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1.
Lancet ; 403(10427): 632-644, 2024 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-38246194

RESUMO

BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Adjuvantes Imunológicos/uso terapêutico , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/cirurgia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/cirurgia
2.
Curr Oncol Rep ; 26(7): 826-839, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38789670

RESUMO

PURPOSE OF REVIEW: This review provides a comprehensive update on recent advancements in melanoma treatment by highlighting promising therapeutics with an aim to increase awareness of novel interventions currently in development. RECENT FINDINGS: Over the last decade there has been considerable expansion of the previously available treatment options for patients with melanoma. In particular, novel immunotherapeutics have been developed to expand on the clinical advancements brought by BRAF targeting and immune checkpoint inhibitors. Despite the success of checkpoint inhibitors there remains an unmet need for patients that do not respond to treatment. This review delves into the latest advancements in novel checkpoint inhibitors, cytokines, oncolytic viruses, vaccines, bispecific antibodies, and adoptive cell therapy. Preclinical experiments and early-stage clinical trials studies have demonstrated promising results for these therapies, many of which have moved into pivotal, phase 3 studies.


Assuntos
Inibidores de Checkpoint Imunológico , Melanoma , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Vacinas Anticâncer/uso terapêutico , Vírus Oncolíticos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Terapia Viral Oncolítica/métodos , Terapia de Alvo Molecular/métodos
3.
Br J Cancer ; 128(12): 2227-2235, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37087488

RESUMO

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, contributes to tumor immune intolerance. Immune checkpoint inhibition may increase interferon levels; combining IDO1 inhibition with immune checkpoint blockade represents an attractive strategy. Epigenetic agents trigger interferon responses and may serve as an immunotherapy priming method. We evaluated whether epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers clinical benefit to patients with advanced solid tumors. METHODS: ECHO-206 was a Phase I/II study where treatment-experienced patients with advanced solid tumors (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary endpoints were safety/tolerability (Phase I), maximum tolerated dose (MTD) or pharmacologically active dose (PAD; Phase I), and investigator-assessed objective response rate (ORR; Phase II). RESULTS: In Phase I, no dose-limiting toxicities were reported, the MTD was not reached; a PAD was not determined. ORR was 5.7%, with four partial responses. The most common treatment-related adverse events (AEs) were fatigue (42.9%) and nausea (42.9%). Twelve (17.1%) patients experienced ≥1 fatal AE, one of which (asthenia) was treatment-related. CONCLUSIONS: Although the azacitidine-epacadostat-pembrolizumab regimen was well tolerated, it was not associated with substantial clinical response in patients with advanced solid tumors previously exposed to immunotherapy.


Assuntos
Azacitidina , Neoplasias , Humanos , Azacitidina/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Interferons/uso terapêutico
4.
Lancet ; 399(10336): 1718-1729, 2022 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-35367007

RESUMO

BACKGROUND: Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival. METHODS: In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12-17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual. FINDINGS: Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52-69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months [IQR 10·2-18·7] in the pembrolizumab group and 14·3 months [10·1-18·7] in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio [HR] 0·65 [95% CI 0·46-0·92]; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months [16·7-25·3] in the pembrolizumab group and 20·9 months [16·6-25·3] in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 [95% CI 0·45-0·82]). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3-4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred. INTERPRETATION: Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.


Assuntos
COVID-19 , Melanoma , Neoplasias Testiculares , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico
5.
J Transl Med ; 21(1): 265, 2023 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-37072748

RESUMO

The Great Debate session at the 2022 Melanoma Bridge congress (December 1-3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Imunoterapia , Melanoma/tratamento farmacológico , Melanoma/genética , Ipilimumab/uso terapêutico , Terapia Combinada
6.
Immunol Rev ; 290(1): 24-38, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31355488

RESUMO

The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell-inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8+ T cells against tumor-associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Membrana/agonistas , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores , Terapia Combinada , Proteínas de Ligação a DNA/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunomodulação/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Neoplasias/diagnóstico , Neoplasias/imunologia , Resultado do Tratamento
7.
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
8.
J Transl Med ; 20(1): 200, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538491

RESUMO

The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2-4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate.


Assuntos
Melanoma , Antígeno CTLA-4 , Terapia Combinada , Humanos , Imunoterapia , Excisão de Linfonodo , Melanoma/genética , Inibidores de Proteínas Quinases/uso terapêutico
9.
Future Oncol ; 18(20): 2483-2487, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35543482

RESUMO

WHAT IS THIS SUMMARY ABOUT?: In this article, we discuss the results of our clinical study that looked at the use of two immunotherapy drugs for the treatment of advanced melanoma. Melanoma is considered advanced when it is no longer curable with surgery. WHAT HAPPENED IN THE STUDY?: The two-drug combination, pembrolizumab and ipilimumab, was given to people with melanoma who's cancer had progressed. This study looked at how effective these two drugs were in terms of controlling the melanoma, as well their safety. These results from the study were then compared to the results from previous studies looking at melanoma treatment with ipilimumab on its own, which previously had been the most commonly used drug. WHAT WERE THE RESULTS?: The study, originally published in the Journal of Clinical Oncology, showed that combination treatment with pembrolizumab and ipilimumab was more likely to be effective than ipilimumab on its own. Not all of the study participants benefited, but many of those who did benefit experienced long-term remission from their melanoma without needing more treatment. Around 1/3 of the participants in the study had their tumors shrink compared to previous studies, which showed that ipilimumab was expected to shrink 1 in 8 tumors. The rates of side effects were similar with the pembrolizumab and ipilimumab combination compared to ipilimumab alone.


Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Anticorpos Monoclonais Humanizados , Humanos , Ipilimumab/efeitos adversos , Idioma , Melanoma/tratamento farmacológico , Melanoma/patologia , Receptor de Morte Celular Programada 1/imunologia
10.
J Transl Med ; 19(1): 278, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193182

RESUMO

Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, 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. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. 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. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd-5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.


Assuntos
Imunoterapia , Melanoma , Humanos , Itália , Melanoma/tratamento farmacológico , Terapia de Alvo Molecular , Microambiente Tumoral
11.
Curr Oncol Rep ; 23(10): 116, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342752

RESUMO

PURPOSE OF REVIEW: For patients with metastatic melanoma, immune checkpoint inhibition has drastically changed outcomes. Here, we review the current and next generations of immune-based anti-cancer therapeutics for patients with metastatic melanoma. RECENT FINDINGS: The need for new anti-cancer therapeutics in patients with metastatic melanoma who have progression of disease despite immune checkpoint blockade is evident. Several novel agents are expected to have FDA approval within the next few years, as they have yielded impressive responses. Despite these optimistic agents, the field of immuno-oncology continues to expand and produce agents with novel mechanisms of action. The next generation of immunotherapy is based upon years of thoroughly researched immuno-oncology. Many of these agents are currently being evaluated in early phase clinical trials, and much of the preliminary data looks promising.


Assuntos
Imunoterapia/tendências , Melanoma/terapia , Terapia Baseada em Transplante de Células e Tecidos , Citocinas/imunologia , Citocinas/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Checkpoint Imunológico/imunologia , Imunidade Inata , Melanoma/imunologia , Melanoma/patologia , Linfócitos T/imunologia , Linfócitos T/transplante , Receptores Toll-Like/agonistas , Receptores Toll-Like/imunologia
12.
J Appl Clin Med Phys ; 22(3): 196-206, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33626240

RESUMO

PURPOSE: Immune checkpoint inhibitors improve survival in metastatic diseases for some cancers. Multisite SBRT with pembrolizumab (SBRT + Pembro) was shown to be safe with promising local control using biologically effective doses (BEDs) = 95-120 Gy. Increased BED may improve response rate; however, SBRT doses are limited by surrounding organs at risk (OARs). The purpose of this work was to develop and validate methods for safe delivery of ultra-high doses of radiation (BED10  > 300) to be used in future clinical trials. METHODS AND MATERIALS: The radiation plans from 15 patients enrolled on a phase I trial of SBRT + pembro were reanalyzed. Metastatic disease sites included liver (8/15), inguinal region (1/15), pelvis (2/15), lung (1/15), abdomen (1/15), spleen (1/15), and groin (1/15). Gross tumor volumes (GTVs) ranged from 80 to 708 cc. Following the same methodology used in the Phase I trial on which these patients were treated, GTVs > 65 cc were contracted to a 65 cc subvolume (SubGTV) resulting in only a portion of the GTV receiving prescription dose. Volumetric modulated arc therapy (VMAT) was used to plan treatments BED10  = 360 Gy. Plans utilizing both 6FFF and 10FFF beams were compared to clinical plans delivering BED10  = 112.50 Gy. The target primary goal was V100% > 95% with a secondary goal of V70% > 99% and OAR objectives per the trial. To demonstrate feasibility, plans were delivered to a diode array phantom and evaluated for fidelity using gamma analysis. RESULTS: All 30 plans met the secondary coverage goal and satisfied all OAR constraints. The primary goal was achieved in 12/15 of the 6FFF plans and 13/15 of the 10FFF plans. Average gamma analysis passing rate using criteria of 3% dose difference and 3, 2, and 1 mm were 99.1  ±  1.0%, 98.5  ±  1.6%, and 95.1  ±  3.8%, respectively. CONCLUSION: Novel VMAT planning approaches with clinical treatment planning software and linear accelerators prove capable of delivering radiation doses in excess of 360 Gy BED10 to tumor subvolumes, while maintaining safe OAR doses.


Assuntos
Neoplasias Pulmonares , Radiocirurgia , Radioterapia de Intensidade Modulada , Estudos de Viabilidade , Humanos , Imunoterapia , Neoplasias Pulmonares/cirurgia , Órgãos em Risco , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador
13.
Cancer ; 126(6): 1166-1174, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31869447

RESUMO

Melanoma is among the few cancers that demonstrate an increasing incidence over time. Simultaneously, this trend has been marked by an epidemiologic shift to earlier stage at diagnosis. Before 2011, treatment options were limited for patients with metastatic disease, and the median overall survival was less than 1 year. Since then, the field of melanoma therapeutics has undergone major changes. The use of anti-CTLA-4 and anti-PD1 immune checkpoint inhibitors and combination BRAF/MEK inhibitors for patients with BRAF V600 mutations has significantly extended survival and allowed some patients to remain in durable disease remission off therapy. It has now been confirmed that these classes of agents have a benefit for patients with stage III melanoma after surgical resection, and anti-PD1 and BRAF/MEK inhibitors are standards of care in this setting. Some patients with stage II disease (lymph node-negative; American Joint Committee on Cancer stage IIB and IIC) have worse melanoma-specific survival relative to some patients with stage III disease. Given these results, expanding the population of patients who are considered for adjuvant therapy to include those with stage II melanoma has become a priority, and randomized phase 3 clinical trials are underway. Moving into the future, the validation of patient risk-stratification and treatment-benefit prediction models will be important to improve the number needed to treat and limit exposure to toxicity in the large population of patients with early stage melanoma.


Assuntos
Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/patologia , Estadiamento de Neoplasias/métodos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Quimioterapia Adjuvante , Humanos , Imunoterapia/métodos , Interferons/uso terapêutico , MAP Quinase Quinase 1/antagonistas & inibidores , Ilustração Médica , Melanoma/genética , Melanoma/cirurgia , Recidiva Local de Neoplasia , Números Necessários para Tratar , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Medição de Risco , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/cirurgia
14.
J Transl Med ; 18(1): 346, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894202

RESUMO

The melanoma treatment landscape changed in 2011 with the approval of the first anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 checkpoint inhibitor and of the first BRAF-targeted monoclonal antibody, both of which significantly improved overall survival (OS). Since then, improved understanding of the tumor microenvironment (TME) and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. The approval of new immune and targeted therapies has further improved outcomes for patients with advanced melanoma and other combination modalities are also being explored such as chemotherapy, radiotherapy, electrochemotherapy and surgery. In addition, different strategies of drugs administration including sequential or combination treatment are being tested. Approaches to overcome resistance and to potentiate the immune response are being developed. Increasing evidence emerges that tissue and blood-based biomarkers can predict the response to a therapy. The latest findings in melanoma research, including insights into the tumor microenvironment and new biomarkers, improved understanding of tumor immune response and resistance, novel approaches for combination strategies and the role of neoadjuvant and adjuvant therapy, were the focus of discussions at the Melanoma Bridge meeting (5-7 December, 2019, Naples, Italy), which are summarized in this report.


Assuntos
Imunoterapia , Melanoma , Antígeno CTLA-4 , Terapia Combinada , Humanos , Itália , Melanoma/terapia , Microambiente Tumoral
15.
Future Oncol ; 16(3): 4429-4438, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31870188

RESUMO

Patients with high-risk stage II melanoma are at significant risk for recurrence after surgical resection. Adjuvant treatment options to lower the risk for distant metastases are limited. Although adjuvant IFN-α2b is associated with improved relapse-free survival in patients with high-risk melanoma, toxicity and limited overall survival benefits limit its use. Adjuvant treatment with the PD-1 inhibitor pembrolizumab significantly improved recurrence-free survival, compared with placebo, in patients with resected stage III melanoma in the Phase III KEYNOTE-054 trial; efficacy in patients with stage II disease has not been established. This article describes the design and rationale of KEYNOTE-716 (NCT03553836), a two-part, randomized, placebo-controlled, multicenter Phase III study of adjuvant pembrolizumab in patients with surgically resected high-risk stage II melanoma. Clinical trial registry & ID: ClinicalTrials.gov, NCT03553836.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Melanoma/terapia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Cutâneas/terapia , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Quimioterapia Adjuvante/métodos , Criança , Ensaios Clínicos Fase III como Assunto , Estudos Cross-Over , Procedimentos Cirúrgicos Dermatológicos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Placebos/administração & dosagem , Placebos/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Adulto Jovem
18.
Cancer ; 125(7): 1113-1123, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30690710

RESUMO

BACKGROUND: Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. METHODS: This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. RESULTS: In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6-5.5 months), and the median OS was 9.0 months (95% CI, 6.1-11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB-positive epithelial cells. CONCLUSIONS: Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment-related rash may be associated with response.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Imunoconjugados/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patologia , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Proto-Oncogene Mas , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Resultado do Tratamento
19.
Oncologist ; 24(11): e1197-e1211, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31064886

RESUMO

BACKGROUND: Immune checkpoint inhibitors, along with BRAF and MEK inhibitors, have dramatically changed the management of and outlook for patients with metastatic melanoma. Analyses of long-term follow-up data and subanalyses based on disease characteristics may inform clinical decision making. METHODS: Reports of clinical trials in metastatic melanoma published between January 1, 2012, and August 30, 2018, were identified using PubMed (terms: melanoma AND [dabrafenib OR trametinib OR vemurafenib OR cobimetinib OR encorafenib OR ipilimumab OR nivolumab OR pembrolizumab]) and were systematically reviewed. Relevant congress proceedings were also assessed. Efficacy data from key phase III trials were analyzed and trends identified. RESULTS: Substantial improvements in objective response rates, progression-free survival, and overall survival were documented across 14 identified publications. Subgroup findings supported that patients with lower disease burden derive greater benefit than patients with more advanced disease, limiting the value of disease burden in the clinical decision-making process. However, these agents consistently conferred benefits despite the presence of poor prognostic features. Several clinically relevant questions remain, including how best to sequence immune checkpoint inhibitors and combination targeted therapy. CONCLUSION: This research, coupled with ongoing investigations, including those on predictive biomarkers, suggests that the treatment decision-making process is likely to become more nuanced. IMPLICATIONS FOR PRACTICE: The management of melanoma has been rapidly advancing with new classes of agents, including immune checkpoint and BRAF inhibitors. With long-term follow-up, their impact on response rates and survival outcomes is well documented. Additional findings from subgroup analyses suggest that patients with lower disease burden derive greater benefit, yet both consistently confer benefit in patients with higher disease burden. Currently, there is a paucity of data to guide first-line treatment selection between immunotherapy and BRAF-targeted therapy in clinical practice or to estimate their impact when sequenced. Gaining these insights will facilitate a more nuanced management approach.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , MAP Quinase Quinase 1/antagonistas & inibidores , Melanoma/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Animais , Humanos , Melanoma/patologia , Metástase Neoplásica , Prognóstico
20.
J Transl Med ; 17(1): 386, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767020

RESUMO

BACKGROUND: Clinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed death 1/ligand one antibodies. METHODS: In this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and Chi-square test (or Fisher's Exact test). The Kaplan-Meier method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS) in all patients and the subsets of patients with clinical benefit or primary resistance. Cox's regression model was used to evaluate the correlation between survival endpoints and variables of interest. To explore clinical factors in a larger, independent patient sample, The Cancer Genome Atlas (TCGA) was analyzed. RNAseq gene expression data as well as demographic and clinical information were downloaded for primary tumors of 517 patients included within TCGA-ccRCC. RESULTS: Of 90 patients, 38 (42.2%) had primary resistance and 52 (57.8%) had clinical benefit. Compared with the cohort of patients with initial benefit, primary resistance was more likely to occur in patients with worse ECOG performance status (p = 0.03), earlier stage at diagnosis (p = 0.04), had no prior nephrectomy (p = 0.04) and no immune-related adverse events (irAE) (p = 0.02). In patients with primary resistance, improved OS was significantly correlated with lower International Metastatic RCC Database Consortium risk score (p = 0.02) and lower neutrophil:lymphocyte ratio (p = 0.04). In patients with clinical benefit, improved PFS was significantly associated with increased BMI (p = 0.007) and irAE occurrence (p = 0.02) while improved OS was significantly correlated with overweight BMI (BMI 25-30; p = 0.03) and no brain metastasis (p = 0.005). The cohort TCGA-ccRCC was examined for the correlations between gene expression patterns, clinical factors, and survival outcomes observing associations of T-cell inflammation and angiogenesis signatures with histologic grade, pathologic stage and OS. CONCLUSIONS: Clinical characteristics including performance status, BMI and occurrence of an irAE associate with outcomes in patients with ccRCC treated with immunotherapy. The inverse association of angiogenesis gene signature with ccRCC histologic grade highlight opportunities for adjuvant combination VEGFR2 tyrosine kinase inhibitor and immune-checkpoint inhibition.


Assuntos
Índice de Massa Corporal , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Imunoterapia/efeitos adversos , Neoplasias Renais/genética , Neoplasias Renais/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/imunologia , Bases de Dados Genéticas , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/imunologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Linfócitos T/imunologia , Resultado do Tratamento , Adulto Jovem
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