Addressing the unmet needs of patients with BRAF-mutated melanoma in Latin America: Expert perspective.

Melanoma represents an increasing public health burden with extensive unmet needs in Latin America (LA). A mutation in the BRAF gene is present in approximately 50% of all melanomas in White populations and is a target of precision medicine, with the potential to dramatically improve patient outcomes. Thus, increased access to BRAF testing and therapy is LA must be explored. At a multi-day conference, a panel of Latin American experts in oncology and dermatology were provided with questions to address the barriers limiting access to testing for BRAF mutation in patients with melanoma in LA, who may be eligible for targeted therapy to improve their prognosis. During the conference, responses were discussed and edited until a consensus on addressing the barriers was achieved. Identified challenges included ignorance of BRAF-status implications, limited human and infrastructural resources, affordability and reimbursement, fragmented care delivery, pitfalls in the sample journey, and lack of local data. Despite the clear benefits of targeted therapies for BRAF-mutated melanoma in other regions, there is no clear path to prepare LA for a sustainable personalized medicine approach to this disease. Due to melanoma's time-sensitive nature, LA must aim to provide early access to BRAF testing and consider mutational status within treatment decision making. To this end, recommendations are provided and include establishing multidisciplinary teams and melanoma referral centers and improving access to diagnosis and treatment.

Merkel cell carcinoma in Latin America: a contribution from an expanded access program for avelumab to address issues from experts' recommendations.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive malignancy, associated with poor outcomes in patients with metastatic disease (mMCC). Management has been dramatically altered as a result of incorporating immune checkpoint blockade agents. MCC data from Latin America (LATAM) come from case-series or individual records. Regional registries are lacking. A need for better registries to improve current knowledge about MCC is highlighted. Our objectives were to describe a real-world experience with avelumab as a second-line (or first-line in unfit patients) treatment in a subset of LATAM participants enrolled in a global Expanded Access Program (EAP) for patients with mMCC, and to evaluate its contribution to the resolution of the concerns described in a recent regional experts review. MATERIALS AND METHODS: We reviewed data of LATAM participants in an avelumab EAP for mMCC treatment (NCT03089658). EAP patient had unresectable or mMCC with progressive disease after one line of chemotherapy, and were ineligible for clinical trials or unfit for chemotherapy. RESULTS: 46 patients (median age: 71.6 years; 60.9% males; median treatment duration: 7.9 months) were included in the LATAM EAP. Physician-assessed objective responses were available for 19 patients. Complete response rate was 15.8% and partial response rate reached 42.1%, summarizing an objective response rate of 57.9%. Stable disease rate was 10.5%, with a disease control response of 68.4%. CONCLUSION: Avelumab showed robust efficacy and a safety profile consistent with global EAP data. Results are aimed to improve current knowledge about mMCC treatment and access to immunooncologic strategies for treating LATAM patients.

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 µg MAGE-A3 antigen plus 420 µg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

Manejo de toxicidades por inmunoterapias / Management of toxicities by immunotherapies

La inmunoterapia vino para quedarse. Partiendo desde el melanoma, fue ganando terreno en tratamiento de otros tumores más prevalentes, razón por la cual actualmente es ineludible para el personal de la salud involucrado en el cuidado de pacientes oncológicos, conocer el manejo de los eventos adversos asociados a las drogas empleadas (AU)

Immunotherapy is here to stay. Moving from melanoma to the most prevalent tumors, in just a few years it becomes one of the first choices for the medical oncologist. It is for this reason that all the health care staff should be aware of the management of the adverse effects of the drugs involved (AU)

Side effects and toxicities of targeted therapies in stage IV melanoma.

As the incidence of melanoma continues to increase worldwide, the search for new therapies for advanced (stage IV) melanoma brings with it new patterns of toxicity to contend with. This review covers the toxicity profiles of new treatments for advanced melanoma currently in development. Therefore, the latest literature on melanoma treatment was surveyed for data on reported toxicities. The new types of treatments can be roughly divided into targeted tyrosine kinase inhibitors and immunomodulating agents. Each has its own set of toxicities particular to type and to individual drug. Targeted tyrosine kinase inhibitors generally cause fatigue, whereas immunomodulatory agents induce a specific set of adverse events known as immune-related adverse events (irAEs). Despite the incidence of adverse events, these agents hold promise for the treatment of stage IV melanoma. With new treatment opportunities come increased chance of toxic reactions. The key to successful melanoma treatment in the future is likely to be novel combinations of new therapeutic agents.

Melanoma early detection and awareness: how countries developing melanoma awareness programs could benefit from melanoma-proficient countries.

Risk factors for melanoma are well known and have guided plans for primary and secondary prevention. The presentation of the disease, however, varies widely depending on the geographic area, ethnicity, and socioeconomic status. For this reason, many countries have developed specific strategies to increase public awareness and favor early diagnosis. Awareness campaigns, doctor education, and screening of high-risk subjects have all contributed to improve disease outcome in developed countries. The role of primary care physicians is particularly relevant in this regard. Developing countries are trying to implement similar measures. Future efforts to further improve the efficacy of preventive strategies should focus on populations that usually escape campaigns, such as elderly men and people with low socioeconomic status. Fast-growing tumors also require specific attention.

Progresos y promesas en melanoma / Progress and promise in melanoma

Melanoma ha sido este año la patología sobre la que se han presentado los datos más interesantes en la reunión de la American Society of Clinical Oncology (ASCO) 2014. A continuación, se describe una breve reseña de los trabajos seleccionados.

Maintenance treatment with chemotherapy and immunotherapy in non-small cell lung cancer: a case report.

A 53-years-old woman was diagnosed with lung adenocarcinoma state IV (synchronous pleural involvement) in April 2009. First-line systemic treatment included six cycles of Carboplatin, Paclitaxel, and Bevacizumab. Partial response was achieved. Maintenance therapy with Bevacizumab and Pemetrexed was given from September 2009 to February 2010. No response changes were observed. Immunotherapy was initiated, and then Pemetrexed was given with the same disease status. Both treatments were well tolerated. Immunotherapy toxicity included reaction at the site of injection grade 2. At present, the patient is still on this treatment. Given the poor prognosis of patients with advanced lung cancer, the combination of both treatments during the stable phase of the disease may improve progression-free survival.

Cutaneous melanoma in Latin America: the need for more data / El melanoma cutâneo en América Latina: la necesidad de mßs datos

OBJECTIVE: To identify the scientific literature on cutaneous melanoma in Latin America and compile all available epidemiologic data to demonstrate the need for reliable regional and country-specific data on incidence and mortality estimates. METHODS: Literature searches were conducted in PubMed, Embase, LILACS, and Google Scholar databases for epidemiologic studies from 1 January 2000 to 31 October 2010 related to melanoma in Argentina, Brazil, Colombia, Mexico, Puerto Rico, and Venezuela. A final search on melanoma cases was carried out using country-specific population-based cancer registries. No statistical analyses were conducted. RESULTS: For all six countries, most epidemiological research on cutaneous melanoma consists of hospital-based or case-control studies. Very few studies report incidence and mortality rates. Attempts to estimate disease rates have relied on national incidence and mortality data and information extracted from cancer registries. While predominance of European ancestry is a known risk factor for developing melanoma, the association of melanoma and ethnicity is not well-documented in some of the populations reviewed. Latin Americans are frequently exposed to ultraviolet (UV) radiation due to the tropical weather, high altitude, and thinning ozone layer in some regions. Tanned skin is viewed as healthy and beautiful. While melanoma public health campaigns have been under way in Latin America for decades, increasing melanoma awareness remains imperative. CONCLUSIONS: There is an urgent need to collect accurate epidemiologic melanoma data in Latin America. Future research in the region should include more comprehensive, countryspecific, population-based studies to allow for comparative evaluation of incidence and mortality rates.

OBJETIVO: Identificar la literatura científica sobre el melanoma cutßneo en América Latina y recopilar todos los datos epidemiológicos disponibles, con objeto de demostrar la necesidad de información fiable a escala regional y de país sobre los datos de incidencia y mortalidad. MÉTODOS: Se realizaron búsquedas bibliogrßficas en las bases de datos PubMed, Embase, LILACS y Google Scholar para encontrar estudios epidemiológicos relacionados con el melanoma llevados a cabo del 1 de enero del 2000 al 31 de octubre del 2010 en Argentina, Brasil, Colombia, México, Puerto Rico y Venezuela. Se efectuó una búsqueda final de casos de melanoma mediante la consulta de los registros poblacionales de cßncer de cada país. No se realizó ningún anßlisis estadístico. RESULTADOS: En los seis países, la mayor parte de la investigación epidemiológica sobre el melanoma cutßneo consiste en estudios hospitalarios o estudios de casos y testigos. Muy pocos estudios informan sobre las tasas de incidencia y mortalidad. Los intentos de calcular las tasas de la enfermedad se han basado en los datos nacionales de incidencia y mortalidad, y en la información extraída de los registros de cßncer. Aunque el predominio de la ascendencia europea constituye un conocido factor de riesgo de melanoma, la asociación entre el melanoma y el grupo étnico no puede demostrarse adecuadamente en algunas de las poblaciones estudiadas. Los latinoamericanos estßn frecuentemente expuestos a la radiación ultravioleta como consecuencia del clima tropical, la elevada altitud y la disminución de la capa de ozono en algunas regiones. La piel bronceada se considera como saludable y bella. Aunque hace decenios que se llevan a cabo campa±as de salud pública dedicadas al melanoma en América Latina, es indispensable incrementar la conciencia de esta enfermedad. Conclusiones: Existe la urgente necesidad de recopilar datos epidemiológicos precisos sobre el melanoma en América Latina. Las futuras actividades...

Cutaneous melanoma in Latin America: the need for more data.

OBJECTIVE: To identify the scientific literature on cutaneous melanoma in Latin America and compile all available epidemiologic data to demonstrate the need for reliable regional and country-specific data on incidence and mortality estimates. METHODS: Literature searches were conducted in PubMed, Embase, LILACS, and Google Scholar databases for epidemiologic studies from 1 January 2000 to 31 October 2010 related to melanoma in Argentina, Brazil, Colombia, Mexico, Puerto Rico, and Venezuela. A final search on melanoma cases was carried out using country-specific population-based cancer registries. No statistical analyses were conducted. RESULTS: For all six countries, most epidemiological research on cutaneous melanoma consists of hospital-based or case-control studies. Very few studies report incidence and mortality rates. Attempts to estimate disease rates have relied on national incidence and mortality data and information extracted from cancer registries. While predominance of European ancestry is a known risk factor for developing melanoma, the association of melanoma and ethnicity is not well-documented in some of the populations reviewed. Latin Americans are frequently exposed to ultraviolet (UV) radiation due to the tropical weather, high altitude, and thinning ozone layer in some regions. Tanned skin is viewed as healthy and beautiful. While melanoma public health campaigns have been under way in Latin America for decades, increasing melanoma awareness remains imperative. CONCLUSIONS: There is an urgent need to collect accurate epidemiologic melanoma data in Latin America. Future research in the region should include more comprehensive, country-specific, population-based studies to allow for comparative evaluation of incidence and mortality rates.

Molecular detection of circulating tyrosinase mRNA: optimization in a preclinical xenograft mouse melanoma model and further evaluation in samples from advanced melanoma patients.

We designed high-affinity primers for the mRNA sequence of human tyrosinase to test the value of molecular detection of circulating melanoma cells by reverse transcription-polymerase chain reaction (RT-PCR). The optimization process included in vitro settings and in vivo studies in a xenograft mouse model. We detected tyrosinase expression with at least 40 pg and 1.5 pg of total RNA extracted from cultured SKmel human melanoma cells, using a first round of PCR amplification and nested PCR, respectively. Human tyrosinase expression was found in the blood of nude mice bearing subcutaneous SKmel tumors, and the expression bands were stronger after manipulation of the tumor mass. We also examined the fate of circulating melanoma cells in the present melanoma model. Tyrosinase expression declined in blood 6 h after a direct intravenous injection of SKmel cells. A preliminary study in human blood samples demonstrated a baseline positive tyrosinase determination in 64% (16/25) of advanced melanoma patients using the RT-PCR nested assay. Baseline tyrosinase expression was significantly associated with disease progression after 12 months, and sequential determination during follow-up of the remaining disease-free patients showed a progressive increase of negative results.

Cellular and humoral immune response to N-Glycolyl-GM3 elicited by prolonged immunotherapy with an anti-idiotypic vaccine in high-risk and metastatic breast cancer patients.

In this study, the immunogenicity and toxicity profile of 1E10, an anti-idiotypic vaccine mimicking the N-glycolyl-GM3 ganglioside, was investigated with an extended vaccination protocol. The year-long vaccination scheme consisted of 6 biweekly intradermal injections (induction phase), followed by 10 monthly boosters (maintenance). Nineteen patients with high-risk (stage III) or metastatic breast cancer were vaccinated with different dose levels of 1E10 (0.5, 1, and 2 mg). The humoral and cellular responses to 1E10 and the targeted ganglioside were assessed at baseline and throughout the treatment. Local skin reactions represented the most common adverse event (National Cancer Institute Toxicity Criteria (NCIC) grades I and II), followed by mild flu-like symptoms lasting for 1 to 2 days. Two patients were removed from the study because of vaccine-related hypersensitivity reactions. A third patient was removed from the study after a transient loss of consciousness with uncertain relation to the vaccine. All patients showed a strong antibody response to the targeted ganglioside. In addition, ganglioside-specific T-cell responses were recorded in 5 of 13 evaluable patients. Vaccination with 1E10 was immunogenic and relatively well tolerated. Because similar results were observed with the 3 tested dose levels, the 0.5-mg dose level was selected for future trials.

Active specific immunotherapy of melanoma with a GM3 ganglioside-based vaccine: a report on safety and immunogenicity.

A novel cancer vaccine was obtained by combining GM3 ganglioside with Neisseria meningitidis outer membrane protein complex to obtain very-small-size proteoliposomes (GM3/VSSP). The authors report the results of a phase 1 study of intramuscular administration of GM3/VSSP/Montanide ISA 51 to patients with metastatic melanoma. Twenty-six patients were included in three dose-level cohorts of 120, 240, and 360 mug. The first five doses (induction phase) were given at 2-week intervals, and the remaining four doses were given monthly. Patients were evaluated for dose-related toxicities and antitumor effects. In addition, serum and peripheral blood mononuclear cells were obtained at baseline and throughout treatment to evaluate humoral and cellular immune responses. One episode of severe hypotension and fever was observed in a patient included at the highest dose level. Other toxicities consisted of local reactions at the site of injection and mild fever and chills. Five doses of GM3/VSSP induced an anti-GM3 IgM response in 44% of patients. Serum reactivity was also observed against melanoma cell lines and tumor biopsies. GM3/VSSP was shown to induce very strong in vitro IFNgamma secretion in all evaluated melanoma patients. Furthermore, in one patient IFNgamma secretion was shown to be GM3-specific. A 62% reduction of a mediastinal mass was documented in one patient (partial response), while a second patient benefited from initial disease stabilization followed by tumor reduction in nonmeasurable soft tissue lesions accompanied by vitiligo.