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1.
Am J Clin Dermatol ; 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39377880

RESUMO

BACKGROUND: The phase III KEYNOTE-913 study was conducted to evaluate the efficacy and safety of pembrolizumab as first-line therapy in patients with advanced Merkel cell carcinoma (MCC). OBJECTIVE: The aim was to report results from the primary analysis of KEYNOTE-913. PATIENTS AND METHODS: Patients with recurrent locally advanced or metastatic MCC received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 treatments (~ 2 years). The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary end points were duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, overall survival (OS), and safety and tolerability. RESULTS: Fifty-five patients were treated with pembrolizumab. The median time from first dose to data cutoff (February 15, 2024) was 50.3 months (range 38.7-59.4). The ORR was 49% (95% confidence interval [CI] 35-63), with 12 complete responses and 15 partial responses. The median DOR was 39.8 months (range 4.8-52.5+), and the 24-month DOR rate was 69%. The median PFS was 9.3 months (95% CI 3-26), and the 24-month PFS rate was 39%. The median OS was 24.3 months (95% CI 12.4 to not reached), and the 24-month OS rate was 51%. Any-grade treatment-related adverse events (AEs) occurred in 38 patients (69%); 13 patients (24%) experienced grade 3-5 AEs. The most common treatment-related AEs were fatigue (n = 12 [22%]), pruritus (n = 12 [22%]), and lipase increase (n = 10 [18%]). One patient died of treatment-related Guillain-Barré syndrome. CONCLUSIONS: Pembrolizumab provided durable antitumor activity and promising survival and had a manageable safety profile in patients with recurrent locally advanced or metastatic MCC, supporting its use in this population. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03783078.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38965194

RESUMO

Anticancer systemic therapy comprises a complex and growing group of drugs. Some of the new agents with novel mechanisms of action that have appeared are difficult to fit in the groups of classical chemotherapy, hormones, tyrosine-kinase inhibitors, and monoclonal antibodies. We propose a classification based on two levels of information: the site of action and the mechanism of action. Regarding the former, drugs can exert their action in the tumor cell, the tumor vasculature, the immune system, or the endocrine system. The mechanism of action refers to the molecular target.

3.
Clin Transl Oncol ; 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951438

RESUMO

BACKGROUND: Novel and highly effective drugs for non-melanoma skin cancer (NMSC) improve patient outcomes, but their high cost strains healthcare systems. Spain's decentralized public health system, managed by 17 autonomous communities (AaCc), raises concerns about equitable access. METHODS: A cross-sectional survey (July-September 2023) was sent to Spanish Multidisciplinary Melanoma Group (GEM Group) members to assess access to new drugs. FINDINGS: Fifty physicians from 15 Spanish AaCc responded to the survey. Access for drug with approved public reimbursement, Hedgehog inhibitors in basal-cell carcinoma and anti PD-L1 antibody in Merkel carcinoma, was observed in 84% and 86% of centers, respectively. For other EMA-approved treatments, but without reimbursement in Spain access decreased to 78% of centers. Heterogeneity in access was mainly observed intra regions. CONCLUSION: Unequal financial support for drugs for NMSC with creates a patchwork of access across Spanish hospitals, with variations even within the same AaCc.

4.
Nat Commun ; 15(1): 5352, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38914547

RESUMO

Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.


Assuntos
Antígeno B7-H1 , Carcinoma de Células Escamosas , Plasticidade Celular , Transição Epitelial-Mesenquimal , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias Cutâneas , Animais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Camundongos , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Imunoterapia/métodos , Transição Epitelial-Mesenquimal/imunologia , Plasticidade Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/imunologia , Receptores Virais/metabolismo , Receptores Virais/genética , Antígeno B7-1/metabolismo , Receptores Imunológicos/metabolismo
5.
J Immunother Cancer ; 12(6)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844408

RESUMO

BACKGROUND: Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM. PATIENTS AND METHODS: Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+. The primary objective was overall response rate. Secondary objectives included OS and safety. OS was estimated by Kaplan-Meier methods. Association between OS and baseline covariates, on-treatment Response Evaluation Criteria in Solid Tumors (RECIST) response, baseline tumor biopsy and circulating-tumor DNA (ctDNA) changes were assessed. RESULTS: 146 patients were treated with tebentafusp: 19 in phase 1 and 127 in phase 2. With a median follow-up duration of 48.5 months, the median OS was 17.4 months (95% CI, 13.1 to 22.8), and the 1-year, 2-year, 3-year and 4-year OS rates were 62%, 40%, 23% and 14%, respectively. Improved survival was associated with lower ctDNA baseline levels and greater ctDNA reductions by week 9 on-treatment, with 100% 1-year, 73% 2-year and 45% 3-year OS rates for patients with ctDNA clearance. Baseline gp100 expression was not associated with survival, despite more RECIST responses among patients with higher expression. No new safety signals were reported with long-term dosing. CONCLUSIONS: This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp.


Assuntos
Melanoma , Neoplasias Uveais , Humanos , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Seguimentos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/farmacologia , Idoso de 80 Anos ou mais , Metástase Neoplásica
6.
Clin Transl Oncol ; 26(10): 2572-2583, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38750345

RESUMO

BACKGROUND: The development of highly active drugs has improved the survival of melanoma patients, but elevated drug prices place a significant burden on health care systems. In Spain, the public health care system is transferred to the 17 autonomous communities (AACC). The objective of this study is to describe the situation of drug access for melanoma patients in Spain and how this decentralized system is affecting equity. METHODS: From July to September 2023, a cross-sectional survey was sent to members of the Spanish Multidisciplinary Melanoma Group (GEM Group). The questionnaire consulted about the real access to new drugs in each hospital. The responses were collected anonymously and analyzed according to several variables, including the AACC. RESULTS: The survey was answered by 50 physicians in 15 AACC. No major differences on access between AACC were observed for indications that are reimbursed by the Spanish Health Care System (adjuvant immunotherapy for stage IIIC-IIID and resected stage IV melanoma). Important differences in drug access were observed among AACC and among centers within the same AACC, for most of the EMA indications that are not reimbursed (adjuvant immunotherapy for stages IIB-IIC-IIIA-IIIB) or that are not fully reimbursed (ipilimumab plus nivolumab in advanced stage). Homogeneously, access to adjuvant targeted drugs, TIL therapy and T-VEC, is extremely low or non-existing in all AACC. CONCLUSIONS: For most indications that reimbursement is restricted out of the EMA indication, a great diversity on access was found throughout the different hospitals in Spain, including heterogeneity intra-AACC.


Assuntos
Acessibilidade aos Serviços de Saúde , Melanoma , Humanos , Melanoma/tratamento farmacológico , Estudos Transversais , Espanha , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Inquéritos e Questionários , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/uso terapêutico , Antineoplásicos/economia , Ipilimumab/uso terapêutico , Nivolumabe/uso terapêutico , Nivolumabe/economia , Imunoterapia
7.
J Leukoc Biol ; 116(3): 440-455, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-38466822

RESUMO

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after T cell receptor (TCR)-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular nicotinamide adenine dinucleotide and nicotinamide mononucleotide concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the oxygen consumption rate/extracellular acidification rate ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ecto-CD38 catalytic activity in TM cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous proinflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morphofunctionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.


Assuntos
ADP-Ribosil Ciclase 1 , Linfócitos T CD4-Positivos , Infecções por HIV , Humanos , ADP-Ribosil Ciclase 1/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Jurkat , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Glicoproteínas de Membrana/metabolismo , Glicólise , Mitocôndrias/metabolismo
8.
Clin Transl Oncol ; 26(2): 532-537, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37505371

RESUMO

INTRODUCTION: Systemic therapy of patients with metastatic renal cell carcinoma (mRCC) has improved in the past years, with the advent of new immunotherapy-based combinations as a standard treatment option for first-line therapy. Nevertheless, particularly in good-risk patients by IMDC criteria, tyrosine-kinase inhibitors (TKI) may remain as an option for some patients. We reviewed our experience with TKI as first-line therapy for mRCC patients, trying to identify subgroups of patients that may still benefit from this strategy. MATERIAL AND METHODS: All patients with mRCC treated with first-line TKI, and adequate follow-up, in University Hospital La Paz (Madrid, Spain) between 2007 and 2020 were analyzed. Patients treated inside a clinical trial were excluded from this analysis. RESULTS: A total of 90 patients treated with first-line TKI were included. Regarding IMDC criteria, 33 patients (36.7%) were good-risk, 41 patients (45.5%) intermediate-risk, and 16 patients (17.8%) poor-risk. With a median follow-up of 49 months, the median overall survival (OS) for good, intermediate, and poor-risk patients was 54, 24, and 16 months (p = 0.004). When intermediate-risk was divided into patients with 1 or 2 risk factors, differences in OS were also statistically significant: patients with 1 risk factor had a median OS of 33 months, while patients with 2 risk factors had a median OS of 16 months, the same as poor-risk patients (p = 0.003). In the multivariate analysis, trying to find out which of the IMDC factors had a more remarkable weight in the prognosis of the patients, both ECOG and hemoglobin levels by themselves were significantly associated with OS. CONCLUSION: In our group of patients, survival outcomes were different among patients with intermediate-risk with 1 or 2 risk factors by IMDC criteria. These could help select patients that may benefit from first-line treatment with a TKI, particularly in settings with difficult access to novel therapies, such as immunotherapy-based combinations.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Tirosina/uso terapêutico
9.
Clin Cancer Res ; 30(4): 767-778, 2024 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-38060199

RESUMO

PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.


Assuntos
Anticorpos Monoclonais Humanizados , Hidrocarbonetos Aromáticos com Pontes , Piperazinas , Pirimidinas , Neoplasias de Mama Triplo Negativas , Humanos , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/metabolismo , Paclitaxel , Proteínas Proto-Oncogênicas c-akt , Taxoides/uso terapêutico , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Cancers (Basel) ; 15(17)2023 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-37686682

RESUMO

Immunotherapy improves the survival of patients with advanced melanoma, 40% of whom become long-term responders. However, not all patients respond to immunotherapy. Further knowledge of the processes involved in the response and resistance to immunotherapy is still needed. In this study, clinical paraffin samples from fifty-two advanced melanoma patients treated with anti-PD-1 inhibitors were assessed via high-throughput proteomics and RNA-seq. The obtained proteomics and transcriptomics data were analyzed using multi-omics network analyses based on probabilistic graphical models to identify those biological processes involved in the response to immunotherapy. Additionally, proteins related to overall survival were studied. The activity of the node formed by the proteins involved in protein processing in the endoplasmic reticulum and antigen presentation machinery was higher in responders compared to non-responders; the activity of the immune and inflammatory response node was also higher in those with complete or partial responses. A predictor for overall survival based on two proteins (AMBP and PDSM5) was defined. In summary, the response to anti-PD-1 therapy in advanced melanoma is related to protein processing in the endoplasmic reticulum, and also to genes involved in the immune and inflammatory responses. Finally, a two-protein predictor can define survival in advanced disease. The molecular characterization of the mechanisms involved in the response and resistance to immunotherapy in melanoma leads the way to establishing therapeutic alternatives for patients who will not respond to this treatment.

11.
Cancers (Basel) ; 15(18)2023 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-37760638

RESUMO

BACKGROUND: Determining the risk of grade 3-5 toxicity and early death (ED) is important to plan chemotherapy in older adult patients with cancer. Our objective was to identify factors predicting these complications at the time of treatment initiation. METHODS: 234 patients aged ≥70 were subjected to a geriatric assessment and variables related to the tumor and the treatment were also collected. Logistic regression multivariable analysis was used to relate these factors with the appearance of grade 3-5 toxicity and ED. Predictive scores for both toxicity and ED were then developed. RESULTS: Factors related to grade 3-5 toxicity were hemoglobin, MAX2 index, ADL, and the CONUT score. Factors related to ED were tumor stage and the GNRI score. Two predictive scores were developed using these variables. ROC curves for the prediction of toxicity and ED were 0.71 (95% CI: 0.64-0.78) and 0.73 (95% CI: 0.68-0.79), respectively. CONCLUSIONS: Two simple and reliable scores were developed to predict grade 3-5 toxicity and ED in older adult patients with cancer. This may be helpful in treatment planning.

12.
Metabolomics ; 19(7): 60, 2023 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-37344702

RESUMO

INTRODUCTION: Breast cancer is the most diagnosed tumor and the leading cause of cancer death in women worldwide. Metabolomics allows the quantification of the entire set of metabolites in blood samples, making it possible to study differential metabolomics patterns related to neoadjuvant treatment in the breast cancer neoadjuvant setting. OBJECTIVES: Characterizing metabolic differences in breast cancer blood samples according to their response to neoadjuvant treatment. METHODS: One hundred and three plasma samples of breast cancer patients, before receiving neoadjuvant treatment, were analyzed through UPLC-MS/MS metabolomics. Then, metabolomics data were analyzed using probabilistic graphical models and biostatistics methods. RESULTS: Metabolomics data allowed the identification of differences between groups according to response to neoadjuvant treatment. These differences were specific to each breast cancer subtype. Patients with HER2+ tumors showed differences in metabolites related to amino acids and carbohydrates pathways between the two pathological response groups. However, patients with triple-negative tumors showed differences in metabolites related to the long-chain fatty acids pathway. Patients with Luminal B tumors showed differences in metabolites related to acylcarnitine pathways. CONCLUSIONS: It is possible to identify differential metabolomics patterns between complete and partial responses to neoadjuvant therapy, being this metabolomic profile specific for each breast cancer subtype.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/efeitos adversos , Cromatografia Líquida , Metabolômica , Espectrometria de Massas em Tandem
13.
Clin Transl Oncol ; 25(12): 3519-3526, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37329429

RESUMO

BACKGROUND: Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison. METHODS: We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy). RESULTS: Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma. CONCLUSIONS: In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype.


Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Humanos , Ifosfamida/uso terapêutico , Estudos Retrospectivos , Desoxicitidina/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Gencitabina , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia , Dacarbazina/uso terapêutico
15.
Melanoma Res ; 33(5): 388-397, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36988401

RESUMO

BRAF and MEK inhibitor, dabrafenib plus trametinib, adjuvant therapy is effective for high-risk resected melanoma patients with BRAF - V600 mutations. However, real-world evidence is limited. We aimed to determine the feasibility of this therapy in routine clinical practice. DESCRIBE-AD, a retrospective observational study, collected real-world data from 25 hospitals in Spain. Histologically confirmed and resected BRAF -mutated melanoma patients aged ≥18 years who were previously treated with dabrafenib plus trametinib adjuvant therapy, were included. The primary objectives were treatment discontinuation rate and time to discontinuation. The secondary objectives included safety and efficacy. From October 2020 to March 2021, 65 patients were included. Dabrafenib and trametinib discontinuation rate due to treatment-related adverse events (TRAEs) of any grade was 9%. Other reasons for discontinuation included patients' decisions (6%), physician decisions (6%), unrelated adverse events (3%), disease progression (5%), and others (5%). The median time to treatment discontinuation was 9 months [95% confidence interval (CI), 5-11]. G3-4 TRAEs occurred in 21.5% of patients, the most common being pyrexia (3%), asthenia (3%), and diarrhoea (3%). Unscheduled hospitalisations and clinical tests occurred in 6 and 22% of patients, respectively. After 20-month median follow-up (95% CI, 18-22), 9% of patients had exitus due to disease progression, with a 12-month relapse-free survival and overall survival rates of 95.3% and 100%, respectively. Dabrafenib and trametinib adjuvant therapy proved effective for melanoma patients in a real-world setting, with a manageable toxicity profile. Toxicity frequencies were low leading to low incidence of unscheduled medical visits, tests, and treatment discontinuations.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Adolescente , Adulto , Melanoma/patologia , Neoplasias Cutâneas/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Oximas , Piridonas , Progressão da Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mutação
16.
Int J Mol Sci ; 24(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36614248

RESUMO

Immunotherapy based on anti-PD1 antibodies has improved the outcome of advanced melanoma. However, prediction of response to immunotherapy remains an unmet need in the field. Tumor PD-L1 expression, mutational burden, gene profiles and microbiome profiles have been proposed as potential markers but are not used in clinical practice. Probabilistic graphical models and classificatory algorithms were used to classify melanoma tumor samples from a TCGA cohort. A cohort of patients with advanced melanoma treated with PD-1 inhibitors was also analyzed. We established that gene expression data can be grouped in two different layers of information: immune and molecular. In the TCGA, the molecular classification provided information on processes such as epidermis development and keratinization, melanogenesis, and extracellular space and membrane. The immune layer classification was able to distinguish between responders and non-responders to immunotherapy in an independent series of patients with advanced melanoma treated with PD-1 inhibitors. We established that the immune information is independent than molecular features of the tumors in melanoma TCGA cohort, and an immune classification of these tumors was established. This immune classification was capable to determine what patients are going to respond to immunotherapy in a new cohort of patients with advanced melanoma treated with PD-1 inhibitors Therefore, this immune signature could be useful to the clinicians to identify those patients who will respond to immunotherapy.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Transcriptoma , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Imunoterapia
17.
J Clin Med ; 12(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36615183

RESUMO

PURPOSE: To explore the tumor proteome of patients diagnosed with localized clear cell renal cancer (ccRCC) and treated with surgery. MATERIAL AND METHODS: A total of 165 FFPE tumor samples from patients diagnosed with ccRCC were analyzed using DIA-proteomics. Proteomics ccRCC subtypes were defined using a consensus cluster algorithm (CCA) and characterized by a functional approach using probabilistic graphical models and survival analyses. RESULTS: We identified and quantified 3091 proteins, including 2026 high-confidence proteins. Two proteomics subtypes of ccRCC (CC1 and CC2) were identified by CC using the high-confidence proteins only. Characterization of molecular differences between CC1 and CC2 was performed in two steps. First, we defined 514 proteins showing differential expression between the two subtypes using a significance analysis of microarrays analysis. Proteins overexpressed in CC1 were mainly related to translation and ribosome, while proteins overexpressed in CC2 were mainly related to focal adhesion and membrane. Second, a functional analysis using probabilistic graphical models was performed. CC1 subtype is characterized by an increased expression of proteins related to glycolysis, mitochondria, translation, adhesion proteins related to cytoskeleton and actin, nucleosome, and spliceosome, while CC2 subtype showed higher expression of proteins involved in focal adhesion, extracellular matrix, and collagen organization. CONCLUSIONS: ccRCC tumors can be classified in two different proteomics subtypes. CC1 and CC2 present specific proteomics profiles, reflecting alterations of different molecular pathways in each subtype. The knowledge generated in this type of studies could help in the development of new drugs targeting subtype-specific deregulated pathways.

18.
Clin Cancer Res ; 29(1): 67-80, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36165912

RESUMO

PURPOSE: To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC). PATIENTS AND METHODS: The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis. RESULTS: Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6-53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2-27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8-6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71-282.9; P = 0.018). CONCLUSIONS: Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Piperazinas/uso terapêutico
19.
Nat Med ; 28(11): 2364-2373, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36229663

RESUMO

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2-10%), the 1 year overall survival rate was 62% (95% CI: 53-70%) with a median overall survival of 16.8 months (95% CI: 12.9-21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.


Assuntos
Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/genética , Neoplasias Uveais/patologia , Melanoma/patologia , Intervalo Livre de Progressão
20.
Clin Genitourin Cancer ; 20(4): 363-370, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35317987

RESUMO

INTRODUCTION: Docetaxel 75 mg/m2 every 3 weeks is the standard schedule for metastatic prostate cancer (mPC). Alternative dosing of 50 mg/m2 every 2 weeks may be an option for frail patients. Our aim is to define which factors influence the choice of schedule and to compare the outcomes of both schedules in daily clinical practice. PATIENTS AND METHODS: We retrospectively included patients with mPC treated with docetaxel in our institution. We compared data from patients treated with 3-weekly, 75 mg/m2 docetaxel or 2-weekly, 50 mg/m2 docetaxel, including basal characteristics, predefined prognostic factors, treatment received, toxicity and survival data. RESULTS: We included 200 patients, 86% of whom presented castration resistant mPC. A total of 158 patients (79%) were treated with 3-weekly scheme. Compared with these patients, patients treated with 2-weekly scheme were significantly older, had higher Eastern Cooperative Oncology Group performance status (ECOG PS) and Charlson Comorbidity Index, presented more visceral metastases and needed opioid treatment more frequently. Patients treated with 2-weekly scheme presented shorter median overall survival; however, these differences were not shown after multivariate analysis with significant prognostic factors. Patients treated with 2-weekly scheme had more treatment delays and suspensions, but less clinically impairing toxicities such as febrile neutropenia, neuropathy and diarrhea; toxic deaths were 5 in the 3-weekly group while none in the 2-weekly group. CONCLUSION: Compared to docetaxel 75 mg/m2 every 3 weeks, dosing of 50 mg/m2 every 2 weeks may be an alternative for older, frailer and more comorbid patients. Two-weekly dosing may be used more frequently in selected patients.


Assuntos
Neoplasias da Próstata , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/etiologia , Estudos Retrospectivos , Taxoides/uso terapêutico
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