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BACKGROUND: Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator's choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods. PATIENTS AND METHODS: Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan-Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted. RESULTS: The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 [95% confidence interval (CI) 0.35-0.78]; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06). CONCLUSIONS: Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM.
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Protocolos de Quimioterapia Combinada Antineoplásica , Melanoma , Nivolumab , Proteínas Recombinantes de Fusión , Neoplasias de la Úvea , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ipilimumab , Puntaje de PropensiónRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICI) have led to a prolongation of progression-free and overall survival in patients with metastatic Merkel cell carcinoma (MCC). However, immune-mediated adverse events due to ICI therapy are common and often lead to treatment discontinuation. The response duration after cessation of ICI treatment is unknown. Hence, this study aimed to investigate the time to relapse after discontinuation of ICI in MCC patients. METHODS: We analyzed 20 patients with metastatic MCC who have been retrospectively enrolled at eleven skin cancer centers in Germany. These patients have received ICI therapy and showed as best overall response (BOR) at least a stable disease (SD) upon ICI therapy. All patients have discontinued ICI therapy for other reasons than disease progression. Data on treatment duration, tumor response, treatment cessation, response durability, and tumor relapse were recorded. RESULTS: Overall, 12 of 20 patients (60%) with MCC relapsed after discontinuation of ICI. The median response durability was 10.0 months. Complete response (CR) as BOR to ICI-treatment was observed in six patients, partial response (PR) in eleven, and SD in three patients. Disease progression was less frequent in patients with CR (2/6 patients relapsed) as compared to patients with PR (7/11) and SD (3/3), albeit the effect of initial BOR on the response durability was below statistical significance. The median duration of ICI therapy was 10.0 months. Our results did not show a correlation between treatment duration and the risk of relapse after treatment withdrawal. Major reasons for discontinuation of ICI therapy were CR (20%), adverse events (35%), fatigue (20%), or patient decision (25%). Discontinuation of ICI due to adverse events resulted in progressive disease (PD) in 71% of patients regardless of the initial response. A re-induction of ICI was initiated in 8 patients upon tumor progression. We observed a renewed tumor response in 4 of these 8 patients. Notably, all 4 patients showed an initial BOR of at least PR. CONCLUSION: Our results from this contemporary cohort of patients with metastatic MCC indicate that MCC patients are at higher risk of relapse after discontinuation of ICI as compared to melanoma patients. Notably, the risk of disease progression after discontinuation of ICI treatment is lower in patients with initial CR (33%) as compared to patients with initial PR (66%) or SD (100%). Upon tumor progression, re-induction of ICI is a feasible option. Our data suggest that the BOR to initial ICI therapy might be a potential predictive clinical marker for a successful re-induction.
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Carcinoma de Células de Merkel/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carcinoma de Células de Merkel/patología , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
BACKGROUND: GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. OBJECTIVES: To characterize these tumours in terms of clinical behaviour and genetic characteristics. METHODS: Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. RESULTS: We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). CONCLUSIONS: Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807.
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Melanoma , Neoplasias Cutáneas , Neoplasias de la Úvea , Análisis Mutacional de ADN , Subunidades alfa de la Proteína de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Humanos , Melanoma/genética , Mutación/genética , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias Cutáneas/genética , Proteínas Supresoras de Tumor , Ubiquitina Tiolesterasa , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/terapiaAsunto(s)
Inhibidores de Puntos de Control Inmunológico , Penfigoide Ampolloso , Humanos , Penfigoide Ampolloso/inducido químicamente , Penfigoide Ampolloso/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Anciano , Femenino , Diagnóstico DiferencialRESUMEN
BACKGROUND: Acral lentiginous melanoma (ALM) is one of the four major subtypes in cutaneous melanoma (CM). Although ALM has a poorer prognosis than other CM subtypes, the prognostic factors associated with ALM have only been verified in small-sized cohorts because of the low incidence of ALM worldwide. OBJECTIVES: To investigate the clinical characteristics of ALM and to evaluate their prognostic values based on a large dataset from the Central Malignant Melanoma Registry (CMMR) of the German Dermatologic Society. METHODS: The Kaplan-Meier method was used to estimate the potential influence of clinical and histological parameters on ALM disease-specific survival (DSS) curves, which were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors for DSS. RESULTS: In total, 2050 patients with ALM were identified from 58 949 patients with CM recorded by the CMMR with follow-up data. In multivariate analyses, age (P = 0·006), ulceration (P = 0·013), tumour thickness (P < 0·001) and tumour spread (P < 0·001) turned out to be significant prognostic factors for DSS in ALM whereas sex, nevus association and level of invasion were not independent factors. CONCLUSIONS: ALM has the same prognostic factors as other subtypes of melanoma. Unfavourable prognosis probably derives from the delay in diagnosis in comparison with other melanoma subtypes.
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Peca Melanótica de Hutchinson/mortalidad , Melanoma/mortalidad , Neoplasias Cutáneas/mortalidad , Adulto , Anciano , Austria/epidemiología , Femenino , Enfermedades del Pie/mortalidad , Alemania/epidemiología , Mano , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Sistema de Registros , Suiza/epidemiología , Melanoma Cutáneo MalignoRESUMEN
Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Ipilimumab/efectos adversos , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Supervivencia sin Enfermedad , Femenino , Humanos , Ipilimumab/uso terapéutico , Masculino , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Nivolumab , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
The immune system is extremely important in the development and progression of Merkel cell carcinoma (MCC). Immune checkpoint blockade has recently been shown to enable efficacious treatment of a variety of tumours. We report the use of an anti-programmed death receptor 1 (PD-1) antibody for treatment of a patient with metastatic MCC. An 80-year-old patient with metastatic MCC received off-label treatment with the anti-PD-1 antibody pembrolizumab after the disease had progressed during therapy with oral etoposide. A positron emission tomography (PET) computed tomography scan performed after three cycles of pembrolizumab revealed responses to therapy with reduced size of the adrenal gland metastases and less PET activity in the adrenal gland and lymph node metastases. Treatment was resumed owing to disease progression after a treatment-free interval of > 4 months. During subsequent months of treatment, the size of the metastases stabilized and uptake of nuclide by all tumour sites once again decreased. These results reveal the potential efficacy of an anti-PD-1 antibody for treatment of metastatic MCC. Thus, they contribute to currently limited data on the use of anti-PD-1 antibodies for the treatment of MCC. Moreover, this is the first report of successful resumption of treatment of metastatic MCC with an anti-PD-1 antibody. Results from ongoing trials will contribute to determination of the relevance of PD-1 blockade in metastatic MCC.
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Neoplasias de las Glándulas Suprarrenales/secundario , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células de Merkel/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Anciano de 80 o más Años , Carcinoma de Células de Merkel/secundario , Humanos , Metástasis Linfática , Masculino , Tomografía de Emisión de PositronesRESUMEN
CLINICAL ISSUE: The incidence of malignant melanoma is continuously increasing. The prognosis of metastatic disease is still limited. STANDARD TREATMENT: Until a few years ago palliative chemotherapy with a limited response rate was the standard treatment for metastatic melanoma. TREATMENT INNOVATIONS: Immunotherapy and targeted therapy provide new treatment options. Immune checkpoint inhibitors have significantly improved the prognosis. DIAGNOSTIC WORK-UP: Regional lymph node sonography, computed tomography (CT) of the neck, chest and abdomen and brain magnetic resonance imaging (MRI) are routinely used. As an alternative to CT scans 18 F fluorodeoxyglucose positron emission tomography (FDG-PET) may be used. PERFORMANCE AND ACHIEVEMENTS: Immunotherapy provides the chance of long-term disease control in metastatic melanoma. Ipilimumab may provide long-term tumor control in approximately 20% of patients. Median overall survival of approximately 2 years is achieved during therapy with anti-programmed cell death (PD) 1 antibodies. For combined therapy of ipilimumab and nivolumab a response rate of almost 60% is achieved and 2year survival is also approximately 60%. The range of immune-mediated side effects demands particular consideration. For response evaluation immune-related response criteria were defined. Furthermore, immunotherapeutic approaches, such as talimogene laherparepvec (T-VEC), which is a modified herpes virus can be used for intralesional injection. PRACTICAL RECOMMENDATIONS: An individual definition of the appropriate therapy for each patient is of particular importance. In the context of modern therapy regimens close patient monitoring is crucial.
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Melanoma/terapia , Neoplasias Cutáneas/terapia , Humanos , Inmunoterapia , Melanoma/diagnóstico por imagen , Nivolumab , Tomografía de Emisión de Positrones , Neoplasias Cutáneas/diagnóstico por imagenRESUMEN
BACKGROUND: Nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented. PATIENTS AND METHODS: HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment. RESULTS: Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index. CONCLUSIONS: In addition to prolonged survival, these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit, compared with dacarbazine in patients with advanced melanoma.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Melanoma/tratamiento farmacológico , Calidad de Vida , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno CTLA-4/genética , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/epidemiología , Melanoma/patología , Persona de Mediana Edad , Nivolumab , Receptor de Muerte Celular Programada 1/genética , Encuestas y CuestionariosRESUMEN
BACKGROUND: Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib. RESULTS: A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors. CONCLUSION: Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.
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Indoles/administración & dosificación , Melanoma/diagnóstico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Adulto , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , VemurafenibRESUMEN
IMPORTANCE: BRAF inhibitors have been licensed for the therapy of BRAF-mutated melanoma. Recently, inflammatory skin lesions clinically resembling erythema nodosum have been reported as therapy side-effects that may lead to treatment discontinuation. OBJECTIVE: To identify and characterize cases with BRAF inhibitor-associated erythema nodosum-like inflammatory skin lesions and development of an algorithm for their management. DESIGN AND SETTING: Retrospective chart review of melanoma patients treated with BRAF inhibitors in 14 departments of Dermatology in Germany and Austria and PubMed search for cases in the literature. RESULTS: Sixteen patients were identified who developed erythema nodosum-like lesions under BRAF inhibitor therapy; 14 had received vemurafenib and two dabrafenib plus trametinib. The most frequently involved body sites were the legs. Histopathology was performed in five cases and revealed panniculitis in three and vasculitis in two patients respectively. Arthralgia and fever were associated symptoms in 44% and 31% of patients respectively. Inflammatory symptoms led to discontinuation of treatment in three patients, while in the majority of cases symptomatic management was sufficient. Skin lesions finally resolved despite continued BRAF inhibitor therapy in seven patients. In the literature, 19 additional patients with similar cutaneous appearance under BRAF inhibitors could be identified. An algorithm for the management of such lesions is proposed. CONCLUSION: Erythema nodosum-like skin lesions histologically correspond to panniculitis and/or vasculitis. Symptomatic treatment may be sufficient. However, additional work-up and interruption of BRAF inhibitor therapy may be necessary in severe cases which are commonly associated with systemic symptoms.
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Eritema Nudoso/tratamiento farmacológico , Imidazoles/uso terapéutico , Indoles/uso terapéutico , Oximas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Piel/patología , Sulfonamidas/uso terapéutico , Adulto , Anciano , Biopsia , Eritema Nudoso/diagnóstico , Eritema Nudoso/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Estudios Retrospectivos , Vemurafenib , Adulto JovenRESUMEN
CLINICAL ISSUE: The incidence of melanoma has rapidly increased in the last decades. Most relevant for patient prognosis is the tumor thickness, hence an early diagnosis is crucial. STANDARD TREATMENT: The basis of treatment is at the primary tumor stage and excision of regional metastases with curative intention. TREATMENT INNOVATIONS: Targeted therapies, such as BRAF and MEK inhibitors have the advantage of a rapid response even in highly advanced stages of the disease. DIAGNOSTIC WORK-UP: For routine diagnostics ultrasound, computed tomography (CT), fluorodeoxyglucose positron emission tomography CT (FDG-PET/CT) and magnetic resonance imaging (MRI) are used. PERFORMANCE AND ACHIEVEMENTS: In the treatment of distant metastases new treatment options are available which more than doubled patient survival rates. Especially immune therapies with immune checkpoint blockers, such as ipilimumab or PD-1 antibodies can lead to long-term survival of patients. In contrast to chemotherapy these new substances have characteristics which make new demands on radiologists related to the possibility of pseudoprogression in immune therapies, which make it necessary to use other response criteria. In addition, autoimmune phenomena, such as a sarcoid-like reactions may mimic new metastases and should be included in the differential diagnosis. BRAF inhibitors may lead to cystic conversions of metastases which again require an evaluation beyond the response evaluation criteria in solid tumors (RECIST), e.g. with the adapted Choi criteria. PRACTICAL RECOMMENDATIONS: Close interdisciplinary communication, functional imaging methods and adapted response criteria, such as the immune-related response criteria will optimize radiological evaluations of melanoma.
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Antineoplásicos/uso terapéutico , Monitoreo de Drogas/métodos , Melanoma/patología , Melanoma/secundario , Terapia Molecular Dirigida/métodos , Neoplasias Cutáneas/diagnóstico , Humanos , Melanoma/tratamiento farmacológico , Estadificación de Neoplasias , Radiología/tendencias , Resultado del TratamientoRESUMEN
BACKGROUND: In a randomized phase III study, trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. PATIENTS AND METHODS: Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire. RESULTS: In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4-5 points with chemotherapy but improved by 2-3 points with trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8-11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4-8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for trametinib decreased from baseline (symptoms improved) for pain (11-12 points), insomnia (10-12 points), and appetite loss (1-5 points), whereas those for diarrhea worsened (15-16 points). Mixed-model repeated-measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent. CONCLUSIONS: This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.
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Melanoma/tratamiento farmacológico , Melanoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Estado de Salud , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Melanoma/mortalidad , Persona de Mediana Edad , Mutación , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/efectos adversos , Pirimidinonas/efectos adversos , Calidad de Vida , Encuestas y CuestionariosRESUMEN
BACKGROUND: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. PATIENTS AND METHODS: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. RESULTS: Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. CONCLUSION: While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.
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Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Indoles/uso terapéutico , Subgrupos Linfocitarios/efectos de los fármacos , Melanoma/tratamiento farmacológico , Oximas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Citocinas/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Imidazoles/efectos adversos , Indoles/efectos adversos , Interferón gamma/biosíntesis , Interleucina-9/biosíntesis , L-Lactato Deshidrogenasa/sangre , Antígenos Comunes de Leucocito/biosíntesis , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Oximas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Receptores CCR7/biosíntesis , Estudios Retrospectivos , Sulfonamidas/efectos adversos , Vemurafenib , Adulto JovenRESUMEN
BACKGROUND: BRAF and MEK inhibitors are new targeted therapies which are used in the treatment of malignancies, in particular of malignant melanoma. SIDE EFFECTS: Cutaneous side effects are common during the treatment with both types of inhibitors. These side effects include inflammatory reactions such as maculopapular and papulopustular exanthema, hand-foot syndrome, panniculitis, paronychia, photo- and radio-sensitization. As a class effect, BRAF-inhibitors induce proliferative disorders of keratinocytes and melanocytes, such as palmoplantar hyperkeratosis (as part of the hand-foot syndrome), verruciform and acanthoma-like lesions, follicular and Grover disease-like hyperkeratoses, keratoacanthomas, squamous cell carcinomas and atypical melanocytic nevi with transition to secondary melanomas. Furthermore, hair alterations and xerosis are possible. CONCLUSIONS: Treatment with BRAF and MEK inhibitors requires close dermatologic monitoring of the patient. This manuscript summarizes the most frequent cutaneous side effects and their management.
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Antineoplásicos/efectos adversos , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/terapia , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Neoplasias Cutáneas/inducido químicamente , Antineoplásicos/uso terapéutico , Erupciones por Medicamentos/diagnóstico , Humanos , Melanoma/inducido químicamente , Melanoma/tratamiento farmacológico , Melanoma/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Factores de Riesgo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Results from the JAVELIN Merkel 200 study led to the approval of avelumab [an anti-programmed death-ligand 1 (PD-L1) antibody] for the treatment of metastatic Merkel cell carcinoma (mMCC) in multiple countries and its inclusion in the treatment guidelines as a preferred or recommended therapy in this setting. Here, we report 4-year follow-up results from the cohort of patients with mMCC who received avelumab as first-line treatment. PATIENTS AND METHODS: In part B of JAVELIN Merkel 200, a single-arm, open-label, phase II study, patients with mMCC who had not received prior systemic therapy for metastatic disease received avelumab 10 mg/kg via intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term overall survival (OS), patient disposition, and subsequent treatment were analyzed. RESULTS: In total, 116 patients received first-line avelumab. At the data cutoff (2 February 2022), the median follow-up was 54.3 months (range 48.0-69.7 months). Seven patients (6.0%) remained on treatment and an additional 21 patients remained in follow-up (18.1%); 72 patients (62.1%) had died. The median OS was 20.3 months [95% confidence interval (CI) 12.4-42.0 months], with a 4-year OS rate of 38% (95% CI 29% to 47%). In patients with PD-L1+ or PD-L1- tumors, the 4-year OS rate was 48% (95% CI 26% to 67%) and 35% (95% CI 25% to 45%), respectively. In total, 48 patients (41.4%) received poststudy anticancer drug therapy, most commonly etoposide (20.7%), carboplatin (19.0%), and avelumab (12.1%). CONCLUSIONS: Avelumab first-line monotherapy in patients with mMCC resulted in meaningful long-term OS, which compared favorably with historical studies of first-line chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Masculino , Femenino , Anciano , Estudios de Seguimiento , Persona de Mediana Edad , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Metástasis de la Neoplasia , Adulto , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismoRESUMEN
BACKGROUND: In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before. METHODS/DESIGN: The HICARE study is a national, multicenter, prospective phase IV study exploring the different types of skin reactions that occur in patients with LASCCHN undergoing radioimmun(chemo)therapy with the EGFR inhibitor cetuximab. 500 patients with LASCCHN will be enrolled in 40 participating sites in Germany. Primary endpoint is the rate of radiation dermatitis NCI CTCAE grade 3 and 4 (v. 4.02). Radioimmunotherapy will be applied according to SmPC, i.e. cetuximab will be administered as loading dose and then weekly during the radiotherapy. Irradiation will be applied as intensity-modulated radiation therapy (IMRT) or 3D-dimensional radiation therapy. DISCUSSION: The HICARE trial is expected to be one of the largest trials ever conducted in head and neck cancer patients. The goal of the HICARE trial is to differentiate skin reactions caused by radiation from those caused by the monoclonal antibody cetuximab, to evaluate the incidence and severity of these skin reactions and to correlate them with outcome parameters. Besides, the translational research program will help to identify and confirm novel peripheral blood based molecular predictors and surrogates for treatment response and resistance. TRIAL REGISTRATION: Clinical Trial Identifier, NCT01553032 (clinicaltrials.gov)EudraCT number: 2010-019748-38.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/terapia , Radioterapia/efectos adversos , Enfermedades de la Piel/etiología , Cetuximab , Quimioradioterapia/efectos adversos , Humanos , Radiodermatitis/patología , Proyectos de InvestigaciónRESUMEN
Radiodermatitis is a very common side effect in cancer treatment often leading to therapy delays and diminution of the patients' health state and quality of life. Despite a wide range of supportive strategies, radiodermatitis is still a major problem necessitating further improvements in prevention and treatment. Lactokine is a milk-based protein shown to assist in the reduction of skin redness. The treatment is a unique FDA-approved skin care system (R1 and R2). In this case presentation we describe the prophylactic use of R1 and R2 in a 63-year-old, female patient with a squamous cell carcinoma of the hypopharynx undergoing a platin-based chemoradiation. The application was feasible and safe and the patient developed only a slight radiodermatitis. To our knowledge this is the first report in the literature on the prophylactic use of R1 and R2. Further evidence will be provided by a prospective, clinical trial we have launched (CREAM-1; study registration in ISRCTN Registry: ISRCTN87302591). We also review the literature to give an overview about common strategies in the management of radiodermatitis.