bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety results from phase I/II study of the PI3Kβ inhibitor GSK2636771 (G) in combination with pembrolizumab (P) in patients (pts) with PD-1 refractory metastatic melanoma (MM) and PTEN loss.
Authors: Tawbi Hussein Abdul-Hassan , Peng Weiyi , Phillips Suzanne , Milton Denai R. , Amaria Rodabe Navroze , Diab Adi , Glitza Isabella Claudia , Patel Sapna Pradyuman , Wong Michael K.K. , Yee Cassian , McQuade Jennifer Leigh , Tetzlaff Michael T. , Lazar Alexander J. , Shephard Michael , Cain Suzanne , Burton Elizabeth M. , Hwu Patrick , Davies Michael A. 
Published: May 2020

e22000 Background: Checkpoint inhibitors (CPI) have improved survival and long-term disease control in 35-40% of pts with MM. Many pts derive no clinical benefit or progress after an initial response. Our group and others have shown that loss of the tumor suppressor protein PTEN occurs in multiple cancers, up to 30% of MM pts, activates the PI3K pathway, and correlates with decreased MM response rates to CPI and decreased T cell infiltrates. In PTEN-null MM preclinical models, inhibition of the PI3Kβ-subunit with GSK2636771 (G) was superior to pan-PI3K inhibitors, increased intratumoral T cell infiltration and the activity of CPI. To test our hypothesis that PI3Kβi reverses resistance to CPI, we are conducting a Phase I/II study (NCT03131908) combining G with P in PD-1 refractory pts with PTEN loss. Methods: The primary objective of Ph I portion is to determine the Maximum-Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of G with P in PD-1 refractory pts (including melanoma, endometrial, TNBC, and prostate cancers) with PTEN loss. Pts receive P at 200mg IV q 3 wks. G starting dose level (DL1) was 300 mg PO qd for 21 days and escalated to 400 mg PO qd (DL2) using a 3+3 design. A dose level -1 (DL-1) (200 mg PO qd) was also included in the event of unacceptable toxicities at higher doses. Ph II will accrue 35 pts at the RP2D. This study is continuously monitored for toxicity and futility. The primary objectives of Ph II are safety, tolerability, and efficacy of the combination as defined by Objective Response Rate (ORR) by RECIST 1.1. Secondary Objectives include the PKs of G and PD effects in tumor tissue as measured by pathway inhibition and T cell trafficking into tumors. Results: 13 pts have been treated, 6 at the 300mg (DL1), 5 at 400mg (DL2), and 2 at 200 mg (DL-1). One DLT (grade 3 hypocalcemia) was observed at the 300mg dose. Two DLTs were observed in the 400mg cohort, one of which was AKI requiring dialysis and the other was a Gr 3 rash. Based on this experience and additional safety data from GSK regarding renal toxicity, DL-1 was declared RP2D at 200mg. 2 pts at the RP2D have passed the DLT evaluation period without toxicities. Conclusions: The combination of G and P is being explored at the RP2D of 200 mg. Renal toxicity precluded higher doses. No objective responses have been observed although 2 pts have experienced prolonged clinical benefit including a MM pt with 27% decrease in tumor burden. Through longitudinal biopsies, we aim to better understand the role PTEN loss plays when targeted in combination with CPI. Clinical trial information: NCT03131908.
Molecular features for selecting Asian metastatic melanoma patients who benefit from check-point inhibitors.
Authors: Byeon Seonggyu , Kim Hyera , Yeo Ja Hyun , Kim Jinchul , Kwon Minsuk , Lee Jiyun , Kim Seung Tae , Lee Jeeyun 
Published: May 2020

e22011 Background: There was few data for molecular characteristics of Asian metastatic melanoma patients with distinct clinical features as compared to West patients with metastatic melanoma. We conducted the molecular profiling for Asian metastatic melanoma patients with check-point inhibitors (CPIs) to find novel biomarkers to CPIs. Methods: 164 Asian patients with metastatic melanoma who received CPIs were simultaneously tested by the next generation sequencing (NGS) in tumor samples. We collected all NGS data and clinic-pathologic factors and also analyzed biomarkers for tumor response to CPIs. Results: The most common subtype was acral melanoma (39.6%) followed by cutaneous melanoma (32.3%), mucosal melanoma (26.2%) and others (1.8%). 163 pts are evaluable for efficacy; we observed 40 complete response (24.4 %), 34 confirmed partial responses (20.7%), 41 stable disease (25.0%) and 48 disease progression (29.3%). The overall confirmed response rate from the dose escalation is 45.1%. There was no significant difference of tumor response among subtypes of melanoma (p = 0.295). NRAS and TP53 mutation and NF2 deletion were significantly related to patients without the response to CPIs (p < 0.05). Meanwhile, MYC and RPS6KB1 amplification were found with those with the response (p < 0.05). The median progression free survival (PFS) to ICIS was 5.9 months (95% CI 3.8 - 8.05 months). Univariate analysis showed that TP53 and BRAF mutation, NF2 deletion, and BIRC2 amplification were poor prognostic values for PFS (p < 0.05). Conclusions: This study reported molecular characteristics of 164 Asian patients with metastatic melanoma. The specific molecular alterations influenced on the tumor response and PFS to CPIs in those.
Metastatic melanoma of the heart: A systematic review.
Authors: Balinski Alexander M. , Kerndt Connor C. , Parry Nathan P. , Rehman Rafey A. , Yeow Raymond Y. , Hayek Salim S. 
Published: May 2020

e22017 Background: Melanomas are highly aggressive tumors that can metastasize to a wide array of organs, including the heart. Cardiac metastasis is rare and most often diagnosed post-mortem. Here, we perform a systematic review evaluating patient demographics, characteristics, management, and outcomes of cardiac melanoma metastases. Methods: A comprehensive literature review was performed in Cochrane Library, PubMed, and EmBase databases. Study quality was determined based on study design and clinical endpoints using the Oxford Center for Evidence Based Medicine (OCEBM) Levels of Evidence categorization. Demographic data, patient symptomatology, imaging findings, management strategies, and patient outcomes were collected and analyzed. Results: Thirty studies, all case reports or case series, met inclusion criteria. In total, 33 patients with cardiac metastasis from melanoma were identified and histologically confirmed. All 30 studies included in this review received an evidence level of 4 based on OCEBM Levels of Evidence categorization. The most common presenting symptom at the time of diagnosis of cardiac metastasis was shortness of breath (36.4%) and the most common physical exam finding was tachycardia (24.2%). The most common site of cardiac metastasis was the left ventricle (41.9%), followed by the right atrium (35.5%). Notable echocardiogram findings included right ventricular inflow obstruction (27.6%) and valvular dysfunction (24.1%). Valvular dysfunction, classified as prolapse, regurgitation, or stenosis, always involved the tricuspid valve. Treatment strategies typically involved surgical intervention (66.7%), chemotherapy (39.4%), or chemotherapy with surgical intervention (15.2%). Of the 22 cases that reported outcomes, the majority (59.1%) were disease-free without evidence of recurrence. Two patients (9.1%) experienced recurrence within one year of treatment and eight patients (36.4%) expired within 12 months. Conclusions: When symptomatic, cardiac melanoma metastases typically present with shortness of breath and tachycardia, with a predilection for the left ventricle and right atrium. Surgical intervention is currently the mainstay of treatment for successful cardiac melanoma metastasis management. [Table: see text]
Observational cross-sectional study evaluating the sociodemographic and clinical characteristics of patients with metastatic melanoma harboring a BRAF V600 mutation, treated with cobimetinib and vemurafenib based on routine clinical practice.
Authors: Álamo de la Gala Maria Carmen , Ochenduszko Sebastian , Crespo Guillermo , Corral Monica , Oramas Rodriguez Juana Maria , Sancho Maria Pilar , Medina Javier , Garicano Goldaraz Fernando , López Leiva Pedro , Campos Balea Begona , Rodriguez Analia Adela , Muñoz-Couselo Eva 
Published: May 2020

e22028 Background: The drug combination of BRAF inhibitors with MEK inhibitors delays the onset of resistance and enhances apoptosis. Objectives: The main objective was to evaluate the percentage of long responders to the combination therapy. Methods: Participants were patients with advanced melanoma harboring a BRAF V600 mutation, who received Cobimetinib + Vemurafenib as first line, and who started treatment at least 12 months before inclusion. Patients were classified as long responders (patients who have reached at least 12 months of objective response -complete response CR/ partial response PR- to the treatment) or non-responders. Sociodemographic, anthropometric, clinical characteristics, baseline tumor characteristics and treatment dose modification were compared between long responders and non-responders. HADS scale, WPAI-GH and SMAQ questionnaires were used to evaluate the anxiety and depression, productivity and treatment compliance respectively, in patients under active treatment at the moment of the study visit. Results: 41 patients were evaluated. Mean (±SD) age was 57.8 (14.0) years. 56.1% were male. Almost one third of the population (29,3%) was classified as long responder. There were no statistically significant differences in the baseline tumor characteristics, demographic data nor in the clinical characteristics neither in treatment dose modification. CR was the best response achieved by 29.3% of patients, 46.3% achieved PR and 12.2% SD (stable disease). Mean of time to response was 6.9 months for CR patient, and 3.3 and 2.2 months for PR and SD patients respectively. Mean of duration of response was 9.4 months for CR patients, and 10.1 and 9.5 months for PR and SD patients respectively. 42.5% of Adverse Events (AEs) were related with the combination treatment. In the 68.5% of AEs the severity was mild, and in 19.4% moderate. In most cases no action was taken (74.9%) and the outcome was recovered (83.4%). Conclusions: Vemurafenib and Cobimetinib have an important impact in long term survival, leading to a steady complete response in one third of the patients.
Real-world clinical outcomes in avelumab-treated patients (pts) in the United States (U.S.) from SPEAR-Merkel –Study informing treatment Pathway dEcisions in Merkel cell cARcinoma (MCC).
Authors: Cowey Charles Lance , Liu Frank Xiaoqing , Kim Ruth , Boyd Marley , Fulcher Nicole , Krulewicz Stan , Kasturi Vijay , Bhanegaonkar Abhijeet 
Published: May 2020

e22029 Background: MCC is a rare, aggressive disease associated with poor prognosis. Avelumab, a fully human anti–PD-L1 monoclonal antibody, was the first immune checkpoint inhibitor approved by the FDA for the treatment of metastatic MCC (mMCC). In the JAVELIN Merkel 200 trial (Clinical trial information: NCT02155647), avelumab resulted in durable responses and a high objective response rate (ORR) in pts with mMCC. This retrospective descriptive study assessed real-world clinical outcomes in avelumab-treated pts with locally advanced MCC (laMCC) and mMCC in a US community oncology setting. Methods: This study included data on avelumab-treated laMCC and mMCC pts from 1/1/17 to 3/31/19 within The US Oncology Network. Study data were captured through 9/30/19 using structured fields and chart review of iKnowMed electronic healthcare records. Real-world ORR was assessed. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Results: 33 pts initiated treatment with avelumab (laMCC n = 11; mMCC n = 22) and were followed up for a median of 10.9 months (range, 0.5-27.2 months). Median age was 77 years (range, 44-90+ years), 78.8% of pts were male, and the majority (84.8%) of pts were treated in the first-line setting. During treatment, 27.2% of pts had emergency department visits and 39.4% were hospitalized; 1% and 23.1%, respectively, were treatment related. Clinical outcomes are reported in the table. Conclusions: This is the first study to examine pts with laMCC treated with avelumab in a real-world setting. Although the sample population is small, results suggest the clinical benefits in the real world in pts with mMCC treated with avelumab are consistent with benefits reported in the JAVELIN Merkel 200 trial. Clinical trial information: NCT02155647 . [Table: see text]
Association of K1505Ac IHC signal loss and response to immunotherapy in patients with metastatic cutaneous melanoma.
Authors: Altman Daniel S. , Vershvovsky Maria , Jiang Wei , Yang Haifeng , Jagannathan Geetha , Redfield Rachel , Mastrangelo Michael J. , Sato Takami , Orloff Marlana M. , Wilson Melissa 
Published: May 2020

e22049 Background: Immune checkpoint inhibitors (ICI) have become a mainstay of treatment for patients with metastatic cutaneous melanoma. Currently, there are no reliable biomarkers to predict which patients will benefit from ICI therapy. K1505Ac immunohistochemistry (IHC) signal loss is equivalent to loss of functional PBRM1 protein, which has previously been shown to predict response to ICI therapy in metastatic renal cell carcinoma. We hypothesized that loss of K1505Ac IHC expression in patients’ tumors may predict benefit to ICI therapy. Methods: An exploratory study was conducted in patients with metastatic cutaneous melanoma (n = 25) who were treated with ICI therapy at Thomas Jefferson University. Retrospective chart review was performed to determine best clinical response using RECIST 1.1 criteria. Tumor samples from these patients were tested for loss of K1505Ac IHC signals to determine the correlation to best clinical response to ICI therapy. The pathologist was blinded to clinical responses during IHC analysis. Results: The chart below demonstrates the percentage of patients with K1505Ac IHC signal loss ≥ 40% and their correlating best clinical response to ICI therapy. Four of five patients (80%) with complete or partial response displayed K1505Ac IHC signal loss ≥ 40%. Fifteen of twenty patients (75%) with stable disease or progression of disease displayed K1505Ac IHC signal loss < 40%. Conclusions: Loss of K1505Ac IHC signal was associated with better clinical response to ICI therapy for patients with metastatic cutaneous melanoma. These findings suggest that K1505Ac IHC signal loss may serve as a biomarker to help determine which patients will benefit from ICI therapy. A larger cohort of patients is currently under investigation to better evaluate this association. [Table: see text]
A randomized phase II study of adjuvant sunitinib or valproic acid in high-risk patients with uveal melanoma.
Authors: Sato Takami , Orloff Marlana M. , Valsecchi Matias Emanuel , Shimada Ayako , Chervoneva Inna , Sharpe-Mills Erin , Klose Haley , Norcini Jessica , Belinsky Jill , Sato Shingo , Hulse Liam , Shields Carol L , Shields Jerry A , Mastrangelo Michael J. 
Published: May 2020

e22059 Background: Uveal melanoma is the most common primary intraocular cancer in adults. Despite successful treatment of primary tumors, up to 50% of patients later die of distant metastases. Currently, no effective adjuvant treatment is available. Presence of both monosomy 3 and 8q amplification (M3 + 8q amp) or DecisionDx-UM Class 2 in the primary uveal melanoma characterizes a group of patients with high metastatic death rates with reported 2-year survival rates ranging from 50% to 78%. This study aims to decrease or delay the death from metastatic uveal melanoma. Methods: Uveal melanoma patients with high risk for systemic metastasis defined as any of the following were eligible: A) M3 + 8q amp; B) Class 2. Patients must show no evidence of systemic metastasis and they need to be enrolled within 6 months of initial treatment of primary uveal melanoma. Patients were randomized to receive either sunitinib 25 mg daily or valproic acid (VPA) 750 mg daily as adjuvant treatment for 6 consecutive months. Improvement of 2-year overall survival (OS) rate from historical reference (70%) to 85% was the primary endpoint. The secondary endpoints included 1) systemic relapse-free survival (RFS) rate at 18 months, 2) ability to complete adjuvant treatment and, 3) toxicity assessment. The study was not powered to compare the efficacy between each arm. Results: A total of 90 patients were enrolled in this study. Two patients were excluded from the study including one in the sunitinib arm (did not start treatment after randomization) and one in the VPA arm (refused to stop VPA at 6 months). Nine of 45 patients in the sunitinib arm and 4 of 43 patients in the VPA arm could not complete the 6-month treatment due to toxicity (sunitinib n = 6, VPA n = 2) or systemic progression (sunitinib n = 3, VPA n = 2). The rest of patients completed the 6-month course of study treatments and all patients were followed at least for 2 years. With a median follow-up of 40.2 months, the 2-year OS rates of the sunitinib and VPA group were 95.6% (90% CI 86.5-98.6) and 90.7% (90% CI 80.1 - 95.8), respectively. The 18-month RFS rates of the sunitinib and VPA group were 75.6% (90% CI 63.1 - 84.3) and 62.8% (90% CI 49.4 - 73.5), respectively. Conclusions: Although the study is still ongoing, adjuvant sunitinib and VPA were considered to be safe and tolerable treatments for high-risk uveal melanoma. Sunitinib showed a tendency for a better outcome, thus a Cohort 2 was created to investigate the safety and potential improvement of 18-month RFS rate with 12 months of treatment with sunitinib. Clinical trial information: NCT02068586.
Performance of a prognostic 31-gene expression profile test in patients with node-negative cutaneous melanoma.
Authors: Gerami Pedram , Covington Kyle R. , Zolochevska Olga , Quick Ann P. , Cook Robert W. , Wayne Jeffrey D. 
Published: May 2020

e22071 Background: The National Comprehensive Cancer Network guidelines recommend considering sentinel lymph node biopsy (SLNB) for cutaneous melanoma (CM) patients with a 5-10% risk of SLN positivity and offering it to those with > 10% risk. However, SLNB limitations include identification of only 1/3 of patients who end up with distant metastasis and a regional metastasis false negative rate ranging from 5-21% indicating a need to detect the risk of metastasis in patients with a negative SLNB. The 31 gene expression profile (31GEP) test uses the molecular biology of the primary tumor to predict 5-year recurrence-free (RFS), distant metastasis-free (DMFS), melanoma-specific (MSS), and overall survival (OS). Therefore, the objective of this study is to determine whether the 31GEP can stratify risk for patients with SLN-negative results to help guide CM management. Methods: 607 primary CM tumors were collected from patients with SLN-negative status who were enrolled in multi-center IRB-approved studies. Tumors were staged according to the AJCC 8th edition and analyzed by 31GEP testing to differentiate low-risk (Class 1A), intermediate-risk (Class 1B/2A), and high-risk (Class 2B) tumor biology. Clinical data were recorded and Kaplan-Meier (KM) and Cox regression analyses were performed to assess the relationship between 31GEP class and patient outcomes including RFS, DMFS, MSS, and OS. Results: KM analysis for 5yr RFS, DMFS, MSS, and OS stratified by 31GEP class are listed in Table. Multivariate Cox regression analysis demonstrated that the 31GEP Class 2B status was an independent predictor of RFS, DMFS, MSS, and OS with hazard ratios of 4.4 (95% CI, 2.7-7.2; p < 0.001), 4.4 (95% CI, 2.3-8.5; p < 0.001), 15.6 (95% CI, 3.4-71.2; p < 0.001), and 5.4 (95% CI, 2.6-10.9; p < 0.001), respectively. Conclusions: The results indicate that the 31GEP can stratify risk for a subset of patients with SLNB-negative results with the highest 5-year survival rates being associated with a Class 1A result. Moreover, GEP Class 2B is a significant independent predictor of metastatic risk in patients who are node negative. [Table: see text]
CDC20 is a novel potential therapeutic target in NF1-mutant melanoma.
Authors: Donnelly Douglas M. , Giles Keith M. , Vega-Saenz de Miera Eleazar , Betensky Rebecca , Winskill Carolyn , Yeh Yu hsin , Osman Iman , Jour George 
Published: May 2020

e22075 Background: NF1-mutant melanoma (NF1-MT) is a distinct molecular subtype with worse overall prognosis than NF1-wild melanoma (NF1-WT). Despite its prevalence in 20% of patients and associated clinical disadvantage, there is no specific targeted therapy available to treat NF1-MT as its biological impact remains understudied. We tested the hypothesis that NF1-MT possess distinct genomic and transcriptomic characteristics from NF1-WT, which can potentially inform therapeutic innovation. Methods: Tumor DNA from metastatic melanoma (MM) patients treated with checkpoint inhibition at NYU was genotyped using exome sequencing. Microenvironment-related transcripts (n = 770) were then compared in NF1-MT versus NF1-WT using unsupervised clustering, differential gene expression, and gene set enrichment analyses. Verification of genomic and transcriptional findings was performed using qPCR and immunohistochemistry (IHC). TCGA melanoma (SKCM) data were analyzed as an independent cohort. Results: Pathogenic NF1 mutations were detected in 31/121 (27%) cases and were significantly associated with higher tumor mutational burden (P = 0.02). NF1-MT showed recurrent homozygous deletion in the membrane regulatory gene SYT1 and amplifications in oncogenes including CCND1 and MDM2, verified by qPCR. NF1-MT showed upregulation of proliferation with significantly increased expression of Ki-67 and cell division cycle protein 20 CDC20 (P = 0.03) validated by IHC (P = 0.03). Cell cycle was the top enriched pathway in NF1-MT (P = 0.003, FDR = 0.04). Analysis of TCGA melanoma data (n = 440) corroborated upregulation of MKI67 and CDC20 in NF1-MT melanoma (P = 0.01, P = 0.03). Conclusions: NF1-MT is associated with a hyper-proliferative tumor phenotype that cannot be only attributed to MAP kinase activation. Our data suggest that NF1-MT may be vulnerable to pharmacological inhibitors of cell cycle progression and proliferation, such as those targeting CDC20 or CDK4/6.