bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOC-MEK: A double-blind randomized phase II trial of docetaxel with or without selumetinib (AZD6244; ARRY-142886) in wt BRAF advanced melanoma.
Authors: Gupta Avinash , Love Sharon , Schuh Anna , Collins Linda , Thomason Adelyn , Asher Ruth , Lisle Richard , Churchman Michael , Shanyinde Milensu , Plummer Ruth , Nathan Paul D. , Danson Sarah , Ottensmeier Christian H.H , Lorigan Paul , Larkin James M. G. , Middleton Mark R. 
Published: March 2020

9068 Background: Inhibitors of mutant BRAF have transformed the treatment of melanoma for the 40% of patients whose tumors harbor V600 mutations. ERK1/2 is constitutively active in melanoma cells regardless of mutation status, and plays key roles in cell cycle entry, invasion, angiogenesis and in resistance to apoptosis. Selumetinib is a highly selective allosteric inhibitor of MEK1/2, suppressing pERK levels in melanoma independent of BRAF and NRAS mutation status. In melanoma cells, docetaxel induces mitochondrial dependent apoptosis by activation of Bax. Activation of ERK1/2 results in degradation of the BH3-only protein Bim and phosphorylation of Bad, inhibiting apoptosis. Selumetinib and docetaxel have demonstrated synergy in a variety of xenograft models, including melanoma. Methods: DOC-MEK (NCT01256359) is a randomised, double-blind, placebo-controlled multi-centre study in patients with wild-type BRAF advanced melanoma. Patients were randomised (1:1) to docetaxel with placebo or selumetinib, with stratification for M stage and performance status. Docetaxel was administered intravenously every 3 weeks at a dose of 75mg/m2 for a maximum 6 cycles. Placebo or selumetinib 75mg was given orally twice per day until disease progression or unacceptable toxicity. Results: Between October 2010 and April 2012 eighty three patients were randomised at 18 sites from 257 patients screened. Progression free survival (PFS) favored combination therapy (HR 0.753, p=0.13), as did response rate (32 vs 14%, p=0.059) and 6 month PFS (40 vs 26%, p=0.19). Patients on docetaxel with selumetinib experienced more rash, diarrhea, febrile neutropenia and edema, but less neuropathy. Overall survival data and outcomes according to tumor NRAS mutation status will be presented. Conclusions: Although PFS and response rates favored docetaxel with selumetinib further interest in the regimen will be dependent on overall survival outcomes and/or the identification of a sub-population that benefit most from this approach. Clinical trial information: NCT01256359.
High-dose interleukin-2 (HD IL-2) in the treatment of advanced melanoma: The University of Pittsburgh experience.
Authors: Davar Diwakar , Saul Melissa , Tarhini Ahmad A. , Tran An , Trent Kerry , Sander Cindy , Kirkwood John M. , Tawbi Hussein Abdul-Hassan 
Published: March 2020

9075 Background: IL-2 is a T-cell growth factor tested in a variety of regimens for advanced melanoma (MEL) and renal cell carcinoma (RCC). High-dose IL-2 (600,000-720,000 IU/kg administered intravenously every 8 hours for up to 14 consecutive doses) was approved by FDA for advanced MEL and RCC in 1998 based upon the durability of responses observed. Early studies of HD IL-2 reported overall (OR) and complete response (CR) rates of 16% and 8% respectively. Severe toxicity limited use to specialized centers with standardized protocols, either intensive care (ICU) or oncology specialty settings. The U Pittsburgh has treated 1022 patients with IL-2 at any dosage and we here present outcomes of 550 MEL pts treated with HD IL-2 in an oncology specialty non-ICU setting. Methods: Clinical and radiological data were collected on all pts treated with IL-2 using the UPCI Cancer Registry and Medical Archival System (MARS). Pharmacy records were reviewed for dosing details. The influence of baseline characteristics on treatment outcomes was assessed using Cox proportional hazards analysis. Results: A total of 848 pts received HD IL-2, of which 298 pts had RCC while 550 had MEL. Detailed pharmacy dosing records were reviewed from 176 pts treated over the past 12 years (2000-2012) who received a total of 3738 cycles. Of 165 pts evaluable for response, OR was documented in 24 pts (14.8%) and CR in 5 pts (3.0%). Median overall survival (OS) was 10.0 mos for all patients and 21.5 mos for responders (CR+PR). Median number of doses per cycle was 7. Toxicity was consistent with prior reports. HD IL-2 required ICU transfers in 5% and 1 death was attributed to HD IL-2. Pts with higher baseline lactate dehydrogenase (LDH) had poorer OS (p < 0.05). Conclusions: In this large and uniformly treated series of recent patients treated with IL-2 OR/CR rates with HD IL-2 are 14.8% and 3.0% respectively. Higher LDH is associated with poorer outcome. Biomarkers of response are currently being evaluated in banked clinical specimens collected from patients under the SPORE in Skin Cancer (P50 CA121973).
Trends and variations in the use of adjuvant immunotherapy for stage III melanoma in the U.S. population.
Authors: Nasabzadeh Teresa J. , Tsai Huei-Ting , Tefera Eshetu , Venna Suraj S. , Potosky Arnold L. , Atkins Michael B. , Jang Sekwon 
Published: March 2020

9077 Background: High dose Interferon alfa-2b (IFN), an adjuvant immunotherapy for patients (pts) with stage III melanoma, was the only approved treatment option in the US from 1995-2011. There is limited information on how high dose IFN has been disseminated to eligible pts in general clinical practice, and whether variations exist in its adoption according to non-clinical factors. Methods: We obtained data on 34,208 pts diagnosed between 1998-2010 with stage III melanoma from the National Cancer Data Base (NCDB). IFN treatment was abstracted as immunotherapy. We investigated the use of immunotherapy according to pt demographic, socioeconomic, and clinical variables. We conducted multiple logistic regression analysis to examine the effect of these variables on the receipt of immunotherapy. Results: 62% of pts in our study population were male, 88% were Caucasian and 31% were over age 65. Overall, 27% of the pts received immunotherapy. There was no significant trend in its adoption between year 1998 and 2010. After adjustment for clinical variables, age at diagnosis, facility type, and geographic region are predictors strongly associated with use of immunotherapy. Only 16% of pts aged 65-74 and 3% over 75 received immunotherapy compared to 42% of those ages less than 45 (adjusted ORs 0.44 [0.32-0.59], 0.05 [0.04-0.14), respectively). Also 24% of pts treated at a comprehensive community cancer program received immunotherapy compared to 30% of those treated at an academic/research program (OR, 0.71 [0.51-0.99]). The frequency of immunotherapy was 25% in the Atlantic region and 17% in the Western region compared to 33% in Northeast (ORs 0.42 [0.18-0.99], 0.31 [0.13-0.74], respectively). Median household income, insurance type and comorbidity were not associated with adoption of immunotherapy after adjustment for all other variables. Conclusions: Less than one-third of all eligible patients received adjuvant immunotherapy in US general practice over the past decade. There is significant variation in its adoption according to non-clinical factors. Further exploration of the reasons for these variations and whether they are linked to important patient outcomes is needed.
A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma.
Authors: Kudchadkar Ragini Reiney , Gibney Geoffrey Thomas , Weber Jeffrey , Chen Ann , Smith Kim , Merek Stephanie 
Published: March 2020

9079 Background: Peginterferon alfa-2b (Sylatron) as adjuvant therapy has been shown to benefit patients with high-risk resected melanoma and some interferon studies have shown that the induction of autoantibodies may correlate with benefit. Ipilimumab (IPI, Yervoy) is a fully human anti-CTLA-4 antibody that induces autoimmune toxicity that in some cases appears to correlate with clinical benefit. This study was performed to assess whether ipilimumab can be safely administered with peginterferon alfa-2b. Methods: This study combined IPI at 3mg/kg every 3 weeks for 4 doses along with concurrent peginterferon alfa-2b at 3 mcg/kg weekly for up to 156 weeks or until disease progression, unacceptable toxicity or patient decision to discontinue. The study was designed to obtain toxicity, tolerability and autoimmune antibody data and to define a well-tolerated dose of the combination. Results: Median age was 61 with 9 female and 8 male subjects. There were 3 patients (pts) with partial responses, 1 stable disease, and 6 with progressive disease in 10 pts evaluable for response thus far. Six pts have not yet completed cycle 1 and therefore are not evaluable for response at the time of this publication but will be presented. One pt withdrew consent prior to finishing cycle 1. Toxicities from peginterferon alfa-2b 3mcg/kg were dose-limiting with 7 pts requiring dose reduction in peginterferon alfa-2b secondary to toxicity. The Grade 3 events leading to dose reductions were nausea and vomiting, leucopenia, dehydration, and hyponatremia. peginterferon alfa-2b was dose reduced to 2 mcg/kg weekly in future pts after these toxicities were noted. No Grade 3 or 4 toxicities attributable to ipilimumab have occurred thus far. No Grade 3 or 4 events have been noted to date in the10 pts initiated at 2 mcg/kg of peginterferon alfa-2b. There was no significant change in the presence autoantibodies (ANA, anti-double stranded DNA, antithyroglobulin, antimicrosomal antibodies, and anticardiolipin antibodies) between responders and non-responders in the evaluable pts. Conclusions: Peginterferon alfa-2b added to IPI results in an excellent response rate in this small population. Peginterferon alpha-2b at 2 mcg/kg weekly with IPI at 3 mg/kg every 3 weeks appears well-tolerated and the combination warrants further exploration. Clinical trial information: NCT01496807.
Response rate to vemurafenib in BRAF-positive melanoma brain metastases.
Authors: Dzienis Marcin Radoslaw , Atkinson Victoria 
Published: March 2020

9081 Background: Brain is a common site for melanoma metastases. Responses to dabrafenib have already been reported in over 50% of patients. We aimed at assessing response rate (RR) to vemurafenib (Vem). Methods: Patients with BRAF positive melanoma and asymptomatic brain metastases at initiation of Vem were eligible. Records were analysed retrospectively to calculate RR (at least 30% decrease in the sum of diameters of target lesions), duration of response and time to CNS progression (TTP). Results: 18 patients with CNS metastasis received Vem (M/F=8/10; median age 50); 9 received no prior therapy to the brain (group A), 6 had previous surgery and/or radiotherapy with residual disease (group B; n=6), 3 patients had prior "brain therapy" but with evidence of progression in CNS before the start of Vem and were added to group A (n=9+3=12). 50% RR was observed in group A; 5 had no prior therapy, 1 relapsed after resection/WBRT. Duration of response was: 8, 8, 8, 16, 32 weeks and 1 not reached yet. Similarly, 50% RR was observed in group B; however contribution of Vem to CNS control in this group was more difficult to assess. Duration of responses: 4, 26, 33 weeks. All except 2 patients progressed in CNS before, or at the time of, systemic progression. Median TTP in group A was: 21 weeks (16-41) in responding patients and 12 weeks (4-22) in those without a response (includes SD). Median TTP in group B = 44 weeks (16-60) in responders, 8 weeks (3-16) in non-responders. Conclusions: Vemurafenib resulted in 50% CNS response rate. Prospective comparison to dabrafenib may be warranted.
Updated interim analysis of UCI 09-53: A phase II, single arm study of pazopanib and paclitaxel as first-line treatment for subjects with unresectable advanced melanoma.
Authors: Ein-Gal Shlomit Y. , Tsang Walter , Alger Beverly , Parmakhtiar Basmina , Jakowatz James G. , Bettis Claudette , Fruehauf John 
Published: March 2020

9082 Background: Metastatic melanoma lacks effective therapy. Pazopanib is an inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm >3 responders to move to the second stage. To date, 31 patients are evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib 800mg continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGFR-2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST 1.1 criteria were used to define treatment response (SD criteria was a minimum interval of 8 weeks). Results: For the 31 evaluable patients treated to date the following results were seen: 1 CR, 9 PR’s, 13 SD’s and 8 PD’s. The overall RR (CR+PR) was 32%. Total disease control rate was 74% (CR+PR+SD). The most common AEs/lab abnormalities were diarrhea (66%) nausea (60%), hypertension (63%), fatigue (63%) and vomiting (29%). Grade 3-4 AEs included hypertension (26%), transaminitis (23%) and neutropenia (17%).One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 15 patients and for paclitaxel in 4 patients. Conclusions: Updated interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 32% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients. Clinical trial information: NCT01107665.
Graded prognostic assessment index for melanoma with brain metastases (MBM).
Authors: Osei-Boateng Kwabena , Alva Venur Vyshak , Dahiya Saurabh , Du Lingling , Garje Rohan , Elson Paul , Chao Samuel T. , Ahluwalia Manmeet Singh 
Published: March 2020

9086 Background: The Graded Prognostic Assessment (GPA) is a commonly used prognostic index in patients with brain metastases (BM). GPA for melanoma consists of Karnofsky Performance Scale (KPS) and the number of BM present. The purpose of this study was to evaluate the utility of GPA index in a contemporary cohort of patients (pts) with MBM at a single institution to predict Overall Survival (OS). Methods: With IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify pts with MBM treated between 2000-2012. The primary endpoint was OS from diagnosis of MBM. Cox proportional hazards models were used for data analysis. Stepwise variable selection was used to identify independent prognostic factors. Results: 90 MBM (51 females) median age 57 years (range 24-87) were included for analysis. The median number of BM was 2 (range, 1-11). KPS was 90-100(52%), 70-80 (43%) and <70 (6%). Extracranial metastases was present in 75 patients (83%). Initial treatment included Stereotactic Radiosurgery (SRS) (49%), Whole Brain Radiotherapy (WBRT) (8%), WBRT + SRS (22%), WBRT + Surgery (S)(14%) and SRS + (S) (7%). Median OS was 7.8 months (95% C.I. 6.8-10.1). GPA was prognostic for OS ( p=0.01), however this was because pts with scores of 4 had worse outcomes (median 5.1months) than the other 3 groups, which had similar OS (median 9.0-12.8 months). In addition, number of BM was not associated with OS (p=0.19). In contrast, KPS (p=0.02), Liver (p=0.04) and hemorrhagic metastasis (p=0.02) were independently prognostic for OS. These factors can be used to derive a new prognostic index with 3 groups: Unfavorable, Intermediate and Favorable (see Table). Conclusions: GPA was prognostic for OS in pts with MBM, however separation of the groups was not clear. A new prognostic index consisting of KPS, liver and hemorrhagic metastases is proposed for MBM. [Table: see text]
Metastatic melanoma patients: Prospective follow-up of pigmented lesions under vemurafenib by digital dermoscopy.
Authors: Perier-Muzet Marie , Dalle Stephane , Duru Gerard , Thomas Luc , Debarbieux Sebastien , Poulalhon Nicolas , Balme Brigitte 
Published: March 2020

9093 Background: Vemurafenib is the first approved by the FDA BRAF V600 inhibitor for the treatment of metastatic melanoma. Many cutaneous side-effects such as squamous cell carcinoma, xerosis, photosensitivity are observed. We first reported the occurrence of second primary melanomas (SPM) under BRAF inhibition. These SPM were shown to be wild-type for BRAF. The exact occurrence of these changes is still unknown. We wanted then to explore prospectively the impact of vemurafenib on cutaneous pigmented lesions using sequential digital dermoscopy. Methods: We registered prospectively following inform consent the pigmented lesions of patients under vemurafenib. We examined the total body surface and captured from 9 to 134 pigmented lesions on 24 patients. Each single lesion was followed monthly from vemurafenib initiation to vemurafenib disruption due to disease progression. Dermoscopic modifications of the melanocytic lesions including external diameter, dermoscopical pattern, pigmentation, network thickness, dots distribution and keratosis appearance were analyzed. Results: The median duration of dermoscopic follow up was 6,9 months ( range from 2 to 16 months), 1098 pigmented lesions were included. At least one modification occurred in 56% of the lesions. Most frequent modifications were the occurrence of dark globules (56%), change in the pigmentation coloration (47%), variations in network thickness (32%), increase of the external size (20,1%), onset of black areas (14%), onset of keratosis (4,4%). Up to 5,3% of lesions spontaneously disappeared; 21 excisions were performed due to significant dermoscopic changes and revealed 10 early melanomas in 5/24 patients (20,8%). The 11 remaining lesions were benign. Conclusions: More than fifty percent of the patients under vemurafenib will experiment significant modifications on their pigmented lesions. In our experience 10/21 removed lesions were early melanomas that could not be otherwise diagnosed using naked-eyes examinations only. Digital dermoscopy is one of the tool that can be use to discriminate earlier the modifications. Such careful monitoring will improved the safety when evaluating BRAF inhibitors in adjuvant setting.
Melanomas of the head-and-neck skin with mutation BRAF-V600K or BRAF-V600R define a melanoma subtype with particular clinical features.
Authors: Starz Hans , Moody Justin , Welzel Julia , Haas Christian J 
Published: March 2020

9098 Background: “Malignant melanoma” is a melting pot of diverse melanocytic tumor entities, which arise in different organs under varying pathogenetic circumstances. Chronic sun exposure is a major factor for the development of cutaneous melanomas of the head-and-neck (HN) region. Methods: 131 patients with metastatic cutaneous melanomas were included in a monocentric retrospective study. The HN skin was the primary tumor site in 41 patients. The mutational hotspots of BRAF and NRAS were analysed by Sanger sequencing. In BRAF and NRAS wildtype cases, additionally exons 11, 13 and 17 of the KIT gene were investigated. HN patients with the mutations BRAF-V600K or BRAF-V600R were defined as group A (n = 11), those with other mutations or wildtype as group B (n = 30). A and B were compared with regard to the emergence of different categories of metastases, using the Kaplan-Meier method and log rank tests. The average follow-up time was 50 months. Results: BRAF-V600K occurred in 10 of the 41 HN patients and in 2 of the 90 non-HN patients (p = 0.003 by T-test), BRAF-V600R in 1 HN and in 1 non-HN patient. KIT mutations were restricted to 2 HN patients. Inversely, NRAS mutations were rare in the HN (3 of 41) versus the non-HN (26 of 90) cohort (p = 0.001). Lymphatic metastasis became apparent in each of the 11 group A patients not later than 35 months after the diagnosis of the respective primary melanoma. 5 out of the 8 group A patients, who underwent sentinel node biopsies (SNB), had nodal micrometastases. During follow-up, regional nodal macrometastases emerged earlier and at a higher rate in group A compared to B (p = 0.044 by log rank test). The same applied even more significantly for satellite/intransit metastases (p = 0.002), whereas for distant metastasis no significant difference was found. Conclusions: BRAF-V600K/R mutations in HN melanomas define a distinct melanoma subtype with an especially high risk of lymphatic metastasis. Clinical implications may be mutation analyses already for primary HN melanomas, and SNB even for thin melanomas of this subtype. Extra-guidelines should be considered for the monitoring of these patients. Special attention to this subgroup is also necessary in clinical trials.
V600E mutations in metastatic melanoma: Case report.
Authors: Inic Momcilo , Inic Zorka Momcilo , Zegarac Milan , Pupic Gordana , Inic Ivana 
Published: March 2020

e20002 Background: Vemurafenib, a selective BRAF kinase inhibitor, is a new medicine against carcinoma.This work will discuss new approaches to the treatment of patients with metastatic melanoma, who have been proved to have BRAF V600 mutation. Methods: The 62-year-old patient was initially diagnosed in 2002 when the excision of melanoma of the left calf was performed. HP was Melanoma invasivum nodular, Breslow III, Clark IV, p T3, without angioinvasion. The stadium of illness was M1a (AJCC). Afterwards, she was operated four times. Chemyotherapy was performed with DTIC and in the further treatment secundary HT VLB-BLM-CDDP. In June 2012 the examination of the control ultrasound of the abdomen and pelvis registered the progression of illness. The liver indicated multiple changes of seundary deposit type, the largest of which was 24mm parailiac left lgl 53mm, inguinal left 23mm. It was confirmed that the patient had the mutation on the BRAF gene and she was included in the clinical study in the illness stadium M1c (AJCC). Subsequently the therapy with vemurafenib 960 mg twice a day was introduced, after which side effects were registered: rash gr. 2, arthralgia gr. 1 (pain in the hand joints) and the swelling of ankle joints gr. 1. The patient continued the vemurafenib therapy. At the latest examination in October 2012, the control CT screening registered the regression of secundary deposit by 40%. Results: Identifying the significance of BRAF has led to the development of numerous new medicines against carcinoma. One of them is vemurafenib (PLKS4032), a medicine inhibiting particularly BRAF V600 mutation. Stage I of studying this medicine showed a complete or partial tumor regression in 81% patients with V600 BRAF mutation, while stage showed a relative reduction of death risk in 63% patients, as well as a relative reduction of tumor progression risk in 74% patients in comparison to dakarbazin. Still, patients who take vemurafenib develop resistance to this medicine within 7 months on average. Conclusions: The development of vemurafenib and the role of BRAF targeted therapy in the treatment of metastatic melanoma ensure a new basis for the clinical research. Further clinical studies will research complex molecular mechanisms underlying resistance and toxicity to vemurafenib.