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PURPOSE: Nivolumab plus relatlimab and nivolumab plus ipilimumab have been approved for advanced melanoma on the basis of the phase II/III RELATIVITY-047 and phase III CheckMate 067 trials, respectively. As no head-to-head trial comparing these regimens exists, an indirect treatment comparison was conducted using patient-level data from each trial. METHODS: Inverse probability of treatment weighting (IPTW) adjusted for baseline characteristic differences. Minimum follow-ups (RELATIVITY-047, 33 months; CheckMate 067, 36 months) were selected to best align assessments. Outcomes included progression-free survival (PFS), confirmed objective response rate (cORR), and melanoma-specific survival (MSS) per investigator; overall survival (OS); and treatment-related adverse events (TRAEs). A Cox regression model compared PFS, OS, and MSS. A logistic regression model compared cORRs. Subgroup analyses were exploratory. RESULTS: After IPTW, key baseline characteristics were balanced for nivolumab plus relatlimab (n = 339) and nivolumab plus ipilimumab (n = 297). Nivolumab plus relatlimab demonstrated similar PFS (hazard ratio [HR], 1.08 [95% CI, 0.88 to 1.33]), cORR (odds ratio, 0.91 [95% CI, 0.73 to 1.14]), OS (HR, 0.94 [95% CI, 0.75 to 1.19]), and MSS (HR, 0.86 [95% CI, 0.67 to 1.12]) to nivolumab plus ipilimumab. Subgroup comparisons showed larger numerical differences favoring nivolumab plus ipilimumab with acral melanoma, BRAF-mutant melanoma, and lactate dehydrogenase >2 × upper limit of normal, but were limited by small samples. Nivolumab plus relatlimab was associated with fewer grade 3-4 TRAEs (23% v 61%) and any-grade TRAEs leading to discontinuation (17% v 41%). CONCLUSION: Nivolumab plus relatlimab demonstrated similar efficacy to nivolumab plus ipilimumab in the overall population, including most-but not all-subgroups, and improved safety in patients with untreated advanced melanoma. Results should be interpreted with caution.
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Background: Melanoma leptomeningeal disease (LMD) has a poor prognosis. However, the management of patients with advanced melanoma has evolved with time, including those with LMD. We reviewed a large cohort of melanoma LMD patients to assess factors associated with survival. Methods: Retrospective clinical data was collected on patients diagnosed with LMD at MD Anderson Cancer Center from 2015 to 2020. Overall survival (OS) was determined from LMD diagnosis to date of death or last follow-up. The Kaplan-Meier method and log-rank test were used to estimate OS and to assess univariate group differences, respectively. Multivariable associations of survival with variables of interest were determined using Cox proportional hazards regression models. Results: A total of 172 patients were identified. The median age at LMD diagnosis was 53 (range 20-79) years, and all patients had radiographic evidence of LMD on magnetic resonance imaging of either brain or spine. In total 143 patients previously received systemic therapy (83%), with a median of 2 prior treatments (range 0-5). 81 patients (47%) had concurrent uncontrolled systemic disease and 80 patients (53%) had elevated serum LDH at the time of diagnosis. With a median follow-up of 4.0 months (range 0.1-65.3 months), median OS for all patients from LMD diagnosis was 4.9 months. Patients (nâ =â 45) who received intrathecal therapy or systemic immunotherapy for LMD had a median OS of 8.0 months and 10.2 months, respectively. On multivariable analysis, decreased performance status, positive CSF cytology, elevated LDH, and whole brain radiation were associated with worse OS. Conclusions: Despite many advances in therapeutic options, the outcomes of melanoma patients with LMD remains poor. However, a subset of patients appears to derive benefit from LMD-directed treatment.
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This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. Within each tumor type, the risk of brain metastasis is related to disease status and molecular subtype (i.e., EGFR-mutant non-small cell lung cancer, HER2-positive and triple-negative breast cancer, BRAF and NRAF-mutant melanoma). Prophylactic cranial irradiation is the standard of care in patients in small cell lung cancer responsive to chemotherapy but at the price of late neurocognitive decline. More recently, several molecular agents with the capability to target molecular alterations driving tumor growth have proven as effective in the prevention of secondary relapse into the brain in clinical trials. This is the case for EGFR-mutant or ALK-rearranged non-small cell lung cancer inhibitors, tucatinib and trastuzumab-deruxtecan for HER2-positive breast cancer and BRAF inhibitors for melanoma. The need for screening with an MRI in asymptomatic patients at risk of brain metastases is emphasized.
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The management of brain metastases, a potentially devastating complication of advanced cancers, has become increasingly complex with advancements in local and systemic therapies. Improved outcomes and extended survival for patients with metastatic solid tumors have led to a surge in the prevalence and possibly incidence of brain metastases, affecting up to 40% of individuals with solid tumors. Enhanced imaging technologies contribute to more accurate and early detection, shaping the understanding of the intricate landscape of this condition. Traditionally, surgery and radiation stood as the mainstays of treatment because of the limited efficacy of systemic therapies within the brain. However, emerging clinical data, particularly in melanoma, lung, and breast cancers, reveal promising results with novel systemic treatments such as immunotherapy and targeted therapies. Despite the historical exclusion of patients with active brain metastases from clinical trials, a shift is occurring toward a more inclusive approach. This chapter delves into the multifaceted challenges associated with managing brain metastases, with a focus on the evolving landscape of systemic approaches as well as the intricacies of shared decision making, providing a comprehensive overview of the current state and future directions in navigating the complexities of brain metastases management.
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Neoplasias Encefálicas , Manejo de la Enfermedad , Humanos , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Terapia CombinadaRESUMEN
Background: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases. Methods: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined. Results: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (nâ =â 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data. Conclusions: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.
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During routine dermatologic examination, a 77-year-old male was noted to have a firm blue subcutaneous nodule on his right lateral upper back. His past medical history included metastatic melanoma of unknown primary involving right and left axillary lymph nodes, treated with ipilimumab/nivolumab with complete response, and subsequent primary uveal melanoma. The subcutaneous nodule was located near his previous right axillary scar for metastatic melanoma. Excision of the nodule showed a plexiform neoplasm involving mid and deep dermis composed of spindle and epithelioid atypical cells admixed with numerous melanophages. Central necrosis was present. Immunohistochemical studies revealed the tumor cells to be diffusely positive for HMB45, with retained expression of BAP1 and p16. The tumor cells were negative for PRAME, nuclear expression of ß-catenin, LEF1, and BRAF V600E. Molecular studies demonstrated BAP1 and GNA11 somatic mutations, a profile different from that exhibited by his prior melanoma. Collectively, these data were interpreted as a metastasis from uveal melanoma and not a recurrence of his metastatic likely cutaneous melanoma after complete response to immunotherapy. This case emphasizes the importance of molecular studies for definitive diagnosis in challenging clinical situations, especially when there is discordance among histopathological, immunohistochemical, and molecular studies. Integration of clinical, histopathological, and molecular features is warranted.
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Secuenciación de Nucleótidos de Alto Rendimiento , Melanoma , Neoplasias Cutáneas , Ubiquitina Tiolesterasa , Neoplasias de la Úvea , Humanos , Masculino , Melanoma/genética , Melanoma/diagnóstico , Melanoma/patología , Melanoma/secundario , Anciano , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/secundario , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/patología , Neoplasias de la Úvea/diagnóstico , Neoplasias de la Úvea/secundario , Neoplasias de la Úvea/metabolismo , Proteínas Supresoras de Tumor/genética , Mutación , Subunidades alfa de la Proteína de Unión al GTP/genética , Nivolumab/uso terapéutico , Neoplasias Primarias Desconocidas/patología , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/diagnósticoRESUMEN
Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.
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Antibacterianos , Microbioma Gastrointestinal , Melanoma , Humanos , Melanoma/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Nivolumab/uso terapéutico , Nivolumab/administración & dosificación , Biomarcadores de Tumor , Vancomicina/uso terapéutico , Adulto , COVID-19/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunologíaRESUMEN
ABSTRACT: Development of brain metastasis is one of the most serious complications of advanced melanoma, carrying a significant burden of morbidity and mortality. Although advances in local treatment modalities such as stereotactic radiosurgery and breakthrough systemic therapies including immunotherapy and targeted therapies have improved the outcomes of patients with metastatic melanoma, management of patients with melanoma brain metastases (MBMs) remains challenging. Notably, patients with MBMs have historically been excluded from clinical trials, limiting insights into their specific treatment responses. Encouragingly, a growing body of evidence shows the potential of systemic therapies to yield durable intracranial responses in these patients, highlighting the need for inclusion of patients with MBMs in future clinical trials. This is pivotal for expediting the advancement of novel therapies tailored to this distinct patient population. In this review, we will highlight the evolving landscape of MBM management, focusing on local and systemic treatment strategies.
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Neoplasias Encefálicas , Melanoma , Radiocirugia , Humanos , Melanoma/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Terapia Combinada , InmunoterapiaRESUMEN
Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.
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Inhibidores de Puntos de Control Inmunológico , Liposarcoma , Terapia Neoadyuvante , Neoplasias Retroperitoneales , Humanos , Liposarcoma/tratamiento farmacológico , Liposarcoma/inmunología , Terapia Neoadyuvante/métodos , Neoplasias Retroperitoneales/tratamiento farmacológico , Neoplasias Retroperitoneales/inmunología , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Persona de Mediana Edad , Anciano , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Sarcoma/terapia , Sarcoma/inmunología , Sarcoma/tratamiento farmacológico , Nivolumab/uso terapéutico , Linfocitos B/inmunología , Linfocitos B/efectos de los fármacosRESUMEN
OBJECTIVES: The advent of immune checkpoint inhibitor (ICI) therapy has vastly improved outcomes for patients with advanced melanoma. However, the symptom burden and intensity with their impact on quality-of-life (HRQoL) and functionality are heterogeneous and unpredictable. We used descriptive exploratory content analysis from interviews to capture the patient experience after they had completed quantitative data collection of their symptom burden and interference with the use of two patient-reported outcome (PRO) instruments. DATA SOURCES: Participants from a single center with advanced melanoma (nâ¯=â¯19) who are undergoing ICI therapy completed the Modified MD Anderson Symptom Inventory and Functional Assessment of Cancer Therapy-Melanoma and recorded semistructured interviews. Interpretive description informed the inductive and iterative analysis approach. CONCLUSION: Participants had a heterogenous experience of ICI and melanoma-related symptoms: distress (84%), fatigue (68%), rash or skin changes (53%), pain (30%), diarrhea (30%), itching (26%), and shortness of breath (21%), with varying interference within HRQoL domains, mood (47%), relations with other people (26%), and activity (21%). Some noted a lack of physical interference (79%). Uncertainty was a pervasive theme in the interviews (68%) despite the majority having positive thoughts about ICI therapy (58%) and expectations of the success of therapy (53%). The physical and emotional burden of a melanoma diagnosis, undergoing therapy, and the uncertainty of the outcomes are pervasive for patients. IMPLICATIONS FOR NURSING PRACTICE: Communication surrounding the diagnosis, prognosis, treatment options, and outcomes need to be clear and acknowledge there are unknowns. Nurses may benefit from using a validated PRO instrument to help document and understand the patient's symptom experience while undergoing ICI therapy.
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Melanoma , Humanos , Melanoma/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Pronóstico , Calidad de VidaRESUMEN
Aim: The OPTIMIzE registry study evaluated real-world outcomes in patients with advanced melanoma receiving immuno-oncology therapies. Materials and methods: Data were collected for patients treated with anti-programmed death 1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 147) or nivolumab plus ipilimumab (n = 81) from 2015-2017 and followed for ≥3 years. Results: Nivolumab plus ipilimumab versus anti-PD-1 monotherapy was associated with a nonsignificantly lower risk of death (adjusted HR: 0.83; 95% CI: 0.54-1.28; p = 0.41), higher disease control rate (72 vs 56%; p = 0.04), and stable quality of life, but more grade 3-4 treatment-related adverse events (54 vs 26%; p < 0.0001). Conclusion: These results support the use of immuno-oncology therapy in advanced melanoma.
Melanoma is a serious form of skin cancer that develops from melanocytes, which are pigment cells that give the skin, hair, and other tissues their color. At advanced stages of spread, melanoma can be life-threatening. However, immunotherapy, a type of therapy that helps the body's immune system to destroy cancer cells, allows some patients with advanced melanoma to live longer. The OPTIMIzE study looked at how well patients with advanced melanoma did when treated with different immunotherapies. These patients were treated in a real-world setting, such as a doctor's office, and were not participating in a clinical trial. Compared with clinical trials, real-world studies like the OPTIMIzE study may include a more varied group of patients because of the less selective study enrollment requirements. In the OPTIMIzE study, patients were treated with either a single immunotherapy (nivolumab or pembrolizumab alone) or a combination of two immunotherapies (nivolumab plus ipilimumab). Both single and combination immunotherapies were effective and tolerable. Patients receiving nivolumab plus ipilimumab had greater tumor shrinkage than patients receiving nivolumab or pembrolizumab alone, but with more side effects from their treatment. Despite the occurrence of side effects with both single and combination immunotherapies, patients reported that their quality of life remained stable while being treated. The OPTIMIzE study shows that immunotherapy is effective and tolerable for patients with advanced melanoma in the real-world setting. This information may help doctors with selecting treatments for their patients with advanced melanoma. Clinical Trial Registration: NCT02780089 (ClinicalTrials.gov).
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Melanoma , Humanos , Melanoma/tratamiento farmacológico , Nivolumab/efectos adversos , Ipilimumab/efectos adversos , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sistema de RegistrosRESUMEN
Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAFV600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Calidad de Vida , Inmunoterapia , Melanoma Cutáneo MalignoRESUMEN
Introduction: Sarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes. Methods: To explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. We used advanced computational methods to investigate key immune properties, such as neoantigens and immune cell composition in the tumor microenvironment (TME). Results: A multifactorial analysis suggested that expression of high quality neoantigens in the context of specific immune cells in the TME are key prognostic markers of progression-free survival (PFS). The presence of several types of immune cells, including T cells, B cells and macrophages, in the TME were associated with improved PFS. Importantly, we also found the presence of both CD8+ T cells and neoantigens together was associated with improved survival compared to the presence of CD8+ T cells or neoantigens alone. Interestingly, this trend was not identified with the combined presence of CD8+ T cells and TMB; suggesting that a combined CD8+ T cell and neoantigen effect on PFS was important. Discussion: The outcome of this study may inform future trials that may lead to improved outcomes for sarcoma patients treated with ICI.
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Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Sarcoma/tratamiento farmacológico , Antígenos de Neoplasias , Linfocitos T CD8-positivos , RNA-Seq , Microambiente TumoralRESUMEN
For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Mutación , Quinasas de Proteína Quinasa Activadas por MitógenosRESUMEN
Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.
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Investigación Biomédica , Neoplasias Encefálicas , Estados Unidos , Humanos , Calidad de Vida , National Cancer Institute (U.S.) , Consenso , Neoplasias Encefálicas/terapiaRESUMEN
Importance: The gut microbiome modulates the immune system and responses to immunotherapy in patients with late-stage melanoma. It is unknown whether fecal microbiota profiles differ between healthy individuals and patients with melanoma or if microbiota profiles differ among patients with different stages of melanoma. Defining gut microbiota profiles in individuals without melanoma and those with early-stage and late-stage melanoma may reveal features associated with disease progression. Objective: To characterize and compare gut microbiota profiles between healthy volunteers and patients with melanoma and between patients with early-stage and late-stage melanoma. Design, Setting, and Participants: This single-site case-control study took place at an academic comprehensive cancer center. Fecal samples were collected from systemic treatment-naive patients with stage I to IV melanoma from June 1, 2015, to January 31, 2019, and from healthy volunteers from June 1, 2021, to January 31, 2022. Patients were followed up for disease recurrence until November 30, 2021. Main Outcomes and Measures: Fecal microbiota was profiled by 16S ribosomal RNA sequencing. Clinical and pathologic characteristics, treatment, and disease recurrence were extracted from electronic medical records. Fecal microbiome diversity, taxonomic profiles and inferred functional profiles were compared between groups. Results: A total of 228 participants were enrolled (126 men [55.3%]; median age, 59 [range, 21-90] years), including 49 volunteers without melanoma, 38 patients with early-stage melanoma (29 with stage I or melanoma in situ and 9 with stage II), and 141 with late-stage melanoma (66 with stage III and 75 with stage IV). Community differences were observed between patients with melanoma and volunteers. Patients with melanoma had a higher relative abundance of Fusobacterium compared with controls on univariate analysis (0.19% vs 0.003%; P < .001), but this association was attenuated when adjusted for covariates (log2 fold change of 5.18 vs controls; P = .09). Microbiomes were distinct between patients with early-stage and late-stage melanoma. Early-stage melanoma had a higher alpha diversity (Inverse Simpson Index 14.6 [IQR, 9.8-23.0] vs 10.8 [IQR, 7.2-16.8]; P = .003), and a higher abundance of the genus Roseburia on univariate analysis (2.4% vs 1.2%; P < .001) though statistical significance was lost with covariate adjustment (log2 fold change of 0.86 vs controls; P = .13). Multiple functional pathways were differentially enriched between groups. No associations were observed between the microbial taxa and disease recurrence in patients with stage III melanoma treated with adjuvant immunotherapy. Conclusions and Relevance: The findings of this case-control study suggest that fecal microbiota profiles were significantly different among patients with melanoma and controls and between patients with early-stage and late-stage melanoma. Prospective investigations of the gut microbiome and changes that occur with disease progression may identify future microbial targets for intervention.
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Microbioma Gastrointestinal , Melanoma , Masculino , Humanos , Persona de Mediana Edad , Microbioma Gastrointestinal/inmunología , Estudios Prospectivos , Estudios de Casos y Controles , Progresión de la Enfermedad , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases. METHODS: TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAFV600 wild-type cohort and a BRAFV600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, brain metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAFV600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAFV600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAFV600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141. FINDINGS: Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAFV600 mutation-positive cohort; the BRAFV600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAFV600 mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAFV600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAFV600 mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAFV600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAFV600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (11 [18%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAFV600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients who received triplet therapy in the BRAFV600 mutation-positive cohort and two (13%) of 15 in the BRAFV600 wild-type cohort. No treatment-related deaths occurred. INTERPRETATION: Atezolizumab plus vemurafenib and cobimetinib provided intracranial activity in patients with BRAFV600-mutated melanoma with CNS metastases. FUNDING: F Hoffmann-La Roche.