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2.
Eur J Cancer ; 179: 87-97, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36509002

RESUMO

BACKGROUND: BRAF mutant melanoma treated with BRAF ± MEK inhibitor (targeted therapy) has a high response rate; however, most patients progress (PD). Some patients have durable response, but it is unknown whether treatment can be discontinued in these patients. We describe the recurrence risk, progression patterns, response to subsequent treatment, and survival of patients with advanced melanoma who ceased targeted therapy prior to PD. PATIENTS AND METHODS: Ninety-four patients who ceased targeted therapy without progression were identified retrospectively from 11 centres: 45 were male; 81 V600E; 88 stage IV. Fifty-nine were treated with BRAF + MEK inhibitor, and 35 were treated with BRAF inhibitor alone. Median treatment duration was 29.6 months (range 0.36-77.9). At cessation, 67 were in complete response, 21 in partial response, and 2 stable disease. RESULTS: After median follow-up from cessation of 42.9 months (range 0.0-88.7), 36 (38%) progressed; median time to progression was 4.7 months (range 0.7-56.9); 30 (83%) were asymptomatic and 7 (19%) had new brain metastases. Progression rates did not differ by best response: 34% for complete response and 43% for partial response (P = 0.65). Treatment duration was strongly associated with risk of progression: Median treatment duration was 18.3 (range 0.85-65.7) months for those who progressed and 34.6 (range 0.36-77.9) months for those who did not (P = 0.0004). Twenty-two received further targeted therapy with 15 (68%) responses. CONCLUSION: Risk of progression after cessation of targeted therapy is strongly associated with treatment duration. Response to retreatment with targeted therapy is high.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Masculino , Feminino , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Progressão da Doença , Quinases de Proteína Quinase Ativadas por Mitógeno , Mutação , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/induzido quimicamente
3.
Lancet Oncol ; 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36460017

RESUMO

BACKGROUND: Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600 mutation-positive melanoma. With a median follow-up of 18·9 months (IQR 10·4-23·8) at the primary analysis, overall survival data were immature. Here, we report the results from the second, prespecified, interim overall survival analysis. METHODS: The multicentre, double-blind, placebo-controlled, randomised, phase 3 IMspire150 study was done at 108 academic and community hospitals in 20 countries. Patients aged 18 years or older with previously untreated unresectable stage IIIc or stage IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive either atezolizumab (840 mg intravenously on day 1 and 15) or placebo plus vemurafenib (960 mg or 720 mg twice daily orally) and cobimetinib (60 mg once daily orally; 21 days on and 7 days off) in 28-day cycles. Atezolizumab and placebo were added to treatment regimens from cycle two onwards. Randomisation was done centrally (Durham, NC, USA) based on a permuted block randomisation scheme (block size of 4) using an interactive web-based response system and was stratified by geographical region and baseline lactate dehydrogenase concentration. Overall survival was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug according to actual treatment received. The primary endpoint was investigator-assessed progression-free survival, which was previously reported. Here, we report the second, prespecified, interim overall survival analysis, which was planned after about 270 overall survival events had occurred. The trial is ongoing, but is no longer enrolling patients, and it is registered with ClinicalTrials.gov, NCT02908672. FINDINGS: Between Jan 13, 2017, and April 26, 2018, 514 patients (median age 54 years [IQR 43-63]; 299 [58%] men and 215 [42%] women) were enrolled in the trial and randomly assigned to the atezolizumab group (256 [50%] patients) or the control group (258 [50%] patients). At the data cutoff (Sept 8, 2021), 273 patients had died (126 in the atezolizumab group and 147 in the control group). Median follow-up was 29·1 months (IQR 10·1-45·4) for the atezolizumab group versus 22·8 months (10·6-44·1) for the control group. Median overall survival was 39·0 months (95% CI 29·9-not estimable) in the atezolizumab group versus 25·8 months (22·0-34·6) in the control group (HR 0·84 [95% CI 0·66-1·06]; p=0·14). The most common adverse events of any grade in the atezolizumab group were blood creatine phosphokinase increased (123 [53%] of 231 patients), diarrhoea (116 [50%]), and pyrexia (115 [50%]). The most common adverse events of any grade in the control group were diarrhoea (157 [56%] of 280 patients), blood creatine phosphokinase increased (135 [48%]), and rash (119 [43%]). The most common grade 3-4 adverse events were increased lipase (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group), increased blood creatine phosphokinase (51 [22%] vs 50 [18%]), and increased alanine aminotransferase (32 [14%] vs 26 [9%]). Serious adverse events were reported in 112 (48%) patients in the atezolizumab group and 117 (42%) patients in the control group. Grade 5 adverse events were reported in eight (3%) patients in the atezolizumab group versus six (2%) patients in the control group. Two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group were considered to be associated with the triplet combination, and one event in the control group (pulmonary haemorrhage) was considered to be associated with cobimetinib. INTERPRETATION: Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAFV600 mutation-positive advanced melanoma. Results of the final analysis are awaited to establish whether a significant improvement in overall survival can be achieved with long-term treatment with this triplet combination versus vemurafenib plus cobimetinib. FUNDING: F Hoffmann-La Roche.

4.
J Immunother Cancer ; 10(12)2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36455990

RESUMO

Non-melanoma skin cancer (NMSC) includes a wide range of cutaneous tumors, the most frequent of which are basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC). Although NMSC is usually cured by surgical resection, in rare cases it can progress to locally advanced and metastatic disease. Risk factors for advanced disease include comorbidities, neglect, and immunosuppression. Advanced NMSC may require systemic treatment if surgery and radiation are not feasible. Chemotherapy, epidermal growth factor receptor (EGFR) inhibitors in CSCC, and hedgehog inhibitors in BCC have been used but are generally of limited benefit, with responses often short-lived and toxicity issues. Given the high mutational burden of NMSC, the use of immunotherapy has been investigated and two anti-PD-1 antibodies, cemiplimab and pembrolizumab, are approved for the treatment of advanced CSCC not curable by surgery or radiation. Both have shown durable responses with good tolerability in patients in phase II trials and anti-PD-1 therapy is now the standard of care for locally advanced and metastatic CSCC. PD-1 blockade is also approved as second-line therapy in advanced BCC, with frequent and durable responses after failure on hedgehog inhibitor therapy. PD-1 checkpoint inhibition is being assessed for NMSC in combination with other modalities, including oncolytic viruses and EGFR inhibitors. Adjuvant and neoadjuvant use of cemiplimab and pembrolizumab is also being investigated with several ongoing trials. Further clinical trials of immunotherapy must be prioritized in NMSC for further improvement in outcomes.


Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/tratamento farmacológico , Inibidores de Checkpoint Imunológico , Carcinoma de Células Escamosas/tratamento farmacológico , Proteínas Hedgehog , Carcinoma Basocelular/tratamento farmacológico , Inibidores de Proteínas Quinases , Receptores ErbB
5.
Mol Ther ; 2022 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-36575794

RESUMO

The COVID-19 pandemic and the need for additional safe, effective, and affordable vaccines gave new impetus into development of vaccine genetic platforms. Here we report the findings from the phase 1, first-in-human, dose-escalation study of COVID-eVax, a DNA vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Sixty-eight healthy adults received two doses of 0.5, 1, or 2 mg 28 days apart, or a single 2-mg dose, via intramuscular injection followed by electroporation, and they were monitored for 6 months. All participants completed the primary safety and immunogenicity assessments after 8 weeks. COVID-eVax was well tolerated, with mainly mild to moderate solicited adverse events (tenderness, pain, bruising, headache, and malaise/fatigue), less frequent after the second dose, and it induced an immune response (binding antibodies and/or T cells) at all prime-boost doses tested in up to 90% of the volunteers at the highest dose. However, the vaccine did not induce neutralizing antibodies, while particularly relevant was the T cell-mediated immunity, with a robust Th1 response. This T cell-skewed immunological response adds significant information to the DNA vaccine platform and should be assessed in further studies for its protective capacity and potential usefulness also in other therapeutic areas, such as oncology.

6.
Oncogene ; 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36418472

RESUMO

BRAF-mutated melanoma relapsing after targeted therapies is an aggressive disease with unmet clinical need. Hence the need to identify novel combination therapies able to overcome drug resistance. miRNAs have emerged as orchestrators of non-genetic mechanisms adopted by melanoma cells to challenge therapies. In this context we previously identified a subset of oncosuppressor miRNAs downregulated in drug-resistant melanomas. Here we demonstrate that lipid nanoparticles co-encapsulating two of them, miR-199-5p and miR-204-5p, inhibit tumor growth both in vitro and in vivo in combination with target therapy and block the development of drug resistance. Mechanistically they act by directly reducing melanoma cell growth and also indirectly by hampering the recruitment and reprogramming of pro-tumoral macrophages. Molecularly, we demonstrate that the effects on macrophages are mediated by the dysregulation of a newly identified miR-204-5p-miR-199b-5p/CCL5 axis. Finally, we unveiled that M2 macrophages programs are molecular signatures of resistance and predict response to therapy in patients. Overall, these findings have strong translational implications to propose new combination therapies making use of RNA therapeutics for metastatic melanoma patients.

7.
Cell Rep ; 41(6): 111601, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36351409

RESUMO

Melanoma is a deadly form of cancer characterized by remarkable therapy resistance. Analyzing the transcriptome of MAPK inhibitor sensitive- and resistant-melanoma, we discovered that APAF-1 is negatively regulated by MITF in resistant tumors. This study identifies the MITF/APAF-1 axis as a molecular driver of MAPK inhibitor resistance. A drug-repositioning screen identified quinacrine and methylbenzethonium as potent activators of apoptosis in a context that mimics drug resistance mediated by APAF-1 inactivation. The compounds showed anti-tumor activity in in vitro and in vivo models, linked to suppression of MITF function. Both drugs profoundly sensitize melanoma cells to MAPK inhibitors, regulating key signaling networks in melanoma, including the MITF/APAF-1 axis. Significant activity of the two compounds in inhibiting specific epigenetic modulators of MITF/APAF-1 expression, such as histone deacetylases, was observed. In summary, we demonstrate that targeting the MITF/APAF-1 axis may overcome resistance and could be exploited as a potential therapeutic approach to treat resistant melanoma.


Assuntos
Melanoma , Terapia de Salvação , Humanos , Apoptose , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Melanoma/patologia , Fator de Transcrição Associado à Microftalmia/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
8.
Lancet Oncol ; 23(11): 1378-1388, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36265502

RESUMO

BACKGROUND: Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up. METHODS: KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment. FINDINGS: Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [<1%]), rash (seven [1%] vs two [<1%]), autoimmune hepatitis (seven [1%] vs two [<1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported. INTERPRETATION: Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.


Assuntos
Melanoma , Neoplasias Cutâneas , Neoplasias Testiculares , Masculino , Humanos , Criança , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/cirurgia , Recidiva Local de Neoplasia/patologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
9.
Eur J Cancer ; 176: 207-217, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36202690

RESUMO

BACKGROUND: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported. METHODS: Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥12 to <18 years) Q3W or placebo for ≤17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥1 dose of treatment and completed ≥1 assessment. RESULTS: The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥80% for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms. CONCLUSIONS: HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma.


Assuntos
Melanoma , Qualidade de Vida , Humanos , Recidiva Local de Neoplasia , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Adjuvantes Imunológicos/uso terapêutico
10.
J Clin Oncol ; : JCO2102961, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36049147

RESUMO

PURPOSE: Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for BRAFV600-mutant metastatic melanoma. METHODS: SECOMBIT is a randomized, three-arm, noncomparative phase II trial (ClinicalTrials.gov identifier: NCT02631447). Patients with untreated, metastatic BRAFV600-mutant melanoma from 37 sites in nine countries were randomly assigned to arm A (encorafenib [450 mg orally once daily] plus binimetinib [45 mg orally twice daily] until progressive disease [PD] -> ipilimumab plus nivolumab [ipilimumab 3 mg/kg once every 3 weeks and nivolumab 1 mg/kg once every 3 weeks × four cycles -> nivolumab 3 mg/kg every 2 weeks]), arm B [ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib], or arm C (encorafenib plus binimetinib for 8 weeks -> ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib). The primary end point was overall survival (OS) at 2 years. Secondary end points included total progression-free survival, 3-year OS, best overall response rate, duration of response, and biomarkers in the intent-to-treat population. Safety was analyzed throughout sequential treatment in all participants who received at least one dose of study medication. RESULTS: A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged. CONCLUSION: Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with BRAFV600-mutant melanoma.

11.
J Immunother Cancer ; 10(9)2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36175037

RESUMO

The broad activity of agents blocking the programmed cell death protein 1 and its ligand (the PD-(L)1 axis) revolutionized oncology, offering long-term benefit to patients and even curative responses for tumors that were once associated with dismal prognosis. However, only a minority of patients experience durable clinical benefit with immune checkpoint inhibitor monotherapy in most disease settings. Spurred by preclinical and correlative studies to understand mechanisms of non-response to the PD-(L)1 antagonists and by combination studies in animal tumor models, many drug development programs were designed to combine anti-PD-(L)1 with a variety of approved and investigational chemotherapies, tumor-targeted therapies, antiangiogenic therapies, and other immunotherapies. Several immunotherapy combinations improved survival outcomes in a variety of indications including melanoma, lung, kidney, and liver cancer, among others. This immunotherapy renaissance, however, has led to many combinations being advanced to late-stage development without definitive predictive biomarkers, limited phase I and phase II data, or clinical trial designs that are not optimized for demonstrating the unique attributes of immune-related antitumor activity-for example, landmark progression-free survival and overall survival. The decision to activate a study at an individual site is investigator-driven, and generalized frameworks to evaluate the potential for phase III trials in immuno-oncology to yield positive data, particularly to increase the number of curative responses or otherwise advance the field have thus far been lacking. To assist in evaluating the potential value to patients and the immunotherapy field of phase III trials, the Society for Immunotherapy of Cancer (SITC) has developed a checklist for investigators, described in this manuscript. Although the checklist focuses on anti-PD-(L)1-based combinations, it may be applied to any regimen in which immune modulation is an important component of the antitumor effect.


Assuntos
Ensaios Clínicos como Assunto , Imunoterapia , Neoplasias , Receptor de Morte Celular Programada 1 , Animais , Lista de Checagem , Inibidores de Checkpoint Imunológico , Fatores Imunológicos , Ligantes , Neoplasias/imunologia , Neoplasias/terapia
12.
J Clin Oncol ; : JCO2200533, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36162037

RESUMO

PURPOSE: Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma. PATIENTS AND METHODS: In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup. RESULTS: At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients. CONCLUSION: Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment.

13.
J Transl Med ; 20(1): 391, 2022 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-36058945

RESUMO

Advances in immune checkpoint and combination therapy have led to improvement in overall survival for patients with advanced melanoma. Improved understanding of the tumor, tumor microenvironment and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. Combination modalities with other immunotherapy agents, chemotherapy, radiotherapy, electrochemotherapy are also being explored to overcome resistance and to potentiate the immune response. In addition, novel approaches such as adoptive cell therapy, oncogenic viruses, vaccines and different strategies of drug administration including sequential, or combination treatment are being tested. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic theràapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers, but they have yet to be fully characterized and implemented clinically. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. Overall, the future research efforts in melanoma therapeutics and translational research should focus on several aspects including: (a) developing robust biomarkers to predict efficacy of therapeutic modalities to guide clinical decision-making and optimize treatment regimens, (b) identifying mechanisms of therapeutic resistance to immune checkpoint inhibitors that are potentially actionable, (c) identifying biomarkers to predict therapy-induced adverse events, and (d) studying mechanism of actions of therapeutic agents and developing algorithms to optimize combination treatments. During the Melanoma Bridge meeting (December 2nd-4th, 2021, Naples, Italy) discussions focused on the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine as well as the impact of COVID-19 pandemic on management of melanoma patients.


Assuntos
COVID-19 , Melanoma , Biomarcadores , Humanos , Imunoterapia/métodos , Itália , Melanoma/genética , Pandemias , Microambiente Tumoral
14.
Eur J Cancer ; 173: 285-296, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35964471

RESUMO

PURPOSE: Nivolumab was approved as adjuvant therapy for melanoma based on data from CheckMate 238, which enrolled patients per American Joint Committee on Cancer version 7 (AJCC-7) criteria. Here, we analyse long-term outcomes per AJCC-8 staging criteria compared with AJCC-7 results to inform clinical decisions for patients diagnosed per AJCC-8. PATIENTS AND METHODS: In a double-blind, phase 3 trial (NCT02388906), patients aged ≥15 years with resected, histologically confirmed AJCC-7 stage IIIB, IIIC, or IV melanoma were randomised to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks, both intravenously ≤1 year. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were assessed in patients with stage III disease, per AJCC-7 and AJCC-8. RESULTS: Per AJCC-7 staging, 42.4% and 57.3% of patients were in substage IIIB and IIIC, respectively; per AJCC-8, 1.1%, 30.4%, 62.8%, and 5.0% were in IIIA, IIIB, IIIC, and IIID. After 4 years' minimum follow-up, the AJCC-7 superior efficacy of nivolumab over ipilimumab in patients with resected stage III melanoma was preserved per AJCC-8 analysis. No statistically significant difference in RFS between stage III substage hazard ratios was observed per AJCC-7 or -8 staging criteria (interaction test: AJCC-7, P = 0.8115; AJCC-8, P = 0.1051; P = 0.8392 ((AJCC-7) and P = 0.8678 (AJCC-8) for DMFS). CONCLUSIONS: CheckMate 238 4-year RFS and DMFS outcomes are consistent per AJCC-7 and AJCC-8 staging criteria. Outcome benefits can therefore be translated for patients diagnosed per AJCC-8.


Assuntos
Melanoma , Neoplasias Cutâneas , Adjuvantes Imunológicos/efeitos adversos , Humanos , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/cirurgia
15.
J Pers Med ; 12(7)2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35887530

RESUMO

Interval metastasis is a particular metastatic category of metastatic localizations in the lymph nodes in patients with melanoma. Interval nodes are generally located at nonregional lymphatic stations placed along the pathway of the spread of melanoma, such as the epitrochlear lymph node station, the popliteal fossa, and the retroareolar station. Imaging techniques for evaluation of patients with interval metastasis from melanoma diseases include ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), lymphoscintigraphy (LS), and positron emission tomography (PET). A literature review was conducted through a methodical search on the Pubmed and Embase databases. The evaluation of lymph node metastases represents a critical phase in the staging and follow-up of melanoma patients. Therefore, a thorough knowledge of the imaging methods available and the interactions between the clinician and the radiologist are essential for making the correct choice for individual patients, for a better management, and to improve treatment and survival.

16.
J Clin Oncol ; : JCO2102659, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35862871

RESUMO

PURPOSE: Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600-mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453). METHODS: Patients with locally advanced unresectable or metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned. RESULTS: Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard. CONCLUSION: In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600-mutant melanoma.

17.
J Immunother Cancer ; 10(7)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35793872

RESUMO

BACKGROUND: Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. METHODS: Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. CONCLUSION: While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.


Assuntos
Melanoma , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias Cutâneas
18.
J Transl Med ; 20(1): 271, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35706041

RESUMO

After the success of immunotherapy in the treatment of advanced metastatic cancer, further evaluation in earlier settings, including high-risk, surgically-resectable disease is underway. Potential benefits of a neoadjuvant immunotherapeutic approach include presurgical tumor shrinkage, reduced surgical morbidity, early eradication of micrometastases and prevention of distant disease, and greater antigen-specific T cell response. For some cancers, pathologic response has been established as a surrogate measure for long-term outcomes, therefore offering the ability for early and objective assessment of treatment efficacy and the potential to inform and personalize adjuvant treatment clinical decision-making. Leveraging the neoadjuvant treatment setting offers the ability to deeply interrogate longitudinal tissue in order to gain translatable, pan-malignancy insights into response and mechanisms of resistance to immunotherapy. Neoadjuvant immunotherapy across cancers was a focus of discussion at the virtual Immunotherapy Bridge meeting (December 1-2, 2021). Clinical, biomarker, and pathologic insights from prostate, breast, colon, and non-small-cell lung cancers, melanoma and non-melanoma skin cancers were discussed and are summarized in this report.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imunoterapia , Neoplasias Pulmonares/patologia , Masculino , Melanoma/patologia , Terapia Neoadjuvante
19.
J Immunother Cancer ; 10(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35728875

RESUMO

BACKGROUND: The randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic BRAF V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram. METHODS: In COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; BRAF V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4+/CD8+ T-cell ratio via immunophenotyping. RESULTS: Extensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by BRAF V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4+/CD8+ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4+/CD8+ ratio was strongly predictive (interaction p=0.0131). CONCLUSIONS: These results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4+/CD8+ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted. TRIAL REGISTRATION NUMBER: NCT02967692.


Assuntos
Biomarcadores Tumorais , Melanoma , Neoplasias Cutâneas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/uso terapêutico , Biomarcadores Tumorais/análise , Ensaios Clínicos Fase III como Assunto , Humanos , Imidazóis , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Oximas , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas , Pirimidinonas , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/tratamento farmacológico
20.
J Transl Med ; 20(1): 257, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672823

RESUMO

Over the past decade, immunotherapy has become an increasingly fundamental modality in the treatment of cancer. The positive impact of immune checkpoint inhibition, especially anti-programmed death (PD)-1/PD-ligand (L)1 blockade, in patients with different cancers has focused attention on the potential for other immunotherapeutic approaches. These include inhibitors of additional immune checkpoints, adoptive cell transfer (ACT), and therapeutic vaccines. Patients with advanced cancers who previously had limited treatment options available may now benefit from immunotherapies that can offer durable responses and improved survival outcomes. However, despite this, a significant proportion of patients fail to respond to immunotherapy, especially those with less immunoresponsive cancer types, and there remains a need for new treatment strategies.The virtual Immunotherapy Bridge (December 1st-2nd, 2021), organized by the Fondazione Melanoma Onlus, Naples, Italy in collaboration with the Society for Immunotherapy of Cancer addressed several areas of current research in immunotherapy, including lessons learned from cell therapies, drivers of immune response, and trends in immunotherapy across different cancers, and these are summarised here.


Assuntos
Biomarcadores Tumorais , Melanoma , Biomarcadores Tumorais/metabolismo , Humanos , Fatores Imunológicos , Imunoterapia , Itália
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