bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of ipilimumab exposure-efficacy/safety response relationships in subjects with previously treated or untreated advanced melanoma.
Authors: Feng Yan , Godfrey CJ , Chu Hui-May , Masson Eric , Williams Daphne , Berman David Mark , Roy Amit 
Published: March 2020

8541 Background: Ipilimumab (IPI) is a fully human monoclonal antibody directed against CTLA-4 that is being developed as a novel immunotherapeutic agent against melanoma and other solid tumors. The objective of this analysis was to retrospectively characterize the exposure-response (E-R) relationships for efficacy (overall survival, OS) in subjects with previously untreated advanced melanoma (pu-MEL), and safety (immune related adverse-events, irAEs) in subjects with previously treated advanced melanoma (pt-MEL) or pu-MEL. Methods: The E-R analysis of OS included 498 pu-MEL from a phase III study (CA184024) of IPI administered at 10 mg/kg + dacarbazine (DTIC) or DTIC + placebo; and the E-R analyses of irAE included 1036 subjects from a phase I study (CA184078), 4 phase IIstudies (CA184004/007/008/022) and CA184024 of IPI administered at doses of 0.3, 3 or 10 mg/kg. The relationship between steady‑state IPI trough concentration (Cminss) and OS was described using a Cox proportional hazards model, and the relationships between Cminss and incidence of irAEs were described by ordinal logistic regression models (separate models for any irAE, as well as skin, liver and GI irAE). Results: The risk of death decreased with increasing Cminss, and is higher for subjects with elevated baseline LDH level. The risk of death was higher for subjects with baseline ECOG status > 0 and was higher with increasing stage of disease (M1C>M1B>M1A>M0). The hazard ratio for OS corresponding to the median Cminss of 49.99 µg/mL was 0.745 relative to subjects in DTIC + placebo group. The probability of Grade 2+ or Grade 3+ GI, skin, liver and any irAEs also increases with Cminss. Prior anti-cancer therapy (including prior DTIC) or concomitant DTIC were the only significant covariates in the E-R irAE models. Conclusions: These model-based analyses suggest that higher Cminss of IPI appears to be associated with improved survival in pu-MEL (based on data from CA184024) and higher Cminss also appears to be associated with increased probability of irAEs in pu-MEL or pt-MEL.
BRAF mutation as a pejorative marker in metastatic melanoma.
Authors: Brissy Sophie , Gaudy-Marqueste Caroline , Mallet Stéphanie , Monestier Sandrine , Hesse Sylvie , Koeppel Marie-Christine , Rojat-Habib Marie-Christine , Nanni Isabelle , Loundou Anderson , Ouafik L'houcine , Bonnet Nathalie , Richard Marie-Aleth , Grob Jean Jacques 
Published: March 2020

8555 Background: BRAF mutation in melanoma has been shown to be associated with a trend in favour of a spontaneous worse outcome after metastases in a series of 197 patients in Australia. Objective: To correlate BRAF status in metastatic melanoma with clinicopathologic features and outcome. Methods: In our department in France 182 patients with metastatic melanoma have been tested for BRAF mutation between September 2009 and September 2011. Survival was assessed by log-rank test. Multivariate analysis was performed with Cox model. Results: From 182 patients, 88 (48.3%) were B-RAF mutant; 77 (87.5%) V600E, 4 (4.5%) V600K, and 7 (8%) other mutation subtypes. BRAF-mutant patients were younger than BRAF wild-type patients at diagnosis of primary melanoma (median age 52.3 vs 60.7 years, respectively, p=0.003), and at diagnosis of distant metastasis (median age 53.6 vs 64.1 years respectively, p=0.002). 34 patients were treated by B-RAF inhibitors. There was no significant difference in other demographic features of patients with metastatic melanoma by mutation status. Features of the primary melanoma significantly associated with a BRAF mutation (p<0.05) were histopathologic subtype (SSM), high mitotic rate (≥1/mm2), lower Breslow thickness (median Breslow: 2.2 vs 3.5 mm for BRAF mutant and BRAF-wild-type patients respectively, p=0.016), truncal location and location on occasionally exposed at sun site.The interval from diagnosis of first ever melanoma to first distant metastasis was not significantly different in BRAF-mutant and wild-type patients. The median overall survival (OS) from diagnosis of primary melanoma was 6.5 years for BRAF wild-type patients. Median OS was not reached in BRAF-mutant patients treated (34 of 88) with a BRAF inhibitor, but also in those not treated (p=0.24, and p=0.06 for treated BRAF-mutant vs BRAF wild-type). The overall survival from diagnosis of first distant metastasis was not significantly different (p=0.75). These results remained unchanged in a multivariate analysis. Conclusions: Our results confirm the characteristics of BRAF-mutant metastatic patients, and the efficacy of B-RAF inhibitors, but not that the presence of mutant-BRAF is per se a pejorative predictive marker.
High-risk uveal melanoma: A prospective study evaluating the role of magnetic resonance imaging of the liver.
Authors: Marshall Ernest , Romaniuk Chris , Ghaneh Paula , Wong Helen , McKay Marie , Chopra Mona , Coupland Sarah , Damato Bertil 
Published: March 2020

8564 Background: Almost 50% of uveal melanomas are fatal. Metastatic death occurs almost exclusively with tumours showing chromosome 3 loss and 8q gain. Metastases, which almost always involve the liver, are resectable in some patients. They are rarely detectable when the patient presents with the primary ocular tumour. Screening is therefore necessary, but there is no consensus as to who should be screened, how often, and for how long. Methods: Uveal melanoma patients with ECOG performance status 0-2 were eligible if their risk of metastatic death at 5 years exceeded 50%. Survival probability was estimated by multivariate analysis of tumour stage, histological grade and genetic tumour type. Patients underwent screening 6monthly, clinical examination, non-contrast liver MRI and liver function tests for at least five years. Results: Between Jan 2000 and November 2010, 279 high-risk patients were referred for screening. Of these, 188 (84 male, 104 female) accepted screening and underwent as least 1 MRI. The median age was 63 years (IQR 16.5). Median basal tumour diameter was 16.5mm (IQR 5.25). Chromosome 3 loss was detected in 175 tumours. Median follow up time was 28.8 months (IQR 29.1). Median relapse-free survival was 33 months (95% CI 28-38) with a 35% relapse-free survival at 5 years. After a median of 18 months (IQR 20), screening detected metastases in 90/188 (48%), 83 of whom were asymptomatic. 12 patients underwent R0 liver resection, which increased the median survival from 10 (95% CI 8.1 - 11.9) to 24 (95% CI 20.2- 27.8) months. The screening programme stimulated a UK NCRI portfolio of clinical trials in which 23 of these patients were subsequently treated. Conclusions: Six-monthly liver MRI detects metastases from uveal melanoma at an early stage, thereby enhancing opportunities for surgical metastatectomy, clinical trial participation and prolonging life.
Biomarker for benefit from ipilimumab: Correlation of breadth of humoral tumor-antigen-specific immunity with outcome.
Authors: Ellis Sarah Gabrielle , Wheater Matthew , Tier Katherine , Cazaly Angelica , Smart James , Theaker Jeffrey , Hepburne-Scott Henry , Bonner-Ferraby Phoebe , Ottensmeier Christian H.H 
Published: March 2020

8566 Background: Checkpoint blockade through CTLA4 with ipilimumab has for the first time improved survival in patients with advanced melanoma. Immune-mediated toxicity and increase in humoral and T-cell anti-NY-ESO-1 immune responses after treatment are both linked with benefit. However there is currently no broadly relevant, immunological biomarker for predicting outcome prior to initiation of therapy. Methods: Using a novel immunological assay developed by Serametrix Corporation we analysed the presence of antibodies to a proprietary panel of tumour associated antigens (TAAs) in 34 patients with advanced melanoma, given ipilimumab at 3mg/kg as second or subsequent line of treatment. Results: 34 patients were consented and analysed, 22 females, 13 males. With a median age of 63 years median overall survival was 24 weeks; 6/34 patients had an objective response to ipilimumab (17.6%, median survival not reached). Antibody (AB) responses were tested against the panel of 26 TAAs. This panel includes BRAF, Cancer/Testis and other described or novel TAAs. We observed a wide range in the incidence and levels of antibody response. 12 patients had no detectable immunity, 6 an AB response to a single antigen, 5 AB response to 2, and 11 patients to 3 or more TAA. Five patients had either pre-existing anti-BRAF antibodies or developed these after CTLA4-blockade. Survival was significantly longer in those patients with pre-existing antibodies to 2 or more TAA, compared to those with 0 or 1 specificities (median survival 39.4 vs 16.4 weeks p=0.02). Conclusions: Patients with advanced melanoma had variable levels of humoral immunity to a large number of TAA, including to BRAF. The presence of antibody response to 2 or more TAA correlated with longer survival following treatment with ipilimumab and appears to provide a biomarker for identifying those patients that are most likely to respond to checkpoint blockade with ipilimumab.
Ipilimumab-induced hypophysitis in melanoma patients.
Authors: CarrÃ© Typhanie , Gaudy-Marqueste Caroline , Albarel Frédérique , Monestier Sandrine , Mallet Stéphanie , Brue Thierry , Richard Marie-Aleth , Grob Jean Jacques 
Published: March 2020

8568 Background: Ipilimumab (Ipi) is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigene-4 (CTLA-4) recently approved for the treatment of metastatic melanoma (MM) and currently under investigation in the adjuvant setting. Methods: Retrospective analysis of patients treated with ipi between June 2006 and September 2011 in our department in Marseille. As some patients are still blinded in trials, the exact number of patient under ipi is unknown. We present a minimal percentage (>%) assuming that the 120 patients received ipi. Results: A total of 120 patients were treated: 76 stages IV MM, from which 16 in the BMS clinical trials (CA184-022, -024, and-025 and MDX 010-20) and 44 stages III MM (in the BMS CA184-029 trial). Stage IV MM were administered 0.3, 3 or 10mg/kg IV dosage, while stages III MM were randomly assigned to receive 10 mg/ kg or placebo (1:1 ratio). Hypophysitis was diagnosed in 12 patients (>10%): 2/76 patients with stage IV MM (>2. 6 %) and 10/44 patients with stage III MM (>22.7). Diagnosis was performed at the 1st, 3rd and 4th administration in respectively 2 (1.6%), 6 (50%) and 4 patients (33.3%). Clinical symptoms included headaches (n=11; 91.6%), asthenia (n=7; 58.3%) and decreased libido (n=2; 1.6%). Adrenal, thyroidal and gonadal axis were affected in respectively 6 (50%), 9 (75%) and 7 patients (58.3%). MRI changes were observed in 7 patients (58.3%): pituitary swelling in 5 patients (41.6%) and heterogeneous enhancement in 4 patients (33.3%) including 2 patients with normal biology. Corticosteroids supplementation was required in 11 patients and thyroidian supplementation in 4 patients. Clinical symptoms regressed within one week in 8 patients (66.6%). Conclusions: Ipi-induced hypophysitis is detectable only if clinicians are aware of these unspecific signs. Only MRI can make diagnosis in some patients without clinical and/or biological signs. Our data suggest that it develops especially for 10mg/kg dosage, after the third administration, and that the rate could be higher in patients with a normal immune system (adjuvant treatment), than in metastatic ones. Hormonal supplementation usually controls the disease.
Assessment of germ-line and somatic alterations in main candidate genes among patients with multiple primary melanoma.
Authors: Palmieri Giuseppe , Sini MariaCristina , De Giorgi Vincenzo , Lissia Amelia , Massi Daniela , Rubino Corrado , Cossu Antonio , Stanganelli Ignazio , Palomba Grazia , Botti Gerardo , Caraco Corrado , Mozzillo Nicola , Ascierto Paolo Antonio , Colombino Maria 
Published: March 2020

8581 Background: We have studied a series of patients with multiple primary melanoma (MPM) for the involvement of the key-regulator genes in susceptibility (CDKN2A) and pathogenesis (BRAF, cKIT, CyclinD1) of such a disease. Methods: Genomic DNA from peripheral blood of 63 MPM patients (54 cases with two primary melanomas, 8 with three, and 1 with four) were screened for germline mutations in p16CDKN2A and p14CDKN2A genes by automated DNA sequencing. Melanoma families were identified according to standardized criteria: 9 (14%) patients were classified as familial cases. Paired synchronous and/or asynchronous MPM tissues (N=100) from same patients (N=46) were analyzed for somatic mutations in BRAF gene and FISH-based amplifications in cKIT and CyclynD1 genes. Results: Overall, 6 (10%) different CDKN2A germline mutations were identified: 5 in p16CDKN2A and 1 in p14CDKN2A. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were significantly more frequent in patients with familial history of melanoma (5/9; 56%) compared with patients without (1/54; 2%) (P<0.001), and in patients with more than two melanomas (3/9; 33%) compared with patients with only two melanomas (3/54; 6%) (P=0.012). The debated A148T polymorphism was found at low level (2/54; 4%) in our series. Regarding genetic alterations at somatic level, BRAF mutations were identified in 36/100 (36%) primary melanoma tissues, whereas amplification of cKIT and CyclinD1 genes was observed in 2/88 (2%) and 10/88 (11%) analyzed tissue samples, respectively. Considering all types of genetic events, paired samples presented a poorly consistent distribution of somatic alterations in same patients (52% consistency). Conclusions: Coexistence of MPM and familial recurrence of melanoma as well as the presence of more than two melanomas seem to be strong indications to address patients to CDKN2A mutational screening. The low consistency in genetic patterns of primary tumors from the same patients provide additional evidence that pathogenetic mechanisms of melanomagenesis are heterogeneous and molecularly different cell types may be generated in multiple primary melanoma.
Phase I trial of extended-dose anti-PD-1 antibody BMS-936558 with a multipeptide vaccine for previously treated stage IV melanoma.
Authors: Kudchadkar Ragini Reiney , Gallenstein Donna , Martinez Alberto J , Yu Bin , Weber Jeffrey S. 
Published: March 2020

8582 Background: BMS-936558, a fully human IgG4 anti-PD-1 antibody, has shown clinical activity in melanoma and renal cancer. Methods: 30 HLA A*0201 positive patients with unresectable, previously treated stage IV melanoma received MART-1/gp100/NY-ESO-1 peptides with adjuvant Montanide ISA 51 injected subcutaneously with BMS-936558 at 1, 3 or 10 mg/kg intravenously every 2 weeks for 24 weeks, followed by BMS-936558 alone every 3 months. No patient had prior ipilimumab. Endpoints were toxicity, correlative studies of immunity measured by ELISPOT and T-cell phenotype assays, and response by RECIST. Results: Median age was 62, with 14 men and 16 women. 73% of patients had M1c disease. One patient had dose limiting optic neuritis; one patient had dose limiting grade 3 interstitial pneumonitis. Of 10 patients at 1 mg/kg, 2 had confirmed partial responses (PR), both one year from initiation of study. 13 patients were treated at the 3 mg/kg cohort; 3 patients did not complete more than 3 doses secondary to progressive disease and one withdrew consent. Of 12 evaluable patients, 3 had confirmed PRs and 2 unconfirmed PRs. In the 10 mg/kg cohort, thus far 6 patients completed one cycle with 2 unconfirmed PRs and one patient stable. Only 2 of the 9 responders after one cycle have progressed with a median follow-up of 7 months. 2/6 patients failing BMS-936558 responded to ipilimumab. At week 12, patients in all cohorts had decreased PD-1 on CD4 and CD8 T-cells (p<0.0001), increased CD4 CTLA-4 levels (p=0.01) and dose related decreases in CD8 T-cells whereas CD4 T-cells increased (both p<0.05). ELISPOT assays showed that patients at all doses had no increased responses in fresh PBMC to MART-1/gp100, but showed dose related decreased responses to viral (CMV, EBV, FLU) peptides over time (p=0.04). Conclusions: BMS-936558 in combination with a peptide vaccine is well tolerated at 1 and 3mg/kg. Accural to the 10mg/kg cohort is on-going. Responses have been observed at all dose levels. PD-1 levels on T-cells decreased, and CTLA-4 levels increased in CD4 T cells in all cohorts. There was a dose-related decrease in CD8 T-cells and in viral-specific T-cells. Further study of BM-936558 is warranted to determine its optimal dose.
A phase IB study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma.
Authors: Hong David S. , Andresen Corina , Mink Jennifer , Ren Min , O'Brien James P. , Nguyen Ly Minh , Falchook Gerald Steven , Kurzrock Razelle , Nemunaitis John J. 
Published: March 2020

8594 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of lenvatinib partial responses were observed in melanoma as well as thyroid, endometrial, and renal cancers. Methods: Patients (pts) with stage 4 or unresectable stage 3 melanoma were treated in sequential cohorts of escalating doses of lenvatinib by continuous once daily dosing and temozolomide (TMZ) days 1-5 every 28 days. Cohort 1: lenvatinib 20mg, TMZ 100 mg; cohort 2: lenvatinib 24 mg, TMZ 100 mg; cohort 3: lenvatinib 24 mg, TMZ 150 mg. Adverse events were recorded according to CTCAE v3.0 and tumor response assessed according to RECIST 1.0. Results: 32 pts were treated: cohort 1: 6 pts, cohort 2: 4 pts, cohort 3: 22 pts. Demographics: median age: 58; males: 63%. Dose limiting toxicities occurred in 0/6 pts in cohort 3 leading to cohort expansion to a total of 22 pts to enable more extensive assessment of toxicity and a preliminary estimate of efficacy. The most common treatment related adverse events in the cohort 3 were fatigue: 50% (gr3: 9%), hypertension: 50% (gr3: 9%), proteinuria: 50% (no gr3), vomiting: 46% (no gr3), hypothyroidism: 46% (no gr3), anorexia: 41% (no gr3), nausea: 41% (no gr3), diarrhea: 36% (gr3: 5%), thrombocytopenia: 32% (no gr3). No treatment-related gr4 events were reported in these categories. The best overall responses per RECIST were partial responses: 5/22 (23%) for cohort 3 pts and 6/32 (19%) for all pts treated at all dose levels. Six-month progression free survival (PFS) rate was 37% and median PFS was 5.4 months. PK/PD analysis and correlation of response with genetic mutational status (BRAF mutations in 31% pts; NRAS mutations in 19% pts) will be presented. Conclusions: Lenvatinib 24 mg once daily in combination with TMZ 150 mg days1-5 every 28 days was given without apparent worsening of either lenvatinib or TMZ related toxicities. Modest clinical efficacy for this combination was observed.
MicroRNAs induced in melanoma treated with combination targeted therapy of temsirolimus and bevacizumab.
Authors: Wagenseller Aubrey G , Shada Amber L , D'Auria Kevin , Murphy Cheryl F. , Sun Dandan , Molhoek Kerrington R. , Papin Jason A , Dutta Anindya , Slingluff Craig L. 
Published: March 2020

8597 Background: Targeted therapies directed at commonly overexpressed pathways in melanoma have clinical activity in numerous trials. Little is known about how these therapies influence microRNA expression, particularly with combination regimens. A better understanding of how microRNAs are altered with treatment may contribute to understanding mechanisms of therapeutic effects as well as mechanisms of tumor escape from therapy. Methods: Using microRNA arrays, we analyzed microRNA expression levels in melanoma samples from a Cancer Therapy Evaluation Program-sponsored phase II trial of combination temsirolimus and bevacizumab in stage III or IV melanoma, which elicited clinical benefit in a subset of patients. Seventeen patients were treated with temsirolimus for one week, then combination of both temsirolimus and bevacizumab. Metastatic melanoma biopsies were evaluated days 1, 2, and 23. Tumor samples were evaluated from 12 patients. Results: microRNA expression remained unchanged with temsirolimus alone; however, expression of 15 microRNAs was significantly upregulated (1.4 to 2.5-fold) with combination treatment, compared to pre-treatment levels. Interestingly, twelve of these fifteen microRNAs have been reported to possess tumor suppressor capabilities in various cancer types, including melanoma. We identified 15 putative oncogenes and B7-H3, IGF-1, and IGF-1R as potential targets of the 12 tumor suppressor microRNAs, based on published experimental evidence. For 18 of 25 pairings of microRNA and target-mRNA, changes in gene expression from pretreatment to post-combination treatment samples were inversely correlated with changes in microRNA expression, suggesting a functional effect of the microRNA changes induced by combination therapy. Clustering analysis based on selected microRNAs revealed signatures characteristic of clinical response to combination treatment and of tumor BRAF mutational status. Conclusions: We have identified microRNAs that may be involved in the mechanism of action of combination temsirolimus and bevacizumab in metastatic melanoma, possibly through inhibition of oncogenic pathways.
Preoperative peripheral blood lymphocyte/monocyte ratio and survival in patients with resected stage IV melanoma.
Authors: Rochet Nicole M. , Porrata Luis F. , Kottschade Lisa A. , Grotz Travis Edward , Markovic Svetomir 
Published: March 2020

8600 Background: The prognosis of stage IV melanoma patients remains poor. Published results have suggested that components of the complete blood count have significant prognostic value in several malignancies. Among the most studied were the absolute lymphocyte count (ALC), and absolute monocyte count (AMC) on clinical outcomes of patients with lymphoid malignancies. Thus, we sought to investigate if the pre-operative ALC (ALC-PO), AMC (AMC-PO) and ALC/AMC ratio (ALC/AMC-PO) affects the risk of disease recurrence and survival after complete surgical resection of metastatic melanoma. Methods: We studied 66 stage IV, resected melanoma patients followed at Mayo Clinic from 2000 to 2010. Log rank chi-square analysis was used to determine the best cut-off values for each pre-operative variable, while proportional hazards models were used to compared survival. Results: The median follow-up of the cohort was 24 months (range: 2.3 – 117 months). ALC-PO, AMC-PO and ALC/AMC-PO, as continuous variables, were all identified as prognostic factors for both relapse-free survival (RFS) and overall survival (OS). The best cut-off values for ALC-PO, AMC-PO and ALC/AMC-PO were 1.9; 0.62; and 2.05, respectively. Using Kaplan-Meier analysis, patients with an ALC-PO ≥ 1.9 x 109/L experienced superior OS and RFS compared with ALC-PO < 1.9 x 109/L patients [median OS of 58 months vs. 34 months, p < 0.04; median RFS of 14 months vs. 5 months, p < 0.009]. Conversely, a low AMC-PO (<0.62 x 109/L) was associated with better OS and RFS compared with higher AMC-PO (≥ 0.62 x 109/L): [median OS of 47 months vs. 14 months, p < 0.007; median RFS of 9 months vs. 5 months, p < 0.02]. When the ALC-PO and AMC-PO were combined as an ALC/AMC ratio, the group with an ALC/AMC-PO ≥ 2.05 experienced a superior OS and RFS compared to patients with ALC/AMC-PO < 2.05: [median OS of 49 months vs. 12 months, p < 0.0001; median RFS of 10 months vs. 4 months, p < 0.0001]. Multivariate analysis showed ALC/AMC-PO to be an independent prognostic factor for RFS and OS (HR = 0.32, p < 0.003; HR = 0.23, p < 0.002). Conclusions: Our study showed, that ALC/AMC-PO ratio is an independent prognostic factor for RFS and OS in patients undergoing resection of metastatic (stage IV) melanoma.