RESUMEN
BACKGROUND: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.
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Melanoma , Neoplasias Primarias Secundarias , Neoplasias Cutáneas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Enfermedad , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Resultado del TratamientoRESUMEN
The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Consenso , Humanos , Oncología Médica , Melanoma/terapia , Países Bajos , Neoplasias Cutáneas/terapiaRESUMEN
The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
Asunto(s)
Oncología Médica , Melanoma , Consenso , Humanos , Melanoma/terapia , Países BajosRESUMEN
Of the solid tumor types that metastasize to the brain, melanoma has the highest propensity to form brain metastases. In addition, much remains unknown regarding the pathophysiology involved in melanoma cell extravasation through the blood-brain barrier, which enables interactions with the microenvironment, and melanoma cell transcriptomic responses to brain-specific cues. However, recent developments in targeted therapy and immunotherapy have generated considerable optimism regarding the treatment of metastatic melanoma. Although robust efficacy data exist on systemic therapy treatment of extracranial melanoma, data in the setting of melanoma brain metastases (MBM) are limited, primarily because patients with MBM are typically excluded from clinical trials. However, several clinical trials focusing on patients with MBM are now complete, and more are underway. Clinical evaluation of serine/threonine-protein kinase B-Raf inhibition in combination with MEK inhibition for MBM produced intracranial response rates of close to 60%, suggesting that inhibition of the mitogen-activated protein kinase pathway has the potential to further improve MBM outcomes. For immunotherapy, there is now increasing evidence that checkpoint inhibitors may also be effective in MBM with a high rate of durable intracranial responses observed with combination therapy. Furthermore, radiotherapy-particularly MBM treatment with mainstay stereotactic radiosurgery-appears to be safe and effective when combined with systemic therapy. Finally, evolving magnetic resonance imaging capabilities have inspired new approaches to the measurement of tumor burden and treatment responses. This review evaluates current published evidence describing MBM as a multifaceted disease and presents an overview of currently available and investigational treatments for patients with MBM.
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Neoplasias Encefálicas/terapia , Melanoma/terapia , Neoplasias Encefálicas/secundario , Terapia Combinada , Humanos , Melanoma/patología , PronósticoRESUMEN
BACKGROUND: The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted. METHODS: Seventy-one adults with advanced STS who received ⩽ 2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS). RESULTS: There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N = 11) over single agent (N = 10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P = 0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each). CONCLUSIONS: While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/análogos & derivados , Resultado del Tratamiento , Adulto JovenRESUMEN
With improved systemic treatment and prolonged survival even with metastatic disease, diagnosing, treating, and monitoring brain metastases has become a central topic in the care of patients with melanoma. Patients with brain metastases from melanoma are typically excluded from pivotal clinical trials. When allowed, inclusion and exclusion criteria are rather selective and do not reflect the larger population of melanoma patients with brain metastases who frequently present with neurological symptoms and signs and require steroid medications. Moreover, the lack of consensus on reporting symptomatic brain involvement complicates the interpretation and implications of trial results for the overall population of patients with melanoma and brain metastasis. Here, we review the evidence regarding brain metastasis from melanoma and discuss the challenges of longitudinal neurological clinical assessments, including tools to capture cognition and quality of life. Finally, we propose the adoption of standardized tools to interpret neurological deficits in patients with melanoma and brain metastases and to assess the neurological status in the context of clinical trials.
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Neoplasias Encefálicas , Melanoma , Calidad de Vida , Humanos , Melanoma/secundario , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapiaRESUMEN
BACKGROUND: Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. PATIENTS AND METHODS: In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). RESULTS: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients. CONCLUSIONS: The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Azacitidina/análogos & derivados , Dacarbazina/análogos & derivados , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/antagonistas & inhibidores , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/farmacocinética , Dacarbazina/administración & dosificación , Dacarbazina/farmacocinética , Decitabina , Supervivencia sin Enfermedad , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inducido químicamente , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Cutáneas/patología , TemozolomidaRESUMEN
BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) reverses the O6-methylguanine (O6-meG) lesion induced by dacarbazine. Depletion of MGMT can be achieved using O6-meG pseudosubstrates. Herein, we report the first phase I experience of the novel O6-meG pseudosubstrate lomeguatrib, combined with dacarbazine. METHODS: This is a phase I dose-escalation study to determine the maximum tolerated dose and recommended phase II dose (RP2D) of lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule. RESULTS: The vast majority of the 41 patients enrolled had metastatic melanoma (36/41) and most had no previous chemotherapy (30/41). The most frequent non-hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 patients had stable disease. CONCLUSION: The RP2D of lomeguatrib was 40 mg orally twice daily for 10 days combined with 400 mg m(-2) of dacarbazine IV on day 2. Oral administration of lomeguatrib substantially increases the haematological toxicity of dacarbazine consistent with experience with other O6-meG pseudosubstrates.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/administración & dosificación , Melanoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , O(6)-Metilguanina-ADN Metiltransferasa/antagonistas & inhibidores , Purinas/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
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Microbioma Gastrointestinal/inmunología , Inmunoterapia , Melanoma/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/terapia , Animales , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/genética , Humanos , Melanoma/inmunología , Metagenoma , Ratones , Neoplasias Cutáneas/inmunologíaRESUMEN
Deeper understanding of DNA repair mechanisms and their potential value as therapeutic targets in oncology heralded the clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors. Although initially developed to exploit synthetic lethality in models of cancer associated with defective DNA repair, our burgeoning knowledge of PARP biology has resulted in these agents being exploited both in cancer with select chemotherapeutic agents and in non-malignant diseases. In this review article, we briefly review the mechanisms of DNA repair and pre-clinical development of PARP inhibitors before discussing the clinical development of the various PARP inhibitors in depth.