bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of body composition on outcomes from anti-programmed death-1 (PD-1) treatment.
Authors: Young Arissa , Quach Henry T. , Davis Elizabeth J. , Moslehi Javid , Williams Grant R. , Johnson Douglas Buckner 
Published: May 2019

9516 Background: Obesity is associated with improved outcomes in melanoma patients (pts) treated with PD-1, whereas low muscle mass, known as sarcopenia, has been associated with poor outcomes in many cancers. We sought to assess the impact of body composition on PD-1 outcomes. Methods: We analyzed pre-treatment CT scans at the L3 slice using Slice-o-matic software (Tomovision V. 5.0) to determine skeletal muscle, visceral adipose, and subcutaneous adipose tissue parameters for 104 pts with metastatic melanoma who received PD-1 monotherapy. We assessed sarcopenia using skeletal muscle index (SMI=skeletal muscle area/m2). We also quantified total adipose tissue index (TATI), and skeletal muscle gauge (SMG = SMI x skeletal muscle density [SMD]). We stratified pts into high/low groups using previously published cutoffs and assessed toxicity (tox), progression-free and overall survival (PFS/OS), and response rate (RR) by group. Results: Sarcopenia (low SMI) was negatively associated with any tox (39% vs. 60%, p=0.04) but not OS, PFS, or RR. Adiposity (TATI) was not associated with outcomes. By contrast, SMG was significantly associated with OS (median 35.5 vs. 16.0m, p=0.01 for high vs. low SMG). Interestingly, when incorporating TATI with SMG, we found that high SMG/high TATI pts (high muscle/high fat) have superior clinical outcomes (Table). Notably, low SMG/high TATI pts (low muscle/high fat) had seemingly the worst outcomes. Conclusions: We found that high SMG, a measure incorporating muscle area and density, was associated with improved OS in PD1 treated pts. Further, pts with high adiposity and high SMG had superior outcomes, potentially identifying the population responsible for the favorable effect of obesity in these pts. Validation and combination treated cohorts will be presented. [Table: see text]
Clinical validation of a prognostic 11-gene assay in prospectively collected FFPE tissue of patients with AJCC v8 stage II cutaneous melanoma (CM).
Authors: Garbe Claus , Sinnberg Tobias , Niessner Heike , Sülberg Heiko , Eigentler Thomas K. , Amaral Teresa 
Published: May 2019

9518 Background: AJCC comprises two markers (Breslow thickness and ulceration) to subdivide stage II CM patients into groups with relatively low, average, or high risk of death. Recent updates of clinical guidelines (NCCN, AAD) suggest that patient management be further tailored to an individual prognosis, e.g. through gene expression profiling (GEP). The aim of this single center study was to clinically validate a prognostic GEP-based risk score (MelaGenix) for stage II CMs. Methods: All obtainable, formalin-fixed paraffin-embedded (FFPE) primaries of AJCC stage II CMs from the Central Malignant Melanoma Registry of Germany archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome (data exchange overseen by independent data clearing house) to determine GEP low- vs. high-score groups with a pre-specified GEP score cut-off (≤0.00 > ). Melanoma specific survival (MSS) was evaluated by Kaplan-Meier (KM) analysis and prognostic performance was assessed by multivariate Cox regression. Results: Study cohort comprised 245 stage II primaries (IIA/B/C n = 118/78/49). Median follow-up was 40 months, 5y/10y MSS was 86/75%, median thickness was 3.0 mm, 142 tumors were ulcerated. GEP low-score group had 5y&10y MSS of 92%; GEP high-score group had 5y/10y MSS of 82/67%. KM log-rank was significant (p = .018); GEP score contributed independent prognostic information in multivariate Cox regression (p = .024 HR = 1.45 [1.05 – 2.00]) vs. covariates pT categories (p = .002 HR = 1.59 [1.19 - 2.13]) and age (p = .001 HR 1.05 [1.02 - 1.09]). Conclusions: MelaGenix has been validated as an independent predictor of MSS in stage II patients and refines prognosis beyond AJCC. MelaGenix could serve as an important prognostic decision tool regarding patient management, especially whether adjuvant systemic treatment is appropriate – once drugs become available. It seems reasonable to include this score in future clinical trials. [Table: see text]
Phase II study of ipilimumab and nivolumab (ipi/nivo) in metastatic uveal melanoma (UM).
Authors: Pelster Meredith , Gruschkus Stephen K. , Bassett Roland , Gombos Dan S. , Shephard Michael , Posada Liberty , Glover Maura , Diab Adi , Hwu Patrick , Patel Sapna Pradyuman 
Published: May 2019

9522 Background: UM is the most common primary intraocular malignant tumor in adults. Approximately 40-50% of patients (pts) with UM will ultimately develop metastatic disease. There is currently no standard approach for metastatic UM. Early studies of single agent immunotherapy (IO) in metastatic UM have yielded meager results. Combination checkpoint inhibitor IO has the potential to improve response rates and survival. Herein, we report the safety and efficacy of ipi/nivo in metastatic UM. Methods: We performed a single-arm phase II study in metastatic UM (CA184-187) for pts with at least 1 measureable lesion and ECOG PS 0-1. Any number of prior treatments were permitted. Pts received nivolumab 1mg/kg IV plus ipilimumab 3mg/kg IV every 3 weeks for a total of 4 doses; maintenance nivolumab was dosed 3mg/kg every 2 weeks or 480mg IV every 4 weeks. The primary efficacy endpoint was best overall response rate (BORR) as determined by irRC. Secondary endpoints were median progression free survival (PFS), median overall survival (OS), and one-year OS. Results: As of the January 31, 2019 data cutoff, 39 pts were enrolled. 35 pts received at least one treatment and were evaluable for toxicity. 5 pts were inevaluable for response due to lack of follow-up imaging, leaving 30 pts evaluable for efficacy. 32 pts (91%) experienced any adverse event (AE), and 29 pts (83%) experienced any treatment related AE (TRAE). Grade 3-4 TRAEs occurred in 14 pts (40%). 10 pts (29%) were removed from the study due to AEs. There were no treatment-related deaths. Median duration of follow up is 60.5 weeks. 19 pts (63%) completed all 4 cycles of ipi/nivo; median duration of treatment was 16 weeks. The BORR was partial response for 5 pts (17%), stable disease (SD) for 16 pts (53%), and progression of disease for 9 pts (30%). 8 pts had SD for at least 6 months. Median PFS was 26 weeks. Median OS was 83 weeks (1.6 years), and one-year OS was 62%. Conclusions: Full results of ipi/nivo safety and efficacy including immune-related AE and clinical characteristics of the responders will be presented at the meeting. Preliminary translational tumor work including RNA analysis has been performed on a subset of responders. Clinical trial information: NCT01585194.
Immunotherapy disparities in metastatic melanoma.
Authors: Oliver Thomas , Pezzi Todd A. , Pezzi Ashley E. , Shreders Amanda , Dao Henry , Crozier Jennifer A. , Pezzi Christopher 
Published: May 2019

9525 Background: Historically, patients with advanced malignant melanoma had a dismal prognosis with an estimated median overall survival of nine months. Therapy response rates and long-term survival have significantly improved with the advent of immunotherapies and targeted chemotherapies. First approved in 2011, there has been subsequent development of more advanced immunotherapeutic agents and targeted chemotherapies, with continued improvement in median overall survival. We examined patterns in the use of immunotherapy and other systemic therapies for metastatic melanoma, as well as the demographic and socioeconomic predictors for the use of these therapies, in order to identify and understand potential barriers to access in the United States. Methods: We used the NCDB for all patients aged 18-years and older who were diagnosed with metastatic melanoma of cutaneous origin from 2004-2014. Patients were included if they had distant metastases or American Joint Committee on Cancer (AJCC) Stage IV. Sociodemographic data, including race, age, insurance status, facility providing care, Charlson/Deyo comorbidity score11, and education by patient’s zip code, were collected. Results: In patients under age 65 with a Charlson-Deyo score of zero, immunotherapy utilization ranged between 8.5–13.4% during 2004 to 2010. In 2011, the usage increased to 16.5% and rose every subsequent year to 29.6% in 2014. Patients were less likely to receive immunotherapy if they had no insurance, were of older age, or received care at a community practice rather than an academic center. Those who received immunotherapy had greater overall survival compared with those who did not. Conclusions: Immunotherapy and targeted agents have become standard of care in those with metastatic melanoma. Adoption of immunotherapy use for metastatic melanoma has been relatively slow despite evidence showing an overall survival benefit; our analysis suggests this is explained in part by socioeconomic barriers.
Palbociclib (P) in advanced acral lentiginous melanoma (ALM) with CDK4 pathway gene aberrations.
Authors: Mao Lili , Cao Yabing , Sheng Xinan , Bai Xue , Chi Zhihong , Cui Chuanliang , Wang Xuan , Tang Bixia , Lian Bin , Yan Xieqiao , Li Siming , Zhou Li , Wei Xiaoting , Li Caili , Qi Zhong Hui , Si Lu , Guo Jun 
Published: May 2019

9528 Background: Genetic Aberrations in the CDK4 Pathway occur in 82% of the ALM pts (Clin Cancer Res,2017, 23(22):6946-6957), which is predominant subtype in China. This study is to evaluate the anti-tumor activity of palbociclib, a CDK4/6 inhibitor, in advanced ALM pts with CDK pathway gene aberrations. Methods: In this phase II trial, patients with advanced ALM with CDK pathway gene aberrations (CDK4 or/and CCND1 amplification or/and CDKN2A loss) were treated with palbociclib 125 mg po, d1-21 of 28 day cycles. According to the study design, this trial will be closed if less than 2 patients yield objective response (OR) or stable disease (SD) at a preset 8-week landmark analysis. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Fifteen pts were enrolled from April to Nov 2018. All pts are included in the data analysis for demographics, safety, ORR, PFS and OS. Median age was 54 y (range, 25-74y), 6(40%) were males,5( 33.3%) had the primary sites of subungual, 4(26.7%) were of stage III. Median numbers of prior therapies: 2 (range: 0-5). Three (20.0%) pts achieved tumor shrinkage at 8 wks, including 1 confirmed partial responses (PR). Two pts had treatment ongoing at the data cutoff (January 2019). Median PFS was 2.5m (range, 1.5-8.8m), estimated mean OS was 8.1m (range, 6.7-9.4m). Four pts deceased due to disease progression. The most common treatment related adverse events (TRAEs) were leukopenia/neutropenia (87%; G3, 33%), thrombocytopenia (27%; G3, 7%), anemia (40%; G3, 7%). Conclusions: Monotherapy with palbociclib demonstrated preliminary activities in advanced melanoma pts with CDK pathway gene aberrations. Therefore, the study met its primary endpoint. Palbociclib had an acceptable safety profile as previous studies. Combination of CDK4/6 inhibitor with other agents is under consideration. Clinical trial information: NCT03454919.
Real-world efficacy of anti-PD-1 antibodies in advanced acral melanoma patients: A retrospective, multicenter study (JAMP study).
Authors: Nakamura Yasuhiro , Namikawa Kenjiro , Yoshino Koji , Yoshikawa Shusuke , Uchi Hiroshi , Goto Katsunobu , Nakamura Yoshiyuki , Fukushima Satoshi , Kiniwa Yukiko , Takenouchi Tatsuya , Uhara Hisashi , Kawai Toru , Hatta Naohito , Funakoshi Takeru , Teramoto Yukiko , Otsuka Atsushi , Doi Haruki , Ogata Dai , Matsushita Shigeto , Yamazaki Naoya 
Published: May 2019

9529 Background: Anti-PD-1 antibodies are used worldwide for patients (pts) with advanced melanoma. Clinical trials have demonstrated its efficacy and safety for nonacral cutaneous melanoma (NACM) in controlled settings. Since acral melanoma (AM) is epidemiologically and molecularly distinct from NACM, data on the real-world efficacy of anti-PD1 antibodies in advanced AM is still lacking. Thus, we aim to analyze the real-world efficacy and safety of anti-PD-1 antibodies in advanced AM. Methods: We retrospectively reviewed clinical records of advanced AM treated in any line with an anti-PD1 antibody at 21 Japanese institutions. Clinical response was assessed by (Response Evaluation Criteria in Solid Tumors) RECIST criteria. Survival was estimated using Kaplan-Meier analysis. Toxicity was assessed according to CTCAE 4.0. Results: A total of 193 pts (median age, 71 years) with advanced AM (subungual, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 pts (74.1%). Nivolumab was used in 168 pts and pembrolizumab in 25 pts. Base-line lactate dehydrogenase (LDH) was within normal level in 102 pts (52.8%). The objective response rate (ORR) of all pts was 16.5% (complete response 3.1%, partial response 13.5%), and median overall survival (OS) was 18.1 months. Normal LDH level was significantly associated with better prognosis than abnormal level (median OS 24.9 vs 10.7 months; P < 0.001). Although baseline demographics and characteristics were almost similar between subungual group and palm and sole group, ORR was significantly lower in the subungual group than in palm and sole group (6/70 pts [8.6%] vs 26/123 pts [21.1%]; P = 0.026); median OS was significantly poorer as well (12.8 vs 22.3 months; P = 0.031). Immune-related adverse events of grades 3 to 5 occurred in 27 pts (14.0%). One patient (0.5%) died of grade 5 myasthenia gravis. Conclusions: Real-world efficacy of anti-PD-1 antibodies in AM pts is limited. Notably, pts with subungual melanoma showed poorer response and survival, making them strong candidates for further research of efficacy of anti-CTLA-4 and anti-PD-1 combination therapy.
Clinical models to predict response and survival in metastatic melanoma (MM) patients (pts) treated with anti-PD-1 alone (PD1) or combined with ipilimumab (IPI+PD1).
Authors: Pires Da Silva Ines Esteves Domingues , Ahmed Tasnia , Lo Serigne , Rai Rajat , Smith Jessica Louise , Park John J. , Nabhan Caroline , Scolyer Richard A. , Carlino Matteo S. , McQuade Jennifer Leigh , Johnson Douglas Buckner , Long Georgina V. , Menzies Alexander M. 
Published: May 2019

9542 Background: Currently there are no robust biomarkers to predict immunotherapy response in MM. Specific clinical and molecular variables have been proposed, but in most cases, these factors have been studied individually. We sought to build a predictive model for response rate (RR), progression-free survival (PFS) and overall survival (OS), by including clinical data available at the point of treatment selection for MM pts treated with PD1 or IPI+PD1. Methods: 786 MM pts were included in 4 cohorts; 447 pts treated with PD1 (discovery, n = 343; validation, n = 104) and 339 pts treated with IPI+PD1 (discovery, n = 229; validation, n = 110). Demographics, disease characteristics and baseline blood parameters were examined. Predictive models were selected using multivariate Cox proportional hazard model, logistic regression and LASSO. ROC curve analyses were performed for each model and validation was measured by discrimination índex (c-statistic). Results: Predictive models for RR and PFS in PD1 pts (AUC = 0.69 and AUC = 0.71, respectively) included mutational status (HR for PFS: BRAF 1; NRAS 0.68; WT 0.57; P = 0.002), primary melanoma site (HR for PFS: occult 1; head and neck 0.67, others 1.04; P = 0.052), elevated LDH (HR for PFS: 1.77, P < 0.0001) and monocyte count > median (HR for PFS: 1.56, P = 0.003). Predictive models for RR and PFS in IPI+PD1 treated pts (AUC = 0.71 and AUC = 0.73, respectively) included AJCC stage M1C/M1D (HR for PFS: 2.12, P = 0.009), elevated LDH (HR for PFS: 2.65, P < 0.0001), liver mets (HR for PFS: 1.63, P = 0.038) and basophil count > median (HR for PFS: 0.50, P = 0.003). ECOG ≥ 1, elevated LDH and brain mets associated with worse OS and were included in predictive models for OS in PD1 (AUC = 0.74) and IPI+PD1 (AUC = 0.85). These models showed consistency with internal and external validation (c-statistic: < 10% difference between the original model and validations for all outcomes). Conclusions: A combination of routinely collected clinical factors are highly predictive of outcome in MM pts treated with PD1 and IPI+PD1. A prognostic index will be presented for each treatment. Such tools may be practical, cheap and valuable for clinical decision making.
Use of immunotherapy for stage-III and IV melanoma and likelihood of regional and distant lymph node resection and surgical resection for distant metastasis.
Authors: Molina George , Kasumova Gyulnara G. , Qadan Motaz , Boland Genevieve Marie 
Published: May 2019

9558 Background: Immunotherapy (IMT) for stages-III and IV melanoma has dramatically changed overall prognosis and treatment strategies. The aim of this study was to evaluate if use of IMT significantly changed the likelihood of regional/distant lymph node (LN) resection and surgical resection for distant metastases (DM) among patients with stages-III and IV melanoma, respectively, in the pre- and post-2011 era. Methods: The National Cancer Database (2004-2015) was used to evaluate the likelihood of regional/distant LN resection and surgical resection for DM among patients with stages-III and IV melanoma, respectively, with use of IMT. Multivariable stepwise with forward selection Poisson regression with robust standard errors was used to adjust for potential confounders (age, gender, race, year of diagnosis, Charlson-Deyo Score, facility type, facility location, insurance status, 2012 median income quartile, and 2013 urban/rural status). A stratified analysis was performed to evaluate differences among facility type. Results: There were 28,847 patients (median age 62 (IQR 53-73); 36.3% female) with stage-III melanoma and 14,443 patients (median age 66 (IQR 56-76); 31.7% female) with stage-IV melanoma. Overall, 24.3% (n = 7,018) and 17.0% (n = 2,459) with stage-III and IV melanoma, respectively, received IMT. The adjusted relative risk (aRR) of regional/distant LN resection among patients with stage-III melanoma was significantly higher with use of IMT (aRR 1.16, 95% CI 1.05–1.28, P = 0.004), while the aRR of surgical resection for DM was significantly lower with use of IMT for stage-IV melanoma (aRR 0.85, 95% CI 0.78–0.92, P < 0.001). Stratified analysis demonstrated that the findings were principally reflective of academic/research hospitals. Conclusions: The higher likelihood of regional/distant LN resection in stage-III melanoma may be due to the curative role of surgery and preceded the post-MSLT-II era. Conversely, in stage-IV melanoma, surgery may be limited to resectable oligometastatic disease given the durable and systemic benefit of first-line IMT.
A phase II study of oral azacitidine (CC-486) in combination with pembrolizumab (PEMBRO) in patients (pts) with metastatic melanoma (MM).
Authors: Burton Elizabeth M. , Woody Timothy , Glitza Isabella Claudia , Amaria Rodabe Navroze , Keung Emily Zhi-Yun , Diab Adi , Patel Sapna Pradyuman , Wong Michael K.K. , Yee Cassian , Hwu Patrick , McQuade Jennifer Leigh , Woodman Scott Eric , Tetzlaff Michael T. , Davies Michael A. , Wargo Jennifer Ann , Rai Kunal , Tawbi Hussein Abdul-Hassan 
Published: May 2019

9560 Background: Immune checkpoint blockade (ICB) have improved survival for many pts with MM, offering durable responses in up to 35% of pts, but many have short-lived or no response ( > 40%). A potential immune escape mechanism is the subversion of cellular epigenetic machinery to impact multiple aspects of the immune response such as suppression of Cancer Testis Antigen (CTA), which can be reversed in preclinical models by DNA hypomethylating agents (HMA), thereby increasing cancer cell immunogenicity. HMAs can also increase T cell infiltration and T cell-mediated tumor killing, and they achieve synergy with CBI in preclinical models. This suggests that epigenetic therapy with CBI is a rational combination to target MM. We hypothesize that CC-486 (an oral HMA) + PEMBRO will be tolerated at biologically relevant doses and enhance response to PEMBRO in pts with MM who are PD-1 naïve and reverse resistance to (ICB) in pts refractory/resistant to PD-1. Methods: This study (NCT02816021) evaluated the safety and efficacy of CC-486 (300 mg PO QD on days 1-14/21 day cycle) + PEMBRO (200mg IV Q 21 days) defined by Objective Response Rate (ORR) by RECIST 1.1 in pts with MM. PD-1 naïve pts were assigned to Arm A and pts with progression on prior PD-1 therapy to Arm B. Unlimited prior systemic therapies were allowed on Arm B. Continuous monitoring for toxicity and futility was performed and assumes an ORR of > 35% (Arm A) and > 15% (Arm B) at 95% power. Tumor biopsies at baseline and post treatment were mandated. Results: 22pts, 11 in each arm, have been treated. The most common AEs were nausea, vomiting, diarrhea, fatigue, and anemia. The most common gr 3/4 toxicities were neutropenia (3), diarrhea (2), dehydration (2), and rectal hemorrhage (1). 5 of 9 evaluable pts in Arm A achieved a PR (55% ORR); 0 of 9 evaluable pts in Arm B pts have responded. Conclusions: Although this regimen was tolerated in both arms, Arm B met futility stopping rules and was closed. The initial response rate in Aim A (55%) is promising, and accrual to this Arm continues. Analyses of longitudinally collected tumor biopsies are underway to interrogate the effects of HMA on the immune response to both arms. Clinical trial information: NCT02816021.