1 is overexpressed on various types of cancer cells, leading to immune evasion. In the past decade, therapeutic antibodies that target the PD-1/PD-L1 axis have been developed to inhibit the immune suppression triggered by these two proteins. At present, five antibodies (two anti-PD-1 and three anti-PD-L1) have received approval by regulatory agencies in the US and Europe. In this work, we aimed to review their clinical applications and adverse effects. Furthermore, using their reported crystal structures, we discuss the similarities and differences between the PD-1/PD-L1 interface and the epitopes that are recognized by the antibodies. Detailed analyses of the contact residues involved in the ligand-receptor and target-antibody interactions have shown partial overlap. Altogether, the data presented here demonstrate that: (1) in contrast to other therapeutic antibodies, anti-PD-1/PD-L1 has a wide range of clinical applications; (2) these targeted therapies are not exempt from adverse effects; and (3) the characterization of the structural domains that are recognized by the antibodies can guide the development of new PD-1- and PD-L1-blocking agents. (REV INVEST CLIN. 2021;73(1):8-16)
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Humanos , Antígeno B7-H1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Imunoterapia/métodos , Anticorpos/uso terapêutico , Neoplasias/terapiaRESUMO
BACKGROUND: Recent studies have observed an association between immune-related adverse events (irAE) and favorable clinical outcomes in the setting of cancer treatment with immune checkpoint inhibitors (ICI). However, results have been variable and inconclusive. Therefore, we have conducted a pan-cancer meta-analysis evaluating the relationship between irAEs and clinical outcomes. MATERIALS AND METHODS: The search included studies published in PubMed, Embase, and Web of Science from conception to 12.28.2019 as well as abstracts published in the ASCO and ESMO meetings from 2015 to 2019. Studies were included if ICI was used in advanced or metastatic cancer settings and excluded if data contained only combination therapy regimens or contained anti-CTLA-4. Raw data for overall response rate (ORR), hazard ratios (HR), number of patients (n), and p values for overall survival (OS) and progression-free survival (PFS) were extracted. Pooled sensitivity (SN), specificity (SP), positive (PPV) and negative predictive values (NPV), and odds ratios (ORs) were calculated using the 2 × 2 table and logit transformed proportions; and summary receiver operating curve (sROC) was generated using the bivariate approach for ORR. Pooled HRs were calculated using the means weighted by inverse of the variance for OS and PFS. Heterogeneity was assumed and random effects model was used throughout the analyses. RESULTS: Final analysis included 32 studies, among which ORR data were available in 15 studies, OS in 17, and PFS in 16. 17 studies evaluated non-small cell lung cancer (NSCLC), two studies melanoma, one study gastric cancer, three studies renal cell carcinoma (RCC), seven studies various cancer types, two studies urothelial carcinoma, and one study head and neck cancer (HNSCC). With respect to ORR, pooled SN, SP, PPV and NPV, and OR were 0.522 [0.423-0.619], 0.810 [0.771-0.844], 0.516 [0.413-0.618], 0.819 [0.764-0.864], and 4.59 [3.24-6.50], respectively. The area under the curve (AUC) derived from the sROC was 0.773. HR for OS and PFS were 0.47 [95% CI 0.37-0.60] and 0.46 [95% CI 0.37-0.56], respectively. Between-study publication bias was present for ORR, OS, and PFS; however, results remained significant after trim-fill analysis. CONCLUSION: irAEs predict OR, OS, and PFS across different types of cancer and may represent useful biomarkers in the clinical setting.
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Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/terapia , Área Sob a Curva , Antígeno B7-H1/antagonistas & inibidores , Viés , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/terapia , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/terapia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Complexo Antígeno L1 Leucocitário/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/terapia , Neoplasias/imunologia , Neoplasias/mortalidade , Intervalo Livre de Progressão , Sensibilidade e Especificidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/terapia , Resultado do TratamentoRESUMO
Immune checkpoint inhibitors (ICI) are a novel class of antineoplastic treatment that enhances immunity against tumors. They are associated with immune adverse events, and several neurological syndromes have been described, including multiple sclerosis and atypical demyelination. We performed a systematic literature review of case reports with neurological immune adverse events that presented with central nervous system demyelination, up to December 2019. We found 23 cases: seven with myelitis, four isolated optic neuritis, one neuromyelitis optica spectrum disorder, five multiple sclerosis, and six with atypical demyelination. Ipilimumab was the most frequently used ICI (11/23). The median time to develop symptoms from the onset of ICI was 6.5 weeks [range 1.0-43.0], and from last ICI dose was 14 days [range 0-161]. Anatomopathological examination was performed in four cases, with the finding of a T-cell mediated immune response. Outcomes were generally favorable after immunosuppression: 18 patients had improvement or a full recovery, three patients did not respond to treatment, three patients died, and in one, treatment was not reported. We describe the patients' clinical presentation, treatment administered, and outcomes. We further speculate on possible pathophysiological mechanisms and discuss potential treatments that may be worth investigating.
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PURPOSE: Considering the recent publication of the results of several clinical trials for metastatic clear cell renal cell carcinoma (mRCC), we performed a systematic review and meta-analysis of randomized studies comparing standard first-line VEGFR-targeted therapy to immune checkpoint inhibitors-based combinations for mRCC patients. METHODS: 3960 patients from 5 randomized clinical trials where available for evaluation. RESULT: In the all-comers population, immunotherapy-based combinations were able to decrease the risk of death over the standard of care by 26% (HR 0.74; 95% CI 0.60-0.92; p = 0.006), to decrease the risk of progression by 21% (HR 0.79; 95% CI 0.72-0.86; p < 0.00001), and to increase the relative risk of response by 40% (HR 1.40; 95% CI 1.11-1.77; p = 0.006). For poor/intermediate-risk patients, the risk of death is decreased by 41% and the risk of progression by 27%. CONCLUSIONS: The benefit of immunotherapy-based combinations in mRCC patients is independent from the IMDC risk group, but it is stronger for poor/intermediate-risk patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Introdução: o câncer já é a principal causa de morte prematura (abaixo dos 70 anos) em cerca de um terço dos países monitorados pela Organização Mundial da Saúde, fenômeno que se relaciona à transição epidemiológica vivida no século XXI. Dentre as neoplasias mais incidentes no mundo destacam-se os tumores de pulmão, equivalentes a 12% dos casos estimados para o ano de 2018, superando os tumores de mama, de intestino/reto e próstata. Ademais, o câncer de pulmão apresenta alta letalidade, sendo responsável por 18% dos óbitos causados por alguma neoplasia, além de um prognóstico ruim, com sobrevida de cinco anos entre 10 e 20%. A década de 2010 foi marcada pelo lançamento de anticorpos monoclonais com ação na inibição do checkpoint imunológico (pelas vias CTLA4 e PD-1/PD-L1), trazendo novas expectativas para o combate a diversos tipos de tumores, incluindo os de pulmão. Esses medicamentos trouxeram algum ganho de sobrevida e um melhor perfil de toxicidade em relação à quimioterapia tradicional, mas a um custo elevado, superando a barreira de R$ 100.000,00 por ano de tratamento. Objetivo: avaliar a eficácia, segurança e efetividade dos inibidores de checkpoint imunológico (ICI), em monoterapia, associados entre si ou associados à quimioterapia, em comparação ao tratamento tradicional para o câncer de pulmão de células não pequenas em estadiamento avançado ou metastático. Métodos: foi conduzida uma revisão sistemática com meta-análise de ensaios clínicos randomizados (ECR) e estudos observacionais publicados nas principais bases de dados eletrônicas (Cochrane Library, EMBASE, LILACS e PUBMED). Os desfechos analisados foram sobrevida global (OS), eventos adversos relacionados ao tratamento (trAE) grau 3 ou maior, eventos adversos relacionados ao uso de imunoterapia (irAE), sobrevida livre de progressão (PFS) e taxa de resposta objetiva (ORR). Resultados: dentre as 2.783 publicações identificadas na literatura, foram selecionados 19 artigos referentes a 14 ECR e apenas um artigo referente a estudo observacional. Nas meta-análises realizadas para os ECR, o uso de ICI, em monoterapia ou em associação com outro ICI ou com quimioterapia, demonstrou ser mais eficaz nos desfechos OS (diferença de média [MD] 2,66 meses; intervalo de confiança [IC] 95% 1,80 a 3,52) e ORR (risco relativo [RR] 1,47; IC95% 1,20 a 1,79). Os dados referentes à PFS não demonstraram ganho de sobrevida (MD 0,07 meses; IC95% -0,61 a 0,76). Quanto à segurança dos ICI, observou-se um melhor perfil de toxicidade no desfecho trAE (RR 0,51; IC95% 0,36 a 0,73), entretanto houve maior incidência de irAE. Também foi possível identificar associação entre a expressão da proteína de membrana PD-L1 nas células tumorais e os desfechos de sobrevida. Conclusão: apesar da heterogeneidade estatística encontrada nas meta-análises e dos conflitos de interesse identificados nos ECR, os resultados obtidos indicam que os ganhos de sobrevida são mínimos e houve incidência de irAE relevantes como colite, hipotireoidismo, hipertireoidismo e pneumonite. A carência de evidências de mundo real, com braços comparadores, somada ao alto custo por ano de vida ganho são limitações para se estimar a efetividade dessas opções terapêuticas e para incorporar essas tecnologias em sistemas de saúde de países em desenvolvimento.
Introduction: cancer has become the main cause of premature mortality (before the age of 70) in one third of the countries. This phenomenon is related to the epidemiologic transition in 21st century. Among the world's main neoplasms, lung tumors represent 12% of estimated cases in 2018, outperforming breast, colon and prostate tumors. Moreover, lung cancer show high lethality, being responsible for 18% of deaths caused by any neoplasm. The disease prognostic is poor, with a five-year survival between 10 and 20%. In 2010's there were launched monoclonal antibodies inhibiting the immune checkpoint system (CTLA4 and PD-1/PD-L1 pathways), bringing new hope against many tumors, including lung cancer. These drugs showed some survival gain and a better safety profile comparing to traditional chemotherapy. Although these benefits, they have a high cost, overcoming the R$ 100.000,00 barrier per year of treatment. Objective: to assess the efficacy, safety and effectiveness of immune checkpoint inhibitors (ICI), as monotherapy, in association with themselves or with chemotherapy, comparing with traditional treatment for advanced or metastatic non-small cell lung cancer. Methods: we did a systematic review with meta-analysis selecting randomized clinical trials (RCT) and observational studies from the main electronic database (Cochrane Library, EMBASE, LILACS e PUBMED). We analyzed overall survival (OS), treatment-related adverse events (trAE) grade 3 or greater, immune-related adverse events (irAE), progression-free survival (PFS) and objective response rate (ORR). Results: among the 2,783 publications identified on the electronic database, we selected 19 papers referring to 14 RCT and only papers of observational study. Considering the meta-analysis we did for the RCT outcomes, ICI showed more efficacy in the outcomes OS (mean difference [MD] 2.66 months; 95% confidence interval [95%CI] 1.80; 3.52) and ORR (relative risk [RR] 1.47; 95%CI 1.20; 1.79). Regarding PFS, we found inconclusive data (MD 0.07 months; 95%CI -0.61; 0,76). In terms of safety, we found a better safety profile in trAE (RR 0.51; 95%CI 0.36; 0.73), but there were high incidence of irAE. We also identified the association between membrane protein PD-L1 expression and survival outcomes. Conclusion: despite the statistical heterogeneity in the meta-analysis and the conflict of interest identified in the RCT, our results suggest small survival gain in the intention-to-treat population and relevant irAE incidence as colitis, hypothyroidism, hyperthyroidism and pneumonitis. There was a lack of real world evidence, which limited our estimates for the effectiveness of these drugs. Moreover, considering the high cost per life gained, there is a relevant barrier to incorporate these technologies in health systems of developing countries.