bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical correlates of response to anti-PD-1 (aPD1)-based therapy in patients (pts) with metastatic melanoma (MM).
Authors: Davis Elizabeth J. , Zhao Shilin , Ye Fei , Rappazzo Katherine , Sosman Jeffrey Alan , Johnson Douglas Buckner 
Published: September 2018

e21000 Background: aPD1, alone or in combination with ipilimumab (IPI), produces durable responses in a subset of MM. Tumor features that correlate with treatment response, including size, number, and location of metastases (mets) are not well defined. Methods: We collected clinical data from mm pts treated at one center who received aPD1 (n = 185) or aPD1 + IPI (n = 42). We correlated number of mets, size of largest tumor, and organ involvement with response rate (RR), progression-free survival (PFS) and overall survival (OS). Results: Among all pts, RR was 67% for aPD1 + IPI and 41% for aPD1 alone. In univariate analyses, responders to aPD1 had lower diameter of largest tumor (4cm vs. 5.5cm; p = 0.02) whereas aPD1 + IPI had equivalent largest tumor diameters (p = 0.65). Regarding sites of mets, liver mets were associated with lower RR in aPD1 treated pts (26% vs. 46%), lower PFS (median 138 vs. 326 days, p = 0.02), and lower OS (median 334 vs. 1080 days, p < 0.01). No associations with RR, PFS, or OS were observed with liver mets in aPD1 + IPI treated pts. We also did not observe any differences between pts who did or did not have lung, lymph node, or brain mets for either aPD1 or aPD1 + IPI. Interestingly, superior RR to aPD1 + IPI was observed in pts with bone mets compared to those without bone mets (91% vs. 58%, p = 0.048). Regarding number of sites, RR to aPD1 was greater in pts with ≤10 mets compared with those with > 10 (46% vs. 28%, p = 0.02), although no consistent relationship was observed at lower cutoffs. In multivariable analyses, diameter of largest tumor (tumor bulk) was independently associated with PFS (OR, 1.11, p < 0.001) and OS (OR 1.08, p < 0.001) whereas AJCC stage, lactate dehydrogenase, liver mets, ECOG performance status, number of mets, and prior therapies were not significant. Tumor bulk and other risk factors were not associated with PFS or OS in aPD1 + IPI. Conclusions: Tumor bulk was strongly and independently associated with clinical outcomes in aPD1 but not IPI + aPD1. Other associations with disease sites (liver and bone) need further validation. In conjunction with molecular biomarkers, clinical predictors may help guide selection of aPD1 or aPD1 + IPI.
Real world treatment patterns and discontinuation of systemic combination therapies in metastatic melanoma.
Authors: Qiu Ying , Li Zhiyi , Tang Jackson , Atanasov Pavel , Mahmood Syed , Grzegorzewski Kris , Chen Lei , Chen Joyce S 
Published: September 2018

e21003 Background: Guidelines for metastatic melanoma (MM) recommend targeted therapy combination (combo) for patients (pts) with BRAF mutation (BRAF+) and immunotherapy for pts irrespective of BRAF status. The study objective was to describe real world characteristics and treatment patterns among mm pts treated with either dabrafenib+trametinib (D+T) or ipilimumab+nivolumab (I+N) combo therapies. Methods: This retrospective observational study utilized Flatiron Health’s electronic health record (EHR) data. Included pts were ≥18 years and treated with either D+T or I+N (post mm diagnosis) from Jan 2013 - Jul 2016. Baseline characteristics, treatment patterns and data on therapy discontinuation were collected from structured data in patient records and unstructured data in physician notes. Non-parametric statistical tests were used in light of sample size limitations. Results: 135 D+T pts and 75 I+N pts were included. Median age was 60 for D+T pts and 64 for I+N pts. 69% of D+T pts were male vs 68% of I+N pts. Most pts were Caucasian (82% for both). Before receiving combo therapy, 100% of D+T pts vs 31% of I+N pts were BRAF+, 38% of D+T pts vs 31% of I+N pts had brain metastasis (mts) (p > .05), 25% of D+T pts vs 16% of I+N pts had high LDH levels (p = .05), and 18% of D+T pts vs 35% of I+N pts reported ECOG = 0 status (p < .01). Median follow-up time was 234 days for D+T pts vs 173 days for I+N pts (p < .01). 64% of D+T pts vs 81% of I+N pts received combo therapy as first line (1L) therapy (p = .02). The 3 and 6 month discontinuation rates were 9% and 24% for D+T 1L pts; 12% and 26% for I+N 1L pts; and 21% and 47% for the subset of I+N 1L BRAF+ pts. 13% of D+T 1L pts vs 28% of I+N 1L pts discontinued treatment over the follow-up period citing toxicity in physician notes (p = .05). Among pts with brain mts, the 3 and 6 month discontinuation rates were 3% and 20% for D+T 1L pts; 24% and 35% for I+N 1L pts; and 33% and 50% for I+N 1L BRAF+ pts. Conclusions: Prior to initiation of combo therapy, D+T pts had more advanced disease: pts were more likely to have brain mts, high LDH level, receive D+T as 2L+ therapy, and less likely to have ECOG = 0 status than I+N pts. I+N 1L pts were more likely to discontinue therapy due to toxicity than D+T 1L pts even with a shorter median follow-up time.
Phase II study of ipilimumab (IPI) in children and adolescents with unresectable stage III or IV malignant melanoma (MEL).
Authors: Pappo Alberto S. , Bergeron Christophe , Gore Lia , Sender Leonard S. , Dunkel Ira J. , Herzog Cynthia E. , Brochez Lieve , Cruz Ofelia , Nysom Karsten , Berghorn Elmer , Simsek Burcin , Shen Jun , Geoerger Birgit 
Published: September 2018

e21006 Background: IPI (anti-CTLA4) is approved for treatment of advanced MEL in adults, and more information on efficacy and safety of IPI in younger patients (pts) is needed. Methods: Pts from study CA184-178 (NCT01696045) age 12 to <18 yrs with previously treated or untreated, unresectable stage III or IV malignant MEL received up to 4 doses of IPI at 3 or 10 mg/kg Q3W. Key exclusion criteria were ocular MEL, active brain metastases, or autoimmune disease. Primary endpoints were 1-yr overall survival (OS) and safety. Results: From April 2013 to June 2016, 12 pts received either IPI 3 mg/kg (n=4) or 10 mg/kg (n=8); 2 did not meet study criteria and were not treated. For the 3 and 10 mg/kg groups, median age was 13 yrs and 15 yrs, 50% and 63% were male, 25% and 13% had elevated baseline lactate dehydrogenase, and 75% and 50% had prior systemic therapy, respectively. Median number of IPI doses received was 4.0 (range: 2–4) for 3 mg/kg and 3.0 (range: 1–4) for 10 mg/kg. At 1 yr, 3/4 pts on 3 mg/kg and 5/8 pts on 10 mg/kg were alive (Table). Two pts on 10 mg/kg had partial response and 1 pt from each group had stable disease (Table). One pt had ongoing partial response >2 yrs without further treatment. Treatment-related grade 1-4 adverse events were reported in 2/4 and 7/8 pts in 3 and 10 mg/kg groups, respectively. There was 1 grade 3-4 immune-mediated adverse reaction with 3 mg/kg (hepatitis) and 5 with 10 mg/kg (hepatitis [2] and pyrexia [2] were most common). The study was stopped early due to slow accrual. Conclusions: At >1 yr of follow-up, IPI demonstrated activity in MEL pts aged 12 to <18 yrs, with a safety profile consistent with that observed in adults. Our trial highlights the difficulties of enrolling children with rare diseases in clinical trials for drugs that are approved in adults, suggesting adolescents should be included earlier in adult trials of promising new drugs. Clinical trial information: NCT01696045. [Table: see text]
Salvage combination ipilimumab and nivolumab after failure of prior checkpoint inhibitor therapy in patients with advanced melanoma.
Authors: Gaughan Elizabeth Mary , Petroni Gina R. , Grosh William W. , Slingluff Craig L. 
Published: September 2018

e21009 Background: The combination of Ipilimumab and Nivolumab is standard initial therapy in patients with advanced melanoma based on trials involving treatment-naïve patients. The benefit in those previously managed with checkpoint monotherapy is not well defined. Methods: We identified metastatic melanoma patients from our Immunotherapy database managed with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. Baseline clinical factors, treatment history, combination therapy outcome by RECIST v1.1 and toxicity data were collected. Descriptive statistics were used to summarize the data. Given the small sample size and limited numbers of deaths, it is too early to look for preliminary associations between outcomes and clinicopathologic factors. Results: We identified 19 patients treated with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. The cohort included 15 men and 4 women with an average age of 63 years. Thirteen patients had M1c disease, and 7 had a BRAF mutation. Patients had received up to four lines of prior immunotherapy including 9 treated with both prior anti-PD1 and anti-CTLA4 monotherapy. Seven patients completed all four doses of combination therapy with 6 proceeding onto maintenance nivolumab. Eight patients stopped treatment due to toxicity and 4 due to progressive disease. Thirteen patients had clinically significant toxicity, with rash, colitis, hepatitis, and hypophysitis reported most frequently. There were no treatment-related deaths. Overall, 2/19 patients (10.5%, 95% CI [1.3% to 33.1%]) had an objective response (CR+PR) and 9/19 patients (47.4%, 95% CI [24.5% to 71.1%]) had disease control (CR+PR+SD). Four of the patients had stable disease for over 6 months. Six of the 19 patients went on to receive subsequent treatment. Median follow-up for patients still alive was 7 months (range 1 to 20 months) and median survival was not reached. Six-month survival was 68.5% (95% CI [39.3% to 85.8%]) Conclusions: The combination of Ipilimumab and Nivolumab can result in melanoma control in patients with progression on prior checkpoint monotherapy with an expected toxicity profile.
Selinexor, a selective inhibitor of nuclear export (SINE), in patients with unresectable melanoma.
Authors: Kendra Kari Lynn , Watson Ryan , Lesinski Gregory B 
Published: September 2018

e21014 Background: Limited effective therapies exist for patients with melanoma after progression on immune- and targeted-therapies. Treatment with selinexor, a potent small molecule inhibitor of exportin-1 (CRM/XPO1), results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leads to growth arrest and apoptosis in vitro, in xenograft models (BRAF +/-), and Phase I solid tumor trial. (Yang et al PLOS One, 2014, Razak et al JCO, 2016). Methods: Objectives of this single institution trial were to determine: the safety in melanoma patients, the clinical benefit rate, and efficacy at the MTD as measured by PFS. Patients received prior immunotherapy and a BRAF inhibitor (mutation positive). Lead-in phase is completed. Median number of prior systemic therapies = 2 (2 – 4). Selinexor (50 mg/m2) was orally administered twice weekly, with 2-3 days off between doses. Toxicities were evaluated every 28-days. Tumor biopsies were collected for correlative analysis. Results: As of Jan 2017, 7 patients (0/7 BRAF mutant) were enrolled. Drug related AEs: neutropenia (grade 4) (1/7 patients), hyponatremia (grade 3) (1/7 patients), thrombocytopenia (Grade 3) (3/7 patients), anemia (Grade 3) (1/7 patients), and thromboembolic events (Grade 3) (1/7 patients). There were no DLT’s. Four patients experienced stable disease (SD); one patient had a minor response, for a disease control rate (DCR) of 71% (5/7). Mean duration of response was 207 days (70 – 335). One patient, removed from therapy due to a CNS met, continued with stable systemic disease off therapy for 177 days. Another patient, taken off therapy due to a non-drug related adverse event, remained SD for 127 days. Conclusions: These preliminary results demonstrate that selinexor is well tolerated with supportive care, is safe for melanoma patients dosed at the 50 mg/m2, and has the potential to control disease progression as a single agent in patients with prior BRAF inhibitor and immunotherapy. Patients are currently enrolling at a flat 60 mg dose. Correlative studies including evaluation of selinexor target engagement and exploratory markers of drug response are underway. Clinical trial information: NCT02120222. Clinical trial information: NCT02120222.
An observational study of patients with advanced melanoma receiving pembrolizumab in a real-world U.S. community oncology practice.
Authors: Cowey Charles Lance , Liu Frank Xiaoqing , Black-Shinn Jenny , Stevinson Kendall Lee , Boyd Marley , Patt Debra A. , Ebbinghaus Scot 
Published: September 2018

e21015 Background: PD-1 monoclonal antibodies are promising immunotherapies approved for treatment of patients (pts) with advanced melanoma. As the first US FDA approved PD-1 antibody, pembrolizumab (pembro) has demonstrated efficacy and safety in clinical trial settings. However, patterns of real world utilization and pt outcomes associated with pembro are limited. Methods: Adult pts with advanced melanoma who initiated pembro between 9/1/ 2014-3/31/2016 were identified retrospectively fromelectronic health records (EHR) of McKesson Specialty Health and followed through 9/ 30/2016. Pts in clinical trials were excluded. Demographic, disease, treatment characteristics and reasons for treatment discontinuation of pembro were abstracted from structured data elements of the EHR with further supplementation of unstructured data within the patient chart (progress notes, radiology scan reports). Overall survival (OS) and physician-reported progression free survival (PFS) from pembro initiation were analyzed using Kaplan Meier analysis. Results: 182 pts, with a median follow-up of 9.9 mos (range = 0.0-25.0), were included. Median age at pembro initiation was 66.0 yrs; 30.8% had an elevated lactate dehydrogenase (LDH); 23.6% had brain metastases and 65.4% had an ECOG performance status of 0 or 1. The most common reason for pembro discontinuation was progression (45.5%) followed by treatment-related toxicity (24.4%). In the overall population, median PFS from pembro initiation was 4.2 mos (95% CI = 3.2-5.3). Median OS was 19.4 mos (14.0-NR) with 12 and 24-month survival probabilities of 61.4% (95% CI = 53.4-68.5) and 43.9% (95% CI = 31.1-55.9). In multivariable analyses, characteristics predictive of worse survival included receipt of pembro at a later line of therapy (HR = 3.36, p = 0.0013 for 3L+), presence of brain metastases (HR = 2.67, p = 0.0007) and elevated LDH (HR = 4.10, p < 0.0001). Conclusions: The study results are consistent with those from pembro clinical trials (KeyNote001) and are in support of the effectiveness of pembro in real world treatment of advanced melanoma. Presence of brain metastases, elevated LDH, and use of pembro 3L+ were associated with worse survival outcome.
Pretreatment features and risk of death from BRAF-positive metastatic melanoma patients treated with vemurafenib.
Authors: Kwapisz Dorota Malgorzata 
Published: September 2018

e21028 Background: Clinicopathologic features of BRAF-positive metastatic melanoma patients were identified. No study to date has examined influence on risk of death features at baseline before starting treatment with vemurafenib. The purpose of the study is to identify demographic, clinical, biochemical, and tumor-related features at baseline before treatment with vemurafenib that are related with increase risk of death in BRAF-positive metastatic melanoma patients. Methods: 323 consecutive patients with metastatic melanoma tested for BRAF mutation were analysed. The presence of BRAF gene V600 mutation was evaluated by the cobas 4800 BRAF V600 Mutation Test. The pretreatment features were collected prospectively after inclusion patients for BRAF inhibitor treatment but before treatment was started. Results: 204 patients had a BRAF mutation. Of these, 115 were treated with vemurafenib. The median time of treatment with vemurafenib was 198 days. Death occurred more frequently among patients with: pretreatment disease symptoms (p = 0.003), ECOG PS ≥1 (p = 0.03), CNS metastases at baseline (p = 0.049) [χ2 test]. The pretreatment elevated serum LDH level (p < 0.0005), leukocytosis (p = 0.042), and hipoalbuminemia (p = 0.002) had an impact on higher incidence of death. AJCC stage 3 was reported more frequently in patients who have died (AJCC 1-2 vs. AJCC 3; p = 0.025, χ2 test). Higher incidence of death in patients with ≥4 localisations of metastases (different organs) was noted (1-3 vs 4-8; p = 0.001, χ2test). The maximum metastasis dimension was greater in the group of patients who have died (p = 0.009; Mann-Whitney test). In the analysed population, all patients whose pretreatment metastasis dimension exceeded 56 mm have died. Age, BMI, and sex were not related with higher risk of death. Conclusions: Pretreatment features may identify patients at higher risk of death. Those with features at baseline such as: disease symptoms, poor performance status, elevated LDH, leukocytosis, hipoalbuminemia, increased metastatic tumor burden, especially when brain is one of the metastatic localisation are in higher risk of death among all patients treated with vemurafenib.
A 'melanoma mortality belt' of ten U.S. states with the highest melanoma mortality rates.
Authors: Geller Alan , Berk-Krauss Juliana , Polsky David , Stein Jennifer 
Published: September 2018

e21039 Background: To our knowledge, no study has looked at U.S. melanoma mortality trends by state. We sought to determine the ten states with the highest melanoma mortality rates (per white population) and those with the lowest, as well as any state-wide demographics that could account for these trends. Methods: State melanoma mortality rates were collected from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program and National Program for Cancer Registries. Data on state characteristics were collectied from the Area Health Resource File (AHRF) and the US Census Bureau. We used a regression model to determine associations between melanoma mortality and the state demographic context, such as median income, per capita income, unemployment rate, education level, and rural versus nonrural. We also examined the effect of access to health care resources by looking at density of dermatologists, density of primary care providers, and total number of hospitals. Results: We identified ten states concentrated across the central United States with the highest melanoma mortality rates. Per capita income was the only significant association for melanoma mortality rates (p = 0.0016, 95% CI 6.88 to 18.09). Median income, unemployment rate, education level, rural versus non-rural, health professional density, and unemployment rate were not associated with melanoma mortality rates by state. Conclusions: There exists a ‘melanoma mortality belt’ across the central United States made up of the ten states with the highest melanoma mortality rates. This trend could not be consistently accounted for by state demographics, even socioeconomic status traditionally thought to correlate with mortality. Only one significant association was seen between melanoma mortality rate and per capita income. Our preliminary findings highlight the multifactorial picture of geographic melanoma mortality inequalities in the U.S.
Clinico-epidemiologic characteristics and patterns of care in Merkel cell carcinoma: Data from a single-institution series.
Authors: Del Rosario Michael , Anderson Eric , Lu Yani , Farrell Stephanie , Plaxe Steven C. , Dasanu Constantin 
Published: September 2018

e21049 Background: Merkel cell carcinoma (MCC) is associated with increased sun exposure. There is an average of 348 days of sunshine per year in our geographic area. Methods: With the IRB approval, we performed a retrospective chart review of all consecutive MCC patients seen at our institution between 2006-2017. Clinico-epidemiologic data such as age, gender, race, stage, tumor size, stage at presentation, and disease course were collected. Therapy and survival were analyzed. Using the surveillance, epidemiology, and end results program (SEER), we identified 4,256 patients with MCC from the years 2006-2013. We compared our data with the SEER findings . Statistical analysis: Chi-square and Fishers’ exact tests were used to assess the significance of associations in large and small populations, respectively. Survival analyses were performed using the Cox proportional hazards. Results: We identified 40 patients with MCC (n = 40) with a median age of 77. Compared to SEER data, our population was entirely Caucasian (100% vs. 95%; p = 0.11) and male predominant (75% vs. 63%; p = 0.11). The patients in our cohort were diagnosed more often with TNM stage I (50% vs. 39%; p = 0.00003) and found to have more often a primary tumor size < 2cm (58% vs. 34%; p < 0.01). Our patients were more frequently treated with lymph node dissection (70% vs. 63%, p = 0.002) and radiation therapy (60% vs. 50%; p = 0.24). Conclusions: Compared to the general population, MCC patients treated at our institution had similar mean age at diagnosis, gender and racial distribution and radiation treatment frequency (all p-values > 0.05). However, our patient population was significantly more likely to be diagnosed at stage I disease, have a primary tumor size less than 2 cm and receive lymph node dissection. Final statistical analysis, including survival analysis, and significance are to be discussed.
Serum 5-s-cysteinyldopa for identifying non-responders to nivolumab treatment of melanoma.
Authors: Omodaka Toshikazu , Minagawa Akane , Uhara Hisashi , Wakamatsu Kazumasa , Koizumi Tomonobu , Koga Hiroshi , Okuyama Ryuhei 
Published: September 2018

e21068 Background: Despite considerable advances in the treatment of metastatic melanoma, reliable markers to monitor treatment response are still lacking. 5-S-cysteinyldopa (5-S-CD) is a precursor of melanin that has been established as a biomarker for melanoma progression. This study evaluated serum 5-S-CD in parallel with lactate dehydrogenase (LD) as a predictor of treatment progress in melanoma patients receiving Nivolumab (Nivo) therapy. Materials and Methods: Twenty-one patients (median age: 77 years; 10 male and 11 female) with metastatic melanoma who were treated with Nivo at Shinshu University Hospital between 2014 and 2016 were retrospectively examined. Primary lesions were in the head and neck in 5 patients, trunk and extremities in 5 patients, acral area in 5 patients, mucosa in 3 patients, and an unknown site in 3 patients. Serum 5-S-CD and LD were recorded and change ratios were calculated between the baseline and values obtained 14-90 days after the initial administration of Nivo, prior to the first imaging examination. The change ratios of each biomarker were evaluated based on the response classifications defined by the RECIST criteria (version 1.1). Results: The respective baseline median concentrations of serum 5-S-CD (normal range: 2.5–6.1 nmol/L) and LD (normal range: 120–230 IU/L) were 26.5 nmol/L and 247 IU/L in partial response (PR) patients (n = 5), 74.2 nmol/L and 428 IU/L in a stable disease (SD) patient (n = 1), and 9.9 nmol/L and 237 IU/L in progressive disease (PD) patients (n = 15). The maximum change ratios of 5-S-CD before the first imaging examination were 0.13–1.14 (median: 0.34) in PR patients and 0.30–15.38 (1.52) in PD patients, as compared with 0.73–0.98 (0.96) in PR patients and 0.63–2.23 (1.04) in PD patients for LD. The maximum change ratios of 5-S-CD were ≥1.3 in 9 of 15 (60%) PD patients but < 1.3 in all (100%) PR and SD patients. Conclusions: The maximum change ratio of serum 5-S-CD in the early phase of Nivo treatment may be a useful and more sensitive marker than that of LD to predict a non-response in metastatic melanoma.