The Merkel Cell Carcinoma Patient Registry: From Promise to Prototype to Patient.

The Merkel Cell Carcinoma (MCC) Patient Registry is a national multi-institutional collaborative effort that will prospectively follow and record outcomes and events in MCC patients. MCC is the prototypical rare tumor, and this Registry will trail blaze new methodologies that will enable multiple investigators to examine real world outcome data in real time. Deliverables from the Registry include precise patient stratification into risk categories, identification of best practices, real-world data for drug development programs, revelations about optimal sequence and combinations therapies, uncovering low incidence toxicities, and the generation of novel testable hypotheses. Importantly, the Registry offers a way forward in the yet-unsolved dilemma of drug development for rare tumors, since the Registry's design will allow the creation of highly defined patient-level data that can be used as a robust comparator for single arm phase I and II clinical trials. The MCC Task Force comprises members from academic medical centers, the drug industry, the National Institutes of Health, and the US Food and Drug Administration. Project Data Sphere, LLC provides a secure, open-access data sharing platform and comprehensive support to optimize research performance and ensure rigorous and timely results. The Registry is currently in development and is based on a REDCap database integrated into the host institution's electronic medical record. We plan to have the first patient accessioned on Project Data Sphere's data platform in the second quarter of 2022. Members of the MCC Registry Task Force represent a joint effort of research and clinical investigators from academia, industry and regulatory science to develop the first publicly held MCC registry on Project Data Sphere's open-access data platform. Our hope is that this shared repository will allow investigators to identify new approaches, improve treatment outcomes, shorten the time from discovery to implementation and, ultimately, improve patient lives.

A cost-utility analysis of avelumab for metastatic Merkel cell carcinoma in Taiwan.

BACKGROUND: Metastatic Merkel cell carcinoma (mMCC) has traditionally been managed with palliative chemotherapy regimens or best supportive care (BSC). Avelumab, a novel anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody for mMCC treatment, is being studied in the pivotal JAVELIN Merkel 200 trial. AIM: Incorporating trial results, this analysis aimed to evaluate the cost-utility of avelumab in Taiwan. METHODS AND RESULTS: A de novo partitioned-survival model with three key health states related to survival (progression-free disease, progressed disease, and death) was applied in this study. The data of clinical efficacy, safety, and patient utilities were obtained from the JAVELIN Merkel 200 trial, literature review, and Taiwanese clinical expert opinion. Cost-utility analysis was performed, and results were presented as cost per quality-adjusted life year (QALY) gained. For treatment-naïve patients, the incremental cost-effectiveness ratios (ICERs) for avelumab vs BSC and avelumab vs chemotherapy were US$44885.06 and US$42993.06 per QALY gained, respectively. As to treatment-experienced mMCC patients, avelumab was associated with ICERs of US$27243.06 (vs BSC)/US$26557.43 (vs chemotherapy) per QALY gained. All ICERs remained consistently within the willingness-to-pay (WTP) threshold of US$53,333.33 per QALY gained. CONCLUSION: This study demonstrated avelumab to be a cost-effective treatment option for both treatment-experienced and treatment-naïve mMCC patients with very poor prognosis in Taiwan.

Assessment of Age, Period, and Birth Cohort Effects and Trends in Merkel Cell Carcinoma Incidence in the United States.

Importance: Merkel cell carcinoma is an aggressive, cutaneous, neuroendocrine cancer that is increasing in incidence. Understanding why the incidence of Merkel cell carcinoma is increasing through underlying factors, such as age effects, calendar period of diagnosis effects, and birth cohort effects, can help guide resource allocation and design of screening programs. Objectives: To evaluate the associations of patient age, calendar period of diagnosis, and birth cohort with the increasing incidence of Merkel cell carcinoma and to provide new incidence projections to 2030. Design, Setting, and Participants: A cross-sectional retrospective study with age-period-cohort analysis and incidence projection modeling using data from the Surveillance, Epidemiology, and End Results Program database of 9 registries from 1987 to 2016 was conducted among 3720 patients with Merkel cell carcinoma. Statistical analysis was conducted from October 20, 2019, to July 29, 2020. Exposures: Age effects (ie, physiology), period of diagnosis effects (ie, changes in diagnostics and clinical awareness), and birth cohort effects (ie, environmental risk factors) over time were assessed. Main Outcomes and Measures: Incidence rates of Merkel cell carcinoma. Results: Among the 3720 patients in the study (2200 male patients [59.1%]; median age, 77 years [interquartile range, 68-84 years]), during the period from 2012 to 2016, the age-adjusted Merkel cell carcinoma incidence rate was 0.66 per 100 000 (95% CI, 0.62-0.70), which represented a 3.5-times (95% CI, 3.0-4.2) increase from 1987 to 1991. The incidence of Merkel cell carcinoma increased with patient age across calendar periods and birth cohorts; the highest incidence rate was observed for those aged 85 years or older, with an age-adjusted rate from 2012 to 2016 of 14.6 per 100 000 for men and 5.5 per 100 000 for women. Although the birth cohort effect has continued to increase over time, the calendar period of diagnosis effect has started to plateau. It is projected that there will be 3023 new cases of Merkel cell carcinoma in 2020 and 5130 new cases in 2030, increased from an estimated 1933 cases in 2010. Conclusions and Relevance: The slowing down of the period effect (ie, changes in diagnostics and awareness) found in this longitudinal cohort study suggests that part of the initial increased incidence of Merkel cell carcinoma was associated with increased detection. However, the projected increase in incidence rate is likely associated with the aging population and increasing risk factor exposure in more recent birth cohorts.

Real-world outcomes among US Merkel cell carcinoma patients initiating immune checkpoint inhibitors or chemotherapy.

Aim: Retrospectively assessed treatment patterns and clinical and economic outcomes in Merkel cell carcinoma (MCC) patients receiving recommended first-line regimens. Materials & methods: MCC patients newly treated with either immune checkpoint inhibitors (ICIs) or chemotherapies (CTs) were selected from the Veterans Health Administration database (2013-2018); 74 patients (ICIs: 20 and CTs: 54) were selected. Results: Median duration of therapy was 300 days for ICIs and 91 days for CTs. Time to next treatment was 245 and 184 days, respectively. Mean total (per patient per month) costs were $15,306 (ICIs) and $10,957 (CTs), of which 51% and 86%, respectively, were non-MCC therapy-related costs. Conclusion: Despite higher costs, utilization of ICIs in first-line MCC shows clinical advantages over CTs in the real world.

Treatment Patterns, Overall Survival, and Total Healthcare Costs of Advanced Merkel Cell Carcinoma in the USA.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive type of cancer with poor outcomes. OBJECTIVE: To describe treatment patterns, overall survival, and healthcare costs associated with advanced MCC (aMCC) using data from Medicare enrollees who received an aMCC diagnosis in the USA States between 2006 and 2013. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2006 to 2013 were used to describe treatment patterns, 1- and 5-year overall survival, and total healthcare costs for the periods 12 months before aMCC diagnosis and 4-12 months afterward in patients aged ≥ 65 years. RESULTS: We identified 257 patients with an aMCC diagnosis, of whom 51% had stage IIIb disease and 49% had stage IV. Within 4 months after diagnosis, 84% of patients (n = 216) received treatment; 45% (n = 115) received surgery, 48% (n = 124) radiation therapy, and 31% (n = 80) chemotherapy. Second-line chemotherapy was administered in 33% of patients (n = 26) receiving first-line chemotherapy. Median overall survival was 27 months in patients whose aMCC was diagnosed at stage IIIb and 12 months in patients whose aMCC was diagnosed at stage IV. Median total 12-month direct healthcare costs were US$48,006 (25th-75th percentile range = US$30,594-US$69,797) per patient. Total costs were highest in patients receiving chemotherapy, either alone or combined with radiation and/or surgery (US$52,854; 25th-75th percentile range = US$34,473-US$71,987). CONCLUSION: Most patients with aMCC received initial treatment, including surgery, radiation, and/or chemotherapy, and approximately one-third of those receiving chemotherapy received second-line chemotherapy. Total 12-month direct healthcare costs were highest in patients who received chemotherapy alone or combined with radiation and/or surgery. These poor survival results and high treatment costs highlight the need for effective new aMCC therapies.

Management of Skin Cancer in the Elderly.

Over the next 30 years, dermatologists face a rising population of elderly patients, causing a marked increase in the incidence of cutaneous malignancies. For this reason, it is important to review the approach to the management of skin cancer in the elderly. In the current medical environment, there has been debate as to how cutaneous malignancy should be treated in elderly patients, especially those with multiple comorbid conditions. Clinicians should use a comprehensive approach that accounts for functional status, impact on quality of life, cost, and potential adverse outcomes when managing high- and low-morbidity skin cancers in the elderly.

Travel burden associated with rare cancers: The example of Merkel cell carcinoma.

BACKGROUND: There are limited data on the travel burden for cancer patients with rare tumor types, such as Merkel cell carcinoma (MCC). OBJECTIVE: The objective of this study was to understand the travel burden of MCC patients. METHODS: This study used data from an MCC registry at the Seattle Cancer Care Alliance (SCCA). All MCC patients enrolled at SCCA with a valid 3-digit ZIP code were included. Patients were followed up from January 1, 2012 until their last follow-up, death, or end of data (January 1, 2017). Travel burden was measured by one-way travel distance to SCCA from each patient's 3-digit ZIP code. Patient demographics, tumor characteristics, and follow-up visit were evaluated and stratified by one-way driving distance of ≤300 and >300 miles. RESULTS: A total of 391 MCC patients were included (68% men, mean age = 67 years [±SD = ±11 years], 67% residing in the West, and 70% white). At diagnosis, 53% of the patients had Stage III or IV MCC. Mean one-way distance traveled by patients was 1,137 (median: 813) miles, and 57% of patients traveled >300 miles. Compared to patients who traveled ≤300 miles, those who traveled >300 miles were more likely to be <70 years old (46% vs 65%; P < 0.001), were diagnosed with advanced stage (III or IV) MCC (46% vs 59%; P = 0.01), had shorter follow-up in the cancer registry (mean: 509 vs 212 days; P < 0.001), and had fewer visits during follow-up (mean: 5.2 vs 2.5; P < 0.001). CONCLUSIONS: In this single cancer center study, the majority of MCC patients trav-eled long distances to receive expert care. Longer travel distances appeared to be associated with younger age, a more advanced stage of cancer at study entry and fewer in-clinic visits, suggesting that travel burden may impact timely and adequate patient care for this rare cancer.

Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab.

BACKGROUND: We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified. METHODS: Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1. RESULTS: Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 µm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1. CONCLUSIONS: While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.

Treatment patterns, comorbidities, healthcare resource use, and associated costs by line of chemotherapy and level of comorbidity in patients with newly-diagnosed Merkel cell carcinoma in the United States.

AIMS: To examine the characteristics of patients with newly-diagnosed Merkel cell carcinoma (MCC), analyze their treatment patterns and comorbidities after diagnosis, and evaluate the economic burden on the MCC patient population in the US. MATERIALS AND METHODS: This observational, non-interventional cohort study identified patients with MCC that were newly-diagnosed between January 1, 2010 through December 31, 2014, and whose data were either in the MarketScan Commercial Claims and Encounters (CCAE) or Medicare Supplemental and Coordination of Benefits databases. Standard descriptive statistics were used to describe patient demographics, clinical characteristics, treatment regimens, and healthcare resource use (HRU) and cost. RESULTS: Following MCC diagnosis, most patients in the study population (n = 2,177) received only surgery (34.5%) or surgery and radiotherapy without chemotherapy (22.0%), while 14.5% of patients received none of these treatments; 27.5% of patients received at least one line of chemotherapy as part of their treatment. Mean total healthcare costs per patient per year (PPPY), as well as mean inpatient, outpatient, and pharmacy costs, were significantly greater for patients who received chemotherapy compared with those who received other or no treatments. Higher HRU and mean costs were associated with increasing patient comorbidity burden, ranging from $62,401 PPPY in Deyo Charlson Comorbidity Index level 1 to $109,690 in level ≥3. LIMITATIONS: The study used claims databases that were limited to patients who are covered by large employer-sponsored insurance and/or Medicare and did not provide information regarding the rationale for treatment choice or resource use. CONCLUSIONS: The choice of treatment is a major factor in determining healthcare costs associated with MCC, with the highest costs in patients receiving chemotherapy. Patients with MCC often exhibit comorbidities, and both HRU and healthcare costs increase significantly with each comorbidity level.

The association between geographic location and incidence of Merkel cell carcinoma in comparison to melanoma: An international assessment.

AIM: The aim of this article was to provide worldwide, population-based incidence rates for Merkel cell carcinoma (MCC). METHODS: We included 11,576 cases from 20 countries for time trend analyses (1990-2007) and 11,028 cases (2.5 billion person-years) from 21 countries for the period 2003-2007 extracted from Cancer Incidence in Five Continents. We computed age-standardised incidence rates (World Standard population) per million person years and sex ratios of these rates. We estimated annual percentage changes (EAPCs) of the incidence and studied the association between geographic latitude and MCC incidence. We examined the body site distribution of MCC. FINDINGS: In the majority of populations, the incidence has increased over time (EAPC, men 2.0-21.0%; women 1.6-27.2%). Rate differences between 1995 and 2007 were typically small (men: 0.8-2.2; women: 0.2-1.7). The incidence was relatively stable in some populations (men: U.S. blacks, Japan, Norway, Denmark; women: Denmark, Norway, Sweden). Incidences from 2003 to 2007 were highest in Australia, New Zealand, the United States and Israel among men and in New Zealand, Australia, Ireland and the Netherlands among women. The incidence of MCC and melanoma among white non-Hispanic males in North America was positively associated with living closer to the equator. The proportion of MCC on the head was higher with advanced age. The head was a less likely primary site among blacks as compared with any other ethnicity. INTERPRETATION: Several countries showed increases in MCC incidence among white non-Hispanics over time. Latitude closer to the equator was associated with the MCC incidence in North American men, but barely in women, possibly due to occupational sunlight exposure patterns.

Informe de evaluación científica en la evidencia disponible: cáncer de piel / Scientific evaluation report on the available evidence: skin cancer

INTRODUCCIÓN: El cáncer de piel es el crecimiento descontrolado de células anómalas de la piel. Se presenta cuando el daño en el ADN de las células de la piel desencadena mutaciones o defectos genéticos que hacen que las células de la piel se multipliquen rápidamente dando lugar a tumores malignos. Existen dos formas de cáncer de piel con características diferentes en apariencia, síntomas y mortalidad, éstos son el carcinoma y el melanoma. El carcinoma basocelular y el carcinoma de células escamosas de la piel, son los tumores malignos más comúnmente diagnosticados en población caucásica. El cáncer de células basales (CB) es el tipo más común de los dos tipos no melanoma y representa cerca de tres cuartos de los cánceres de piel no melanoma. El factor más común involucrado en el desarrollo del carcinoma basocelular es la exposición a la luz ultravioleta. El melanoma afecta a los melanocitos, células pigmentarias de la piel que le dan el color. Consiste en el crecimiento y la multiplicación descontrolada de estas células que invaden la piel. Es el cáncer de piel más grave y el sexto cáncer más común en América del Norte, su incidencia aumenta con la edad. TECNOLOGÍAS SANITARIA DE INTERÉS: Avelumab para el tratamiento de primera línea del carcinoma de células de Merkel (CCM) metastásico. Dabrafenib, Trametinib y Vemurafenib para el tratamiento de primera línea de melanoma no resecable o metastásico, en pacientes con mutación BRAF V600. Vismodegib para el tratamiento de primera línea del carcinoma de células basales o basocelular (CCB) metastásico, en pacientes sintomáticos o localmente avanzado en pacientes no candidatos para cirugía. EFICACIA DE LOS TRATAMIENTOS: Eficacia de los tratamientos: Avelumab, Dabrafenib, Trametinib, Vemurafenib y Vismodegib. Carcinoma de células de Merkel: Avelumab: No se identificó evidencia directa que evaluara el efecto de Avelumab en comparación a placebo en personas mayores de 15 años con carcinoma de células de Merkel (CCM) metastásico sin tratamiento previo, por lo que recurrió a evidencia indirecta, seleccionándose un estudio no aleatorizado, denominado JAVELIN, para el outcome solicitado respecto a mortalidad global. De acuerdo a esta evidencia no está claro si avelumab tiene un efecto sobre la mortalidad, porque la certeza de la evidencia es muy baja; y no está clara la frecuencia de efectos adversos atribuibles a avelumab, porque la certeza de la evidencia es muy baja. Melanoma: Dabrafenib: Se identificó un ensayo clínico aleatorizado denominado BREAK 3 con evidencia directa; que evaluó los efectos de usar dabrafenib en comparación a dacarbazina en personas con melanoma no resecable o metastásico, BRAF mutado. De acuerdo a esta evidencia dabrafenib podría no disminuir la mortalidad en comparación con quimioterapia, pero la certeza de la evidencia es baja; y dabrafenib probablemente se asocia a más efectos adversos severos que quimioterapia. Trametinib: Se identificó el ensayo clínico aleatorizado denominado METRIC, con evidencia directa; que evaluaba los efectos de usar trametinib en comparación a quimioterapia (dacarbazina o paclitaxel), en personas con melanoma no resecable o metastásico avanzado, BRAF mutado sin tratamiento previo para su enfermedad avanzada con anti BRAF o Inmunoterapia. De acuerdo a esta evidencia trametinib podría disminuir la mortalidad en comparación con quimioterapia, pero la certeza en la evidencia es baja; y trametinib probablemente se asocia a más efectos adversos severos que quimioterapia. Vemurafenib: Se identificó un ensayo clínico aleatorizado denominado BRIM-3 con evidencia directa que evaluó los efectos del uso de vemurafenib en comparación a quimioterapia (dacarbazina) en personas con melanoma metastásico, BRAF mutado, sin tratamiento previo (primera línea). De acuerdo a esta evidencia vemurafenib podría disminuir la mortalidad en comparación con quimioterapia, pero la certeza de la evidencia es baja; y vemurafenib aumenta los efectos adversos severos. Dabrafenib y Trametinib comparados con Vemurafenib: Se identificó un único ensayo abierto aleatorizado, denominado COMBI-v con evidencia que evaluó los efectos del uso de dabrafenib y trametinib comparados con vemurafenib en personas con Melanoma avanzado, BRAF mutado, sin tratamiento previo. De acuerdo a esta evidencia la combinación de dabrafenib y trametinib podría disminuir la mortalidad por sobre vemurafenib, pero la certeza de la evidencia es baja; y la combinación de dabrafenib y trametinib probablemente se asocia a menos efectos adversos severos que vemurafenib. Cobimetinib más Vemurafenib comparado con Vemurafenib más placebo: Se identificó un único ensayo clínico aleatorizado, denominado coBRIM, con evidencia directa que evaluó los efectos del uso de cobimetinib más vemurafenib comparado con vemurafenib más placebo en personas con melanoma avanzado, BRAF mutado, sin tratamiento previo (primera línea). De acuerdo a esta evidencia la combinación la adición de cobimetinib al tratamiento con vemurafenib disminuye la mortalidad; y la adición de cobimetinib al tratamiento con vemurafenib aumenta los efectos adversos severos. Carcinoma de células basales o Basocelular: Vismodegib: No se identificó evidencia directa que evaluara el efecto de vismodegib en comparación a placebo en personas mayores de 15 años con carcinoma de células basales o basocelular (CCB) metastásico sintomático; o localmente avanzado y no candidatos para cirugía o RDT, por lo que recurrió a evidencia indirecta debido a que no reportaba el outcome de mortalidad buscado, seleccionándose una revisión sistemática, que incluyó 10 estudios no controlados no aleatorizados. De acuerdo a esta evidencia, no está claro si el uso de vismodegib tiene un efecto sobre la mortalidad, porque la certeza de la evidencia es muy baja; y no está clara la frecuencia de efectos adversos atribuibles a vismodegib, porque la certeza de la evidencia es muy baja. ALTERNATIVAS DISPONIBLES: Melanoma: Cuando los casos de melanoma maligno se diagnostican en una etapa temprana, la resección quirúrgica puede ser curativa. Sin embargo, algunos pacientes tienen enfermedad metastásica en el momento de la presentación, y algunos desarrollan metástasis después del tratamiento inicial. Cuando esto sucede, existen diferentes estrategias de tratamiento que pueden tener éxito. Metastasectomía quirúrgica: en pacientes con una o una cantidad muy limitada de metástasis, la extirpación quirúrgica de todas las enfermedades metastásicas puede ocasionalmente producir un beneficio duradero. La inmunoterapia se debe considerar en pacientes que se han sometido a una resección definitiva de todas las enfermedades metastásicas. La metastasectomía también puede tener un papel importante en la erradicación de la enfermedad residual en pacientes que han tenido una buena respuesta a la terapia sistémica. Inmunoterapia: la inmunoterapia es una importante modalidad de tratamiento sistémico para el melanoma metastásico. Las respuestas a la inmunoterapia pueden desarrollarse entamente, y los pacientes pueden tener un empeoramiento transitorio de la enfermedad antes de que la enfermedad se estabilice o el tumor regrese. Los pacientes que tienen una respuesta continua a la inmunoterapia deben ser reevaluados para una posible resección quirúrgica de metástasis residuales. Terapia dirigida: Mediante la identificación de mutaciones del gen BRAF en la vía MAPK, que ocurre en al menos un 50% de los pacientes con melanoma cutáneo, el que puede ser tratado con terapias dirigidas con pequeñas moléculas que inhiben la proteína BRAF, MEK o ambas. CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7° y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable, de acuerdo a lo establecido en el Título III, de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo Ministerio.

Respuesta ultrarrápida de tecnología sanitaria: avelumab / Ultrafast response of sanitary technology: avelumab

INTRODUCCIÓN: El Avelumab es un anticuerpo monoclonal de inmunoglobulina G1 humana dirigido contra el ligando 1 de muerte programada (PD-L1). El PD-L1 es una proteína presente en la superficie de las células tumorales, que actúa evitando el ataque por las células del sistema inmune. El Avelumab se une a este ligando y bloquea la interacción entre el PD-L1 y sus receptores. Esto elimina los efectos supresores de PD-L1 en los linfocitos T CD8+ antitumorales, generando como resultado la restauración de la respuesta de los linfocitos T citotóxicos. Se ha propuesto el Avelumab para el tratamiento de pacientes con carcinoma de células de Merkel metastásico (mMCC). La EMA (European Medicines Agency) 5 autorizó su comercialización con designación huérfana en septiembre de 2017 para el tratamiento en monoterapia de adultos con mMCC. La FDA (Food and Drug Administration)6 lo hizo en marzo del corriente año, para el tratamiento de adultos y pacientes pediátricos >12 años con mMCC. OBJETIVO: Evaluar la eficacia y seguridad del Avelumab en el tratamiento del carcinoma de células de Merkel metastásico, para su registro bajo condiciones especiales. METODOLOGÍA: Se realizó una búsqueda en Medline, Clinical trials.gov, Cochrane database, NICE (National Institute for Health and Care Excellence), PROSPERO, Univadis, JAMA, Orphanet, Trip database, LILACS, EPISTEMONIKOS y en agencias reguladoras de países de alta vigilancia. Asimismo, se tuvo en consideración la información aportada por el solicitante. La estrategia de búsqueda fue: Avelumab AND metastatic Merkel cell carcinoma. Límites: Seres humanos, sin restricción de lenguaje. De la búsqueda realizada, se encontraron: 2 estudios de Fase 1, los cuales fueron aportados por el solicitante y 1 estudio Fase 2. El NICE (National Institute for Health and Care Excellence) informa que se encuentra en desarrollo una evaluación que será publicada en abril de 2018. CONCLUSIÓN La respuesta objetiva (RC + RP) informada fue 31,8%. La respuesta completa sólo se informó en 8 pacientes (9%). Los autores informaron que, según la estimación de Kaplan Meier, la mediana de sobrevida global fue de 12,6 meses (IC95% 7,5 a 19). Los EA más frecuentes fueron fatiga y los relacionados con la infusión. Los EA inmunomediados posibles relacionados con el tratamiento, fueron informados en 6 pacientes (7%). En 5 pacientes (6%), informaron EA serios relacionados con el tratamiento. Si bien la búsqueda bibliográfica se basó en el Avelumab, se detectó un estudio fase 2 que evaluó la eficacia del Pembrolizumab en el tratamiento del carcinoma de células de Merkel avanzado (estadios IIIB y IV). Según la Disposición ANMAT 269/20168 , el Pembrolizumab se encuentra inscripto en el Registro de especialidades Medicinales "Bajo Condiciones Especiales" para el tratamiento de pacientes con melanoma metastásico o irresecable, cuya enfermedad ha progresado después del tratamiento con Ipilimumab. En función de la evaluación realizada, se considera que el Avelumab no es el único tratamiento para esta condición clínica, pero podría ser indicado bajo condiciones especiales.

Copy number analysis by low coverage whole genome sequencing using ultra low-input DNA from formalin-fixed paraffin embedded tumor tissue.

Unlocking clinically translatable genomic information, including copy number alterations (CNA), from formalin-fixed paraffin-embedded (FFPE) tissue is challenging due to low yields and degraded DNA. We describe a robust, cost-effective low-coverage whole genome sequencing (LC WGS) method for CNA detection using 5 ng of FFPE-derived DNA. CN profiles using 100 ng or 5 ng input DNA were highly concordant and comparable with molecular inversion probe (MIP) array profiles. LC WGS improved CN profiles of samples that performed poorly using MIP arrays. Our technique enables identification of driver and prognostic CNAs in archival patient samples previously deemed unsuitable for genomic analysis due to DNA limitations.

Metabolic assessment of Merkel cell carcinoma: the role of 18F-FDG PET/CT.

OBJECTIVES: Merkel cell carcinoma (MCC) is a rare aggressive skin tumor associated with a high mortality rate. The present study evaluated the role of fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in subsequent management of patients with MCC. METHODS: A total of 101 consecutive F-FDG PET/CT studies of 46 patients with MCC (28 men, 68±15.4 years) were retrospectively evaluated and the role in clinical care was documented. RESULTS: There were 40 positive studies (40%) in 28 patients (61%); of these, 33 studies (33%) in 27 patients (59%) showed metastatic disease. Fifty-two PET/CT studies (51%) in 23/46 (50%) patients were negative. Fifty-three studies (52%) were performed for staging or restaging in 41 patients, 29 scans (29%) were performed for routine follow-up in 10 patients, nine studies were carried out for suspected recurrent disease in eight patients, and 10 studies were carried out for assessment of response to therapy in seven patients. On the basis of PET/CT results, there was a change in disease stage in 12 studies in 12 patients (26%) and further change in the management of seven patients (15%). Overall, 2/29 routine follow-up studies were positive with further impact on management in one patient. CONCLUSION: F-FDG PET-CT altered the stage of one of four patients and changed the management of one of seven MCC patients. In the majority of patients, a negative F-FDG PET-CT study excluded active MCC with a high degree of confidence. PET-CT contributed toward patient management when performed for staging and restaging, monitoring response to treatment, and suspected recurrent disease, but not in the routine follow-up of asymptomatic patients with MCC.

15-Year Experience of 18F-FDG PET Imaging in Response Assessment and Restaging After Definitive Treatment of Merkel Cell Carcinoma.

UNLABELLED: The objective of this study was to evaluate the utility of (18)F-FDG PET in restaging and response assessment of patients who underwent definitive treatment for Merkel cell carcinoma (MCC). METHODS: A retrospective review of patients undergoing (18)F-FDG PET imaging for MCC between January 1997 and October 2010 at the Peter MacCallum Cancer Centre with follow-up until February 2015 was performed. Data analysis was performed on patients who were treated definitively and underwent post-treatment PET imaging performed either as a restaging scan for ongoing monitoring, suspicion of recurrence, or assessment for suitability of salvage treatment or as response assessment within 1-6 mo of treatment. Management plans were recorded prospectively before (18)F-FDG PET imaging and compared with post-imaging management to assess the impact of the study as per our previously defined categories: high if the primary treatment modality or intent was changed and medium if the radiotherapy technique or dose was altered. In total, 62 patients were included in the analysis. Thirty-six patients underwent 53 restaging scans, and 37 patients underwent a response-assessment scan. The median follow-up of patients in the restaging group was 5.3 y (95% confidence interval [CI], 4.6-9.4), and it was 5.7 y (95% CI, 4.3-10.8) in the response-assessment group. RESULTS: Restaging (18)F-FDG PET scans had a high impact in 24 of 53 cases (45%) and a medium impact in 6 of 53 cases (11%). In the response-assessment group, 24 of 37 patients had a complete metabolic response (CMR). Patients without a CMR had a 15% 1-y overall survival (95% CI, 0.04-0.55). Those with a CMR had an 88% 2-y overall survival (95% CI, 0.75-1.00) and a 68% 5-y overall survival (95% CI, 0.49-0.95). The presence of a CMR (P < 0.001) and nodal involvement (P = 0.016) were statistically significant prognostic factors for overall survival. CONCLUSION: (18)F-FDG PET imaging had a high impact on restaging after definitive treatment in patients with MCC. Metabolic response was significantly associated with overall survival. (18)F-FDG PET may play an important role in ongoing post-treatment management of MCC.

Assessment of cancer cell line representativeness using microarrays for Merkel cell carcinoma.

When using cell lines to study cancer, phenotypic similarity to the original tumor is paramount. Yet, little has been done to characterize how closely Merkel cell carcinoma (MCC) cell lines model native tumors. To determine their similarity to MCC tumor samples, we characterized MCC cell lines via gene expression microarrays. Using whole transcriptome gene expression signatures and a computational bioinformatic approach, we identified significant differences between variant cell lines (UISO, MCC13, and MCC26) and fresh frozen MCC tumors. Conversely, the classic WaGa and Mkl-1 cell lines more closely represented the global transcriptome of MCC tumors. When compared with publicly available cancer lines, WaGa and Mkl-1 cells were similar to other neuroendocrine tumors, but the variant cell lines were not. WaGa and Mkl-1 cells grown as xenografts in mice had histological and immunophenotypical features consistent with MCC, whereas UISO xenograft tumors were atypical for MCC. Spectral karyotyping and short tandem repeat analysis of the UISO cells matched the original cell line's description, ruling out contamination. Our results validate the use of transcriptome analysis to assess the cancer cell line representativeness and indicate that UISO, MCC13, and MCC26 cell lines are not representative of MCC tumors, whereas WaGa and Mkl-1 more closely model MCC.