bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of ipilimumab in melanoma patients who received prior immunotherapy on phase III study MDX010-020.
Authors: Kaufman Howard , Lutzky Jose , Clark Joseph , Margolin Kim Allyson , Lawson David H. , Amin Asim , Collichio Frances A. , Pecora Andrew , Urba Walter John , Bennett Kelly L. , McDermott David F. 
Published: March 2020

9050 Background: MDX010-020 was a phase III comparison of ipilimumab (Ipi), gp100 vaccine or the combination for advanced melanoma. A subset of patients (pts) received other immunotherapy (IM) for advanced disease prior to receiving Ipi, providing the opportunity to evaluate safety and efficacy of Ipi following IM. A prior analysis has shown that pts receiving prior IL-2 had a similar overall survival (OS) to pts who had not received prior IL-2 [Hodi et al NEJM2010]; we now report expanded results for pts receiving any prior IM (interferons and/or interleukin). Methods: Eligible pts (n=676) had unresectable stage III/IV melanoma and were randomized 3:1:1 to q3 wks x 4 doses of Ipi + gp100 or Ipi + placebo or gp100 + placebo. All Ipi doses were 3 mg/kg i.v. OS was retrospectively analyzed for pts receiving any prior IM; immune-related adverse events (irAEs) during induction were evaluated for pts who received any prior IM (322 pts, 48%) and for pts who received prior IL-2 (154 pts, 23%). Results: Demography and OS are summarized below. irAEs of any grade were reported for 60% (Ipi) and 54% (Ipi + gp100) of pts receiving any prior IM. Those receiving prior IL-2 specifically had 73% (Ipi) and 58% (Ipi + gp100) incidence of any grade irAEs. Incidence was similar for those not receiving prior IM or prior IL-2. Diarrhea, rash, and pruritus were the most common events in all groups. Conclusions: Results for OS in this subgroup analysis were similar for both those receiving any prior IM and those who did not receive prior IM and to the overall 020 population. In addition, safety profiles were similar irrespective of prior immunotherapy. Clinical trial information: NCT00094653. [Table: see text]
Melanoma of ocular, mucosal, and genital sites: Epidemiology and survival outcomes.
Authors: Bishop Kenneth D. , Olszewski Adam J. 
Published: March 2020

9051 Background: Melanomas arising from noncutaneous sites are rare entities with poorly defined staging, prognosis and no evidence-based treatment guidelines. Methods: We analyzed melanoma cases in the Surveillance, Epidemiology and End Results database between 1988 and 2007. Differences in clinical and pathologic features, treatment, and mortality were studied according to primary site of disease. The risk of melanoma-related death was calculated from life tables based on expected survival. Relative survival was compared in a multivariable parametric model using individual data. Results: We identified 209,861 cases of melanoma, of which 9,267 (4.4%) were noncutaneous. These were notable for older age, higher proportion of women, racial minorities, and advanced-stage disease. Mortality was high, even in subgroups with localized stage at diagnosis. Mucosal melanomas of the gastrointestinal and genitourinary tract had the highest excess mortality hazard ratios (HR) in the multivariate model. A substantial proportion of patients underwent organ-specific radical resection (32% eye enucleation, 40% radical head/neck surgery, 31% gastrectomy, 23% abdominoperineal resection). Conclusions: Melanoma arising from mucosal sites portends markedly worse prognosis than cutaneous melanoma. Prospective studies of systemic adjuvant treatment are needed for this disease, which is rarely curable even with aggressive local therapy. [Table: see text]
Analysis of serum biomarkers and tumor genetic alterations from a phase II study of lenvatinib in patients with advanced BRAF wild-type melanoma.
Authors: Sachdev Pallavi , Hamid Omid , Kim Kevin , Hauschild Axel , O'Day Steven , Andresen Corina , Funahashi Yasuhiro , Kadowaki Tadashi , O'Brien James P. , Flaherty Keith 
Published: March 2020

9058 Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. Phase I and II studies of lenvatinib demonstrate that a subset of advanced melanoma patients (pts) appears to derive benefit from lenvatinib treatment (tx), prompting a need to identify predictive biomarkers for response to lenvatinib. Methods: Serum and archival tumor samples were collected from 93 enrolled pts in the BRAF wild-type (wt) cohort of the lenvatinib phase II study of advanced melanoma. Concentrations of 50 factors were measured in pre- and post-tx serum samples; 58 archival tumor tissues were obtained and gene mutation (mut) (n=53) and gene expression profiling (GEP) (n=39) analyses were performed. For mut analysis, targeted resequencing was performed on a select panel of genes using the Ion PGM Sequencer and mut validation studies were performed. For GEP analysis, the nCounterAnalysis System was used to measure the expression level of 330 genes. Results: Clinical benefit rate (32%) and objective response rate (9%) by independent radiologic review were observed in the BRAF wt cohort. In serum biomarker analysis, lenvatinib tx resulted in a decrease in soluble VEGFR2 and increase in VEGF and PlGF levels consistent with target engagement. Correlation with clinical outcome demonstrated that baseline (BL) levels of Ang-2, IL8, PlGF, and PDGFBB associated with OS, but only pts with low BL Ang-2 levels also demonstrated improved response. High BL levels of FLT3LG and eotaxin associated with longer OS and improved response. In GEP analysis, expression levels of a set of genes including TARBP2, ZNF544, and NF1 (targets identified in phase I and preclinical studies) associated with OS. In gene mut analysis, NRAS mut showed a trend towards longer OS. Pts with NRAS mut along with wt PIK3CA status demonstrated longer OS. Conclusions: Lenvatinib demonstrated limited response in BRAF wt advanced melanoma pts. A subset of pts may derive extended clinical benefit. NRAS mut/PIK3CA wt status and low BL Ang-2 levels appear to associate with improved clinical outcome in this pt population and require further study to assess their predictive value. Clinical trial information: NCT01136967.
Clinical characteristics and survival of BRAF-mutant (BRAF+) metastatic melanoma patients (pts) treated with BRAF inhibitor (BRAFi) dabrafenib or vemurafenib beyond disease progression (PD).
Authors: Chan Matthew , Haydu Lauren , Menzies Alexander M. , Azer Mary W. F. , Klein Oliver , Guminski Alexander , Kefford Richard , Long Georgina 
Published: March 2020

9062 Background: Accelerated tumor growth has been demonstrated on BRAFi cessation in BRAFi-resistant melanoma cell lines. In BRAFi-treated pts initial response rates are high but most have PD at 6+ months. The benefit of ongoing BRAFi after PD is unknown. We sought to describe the characteristics of pts treated beyond progression (TBP) vs those not TBP, and whether TBP prolongs survival. Methods: Clinicopathologic data were collected on 112 pts enrolled in phase I-IV clinical trials at Westmead Hospital and Melanoma Institute Australia from July 2009 to Sept 2012 with unresectable stage IIIC or IV BRAF+ melanoma treated with single agent dabrafenib or vemurafenib. TBP was defined as ongoing BRAFi >28 days beyond RECIST PD. Pt and disease characteristics at baseline and at PD were examined, as well as survival data. Results: 92/112 (82%) pts had RECIST PD. 36/92 (39%) pts were TBP (mean 144 days, median 93 days, range 29–572 days). Pts TBP were significantly more likely to have achieved a RECIST response (CR/PR) prior to PD, have a lower ECOG at PD, presence of brain metastases at PD, have PD treated locally and a smaller RECIST sum of diameters (SoD) at PD, compared with those not TBP (all p<0.05). Median OS from commencement of BRAFi in those TBP was longer than those not TBP (15.0 vs 6.5 months, p<0.001), as was OS from RECIST PD (7.4 vs 1.9 mo, p=0.001). In multivariate analysis of all pts, TBP improved OS from RECIST PD (HR 0.32, p=0.012) even after adjusting for other potential prognostic factors at PD (see table). Within the TBP cohort, RECIST SoD at PD was the only factor that influenced OS from PD (p=0.009), and presence of brain metastases did not. Conclusions: Treatment with BRAFi may be continued after RECIST PD in selected pts, and is associated with a prolonged OS compared with ceasing treatment at PD. [Table: see text]
Upstream MAPK pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.
Authors: Goldinger Simone M. , Murer Carla , Stieger Pascale , Dummer Reinhard 
Published: March 2020

9071 Background: The presence of activating BRAF mutations in about 60% of all metastatic melanomas (mM) has led to the development of inhibitors (i) targeting the RAF and MEK kinases. MEK is the downstream effector of BRAF. However, the blockage of the MAPK pathway is limited due to the development of resistance mechanisms. MEK resistance can confer cross-resistance to BRAF inhibition, whereas BRAF resistance is independent from the MAPK pathway. Hence, it seems reasonable to start a MAPK pathway inhibition by a BRAFi. An upstream inhibition beginning the treatment reversed with a MEKi followed by a BRAFi has not yet been clinically explored. Methods: Patients at the Dermatology Department of the University Hospital of Zurich with mM harboring a BRAF mutation formed the study cohort. Patients were divided into a group who was treated initially with a BRAFi (vemurafenib or LGX818) followed by a MEKi (AZD6244, trametinib, or MEK 162), and a group who first received a MEKi and was later treated with a BRAFi. Duration of disease control (DDC) was measured in time from the initiation of the treatment to discontinuation due to disease progression or toxicity. Results: A total of 16 patients (7 females, 9 males, age 30-73 years) with BRAF mutated mM were evaluated. The median DDC (mDDC) was similar in both groups. When patients were treated first with a BRAFi (n=7), the mDDC for BRAFi was 7.6 and for MEKi 1.7 months, respectively. In contrast, when the treatment sequence was inversed (n=9), the mDDC for MEKi was 3.9 and for BRAFi 4.7 months. We observed some benefit (partial response, stable disease) using chemotherapy after BRAFi/MEKi progression. Conclusions: This analysis indicates that the sequential MEK-RAF inhibition of the MAPK pathway is acceptable in BRAF mutant mM patients. The sum of the DDC of both groups (9.3 and 8.6 months) is comparable to the promising BRAFi/MEKi combination therapy (median PFS 9.4 months). Besides the sequenced administration analyzed here, an intermittent administration should be further studied.
Thrombocytopenia associated with ipilimumab therapy of advanced melanoma at a single institution.
Authors: Sajjad Monique Z. , George Timothy , Weber Jeffrey S. , Sokol Lubomir 
Published: March 2020

9072 Background: Ipilimumab (IPi) is a monoclonal IgG1κ antibody targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) that was approved for the treatment of metastatic melanoma (MM). IPi therapy is associated with immune-related adverse events (irAEs) (Weber et al. J Clin Oncol2012 Jul 20;30(21):2691-7). Hematologic toxicity has rarely been reported. Methods: We analyzed 172 pts with MM treated adjuvantly or for metastatic disease with IPi on 2 clinical studies and an expanded access program (protocols MCC15283, MCC15722 and MCC15977). Clinical characteristics and hematologic parameters related to therapy were recorded. Medications, infections, comorbidities, prior therapies, and pathology reports from bone marrow (BM) biopsies were reviewed. Results: Of 172 subjects, 10 (5.8%) pts with normal platelet counts prior to therapy, developed thrombocytopenia (TCP) following IPi. Median number of doses was 8.5 (range 1-19). Median age at development of TCP was 64 years (range 21-93). Median time to development of TCP was 16.5 months (range 0.25 – 39). Of ten pts, three developed grade (gr) 1 or 2 TCP, three developed gr 3 and four pts developed gr 4 thrombocytopenia. BM analysis in pts with gr 4 TCP showed normal hematopoiesis and no evidence of melanoma. Six of 10 (60%) pts required therapy and were initiated on prednisone, but were deemed steroid refractory. No sustained responses to subsequent treatments with IVIG, rituximab, danazol, and/or splenectomy were observed. Three pts with grade 4 TCP were treated with eltrombopag. One of them achieved a sustained complete response lasting > 20 months. The other 2 pts who received eltrombopag discontinued treatment due to vascular events. Three out of 10 (30%) pts with any gr of TCP experienced mild bleeding episodes in the form of epistaxis. One pt with gr 4 thrombocytopenia experienced severe gastrointestinal bleeding requiring hospitalization. No deaths related to bleeding occurred. Conclusions: This is the first case series of hematologic irAEs in pts treated with IPi on clinical trials, suggesting that steroid refractory TCP may occur with IPi treatment . The timing and severity of IPi associated TCP is highly variable so careful hematologic monitoring should be considered.
Relevance of MIA and S-100 to monitor BRAF inhibitor (iBRAF) therapy in metastatic melanoma patients.
Authors: Sanmamed Miguel F. , Fernandez-Landazuri Sara , Castanon Eduardo , Echeveste Jose , Lozano Maria D. , Idoate Miguel A. , Perez-Gracia Jose Luis , Gonzalez Alvaro , Martin-Algarra Salvador 
Published: March 2020

9074 Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA=9 ug/L, S-100=0.1 ug/L, and LDH=290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p<0.05), while the frequency of elevated S-100 and LDH was similar. Among patients treated with iBRAF, the response rate was 87.5% (5 CR, 9PR). In responding patients, MIA and S100 levels decreased dramatically, but not LDH (Table). At the time of this report, thirteen patients have progressed. Upon progression, MIA and S-100 increased significantly above levels achieved at best response (Table). Conclusions: Serum MIA and S-100 are potentially useful markers in the clinical and follow-up management of patients receiving iBRAF therapy. Validation in a larger series is needed. [Table: see text]
A phase I study of the combination of sorafenib (Sor) and bortezomib (Bor) in patients (pts) with metastatic melanoma (MM).
Authors: Sullivan Ryan J. , Ibrahim Nageatte , Lawrence Donald P. , Aldridge Julie , Hodi F. Stephen , Flaherty Keith , Conley Christine , DeNoble Sarah , Mier James Walter , Cho Daniel C. , Atkins Michael B. , McDermott David F. 
Published: March 2020

9076 Background: Sor is a small molecule tyrosine kinase inhibitor that has many targets and previously was developed for the treatment of MM. Bor is a proteasome inhibitor widely used to treat multiple myeloma and other malignancies. In preclinical studies, the combination of Sor and Bor has been shown to modulate expression of BCL-family members and augment cytotoxicity in MM cell lines. Methods: Pts with MM were enrolled in cohorts of 3 during dose escalation to determine the maximum tolerated dose (MTD) of Sor twice daily (BID) in combination with Bor given days 1, 8, 15 of a 28 day cycle. The MTD was defined as the highest dose level at which less than 33% of pts exhibited a dose limiting toxicity (DLT). Efficacy, as measured by 6-month progression free survival (PFS) and response rate (RR) per RECIST, was documented. Results: Eleven pts were enrolled in 3 dose levels. DLTs (fatigue and rash respectively) were seen in 2 of 3 patients enrolled at the highest dose level (Sor 400 mg and Bor 1.3 mg/m2). The next lowest dose level (Sor 400 BID and Bor 1.0) enrolled 5 pts and none had DLTs. Thus, this dose level was defined as the MTD. Toxicities seen in >20% of pts included hypertension, pruritus, hand-foot syndrome, mucositis, nausea, vomiting, rash, constipation, abdominal pain, anorexia and fatigue. Of 9 response evaluable pts, none had radiographic evidence of tumor response. Two of 11 (18%) pts remained progression free for greater than 6 months. Conclusions: The combination of Sor and Bor is safe, but minimally active in pts with MM. In the absence of tumor response at or above the MTD, the study was closed with only 5 pts treated at the provisional MTD and enrollment to a planned dose expansion cohort will not occur. Clinical trial information: NCT01078961.
Melanoma recurrence risk stratification using Bayesian systems biology modeling.
Authors: Styrmisdottir Edda Lind , Scanlon Patrick , Hanniford Douglas , Eberhardt John , Jones Thomas , Hernando Eva , Osman Iman 
Published: March 2020

9089 Background: Estimating the risk of recurrence in patients with melanoma is extremely challenging. Standard of care is AJCC staging system, but the accuracy and robustness of this method is still under development. We conducted a proof of concept study exploring the use of machine-learned Bayesian Belief Networks (ml-BBNs) using a miRNA profiled cohort of melanoma patients with extended follow up to create Bayesian Biological Systems Models (BBSMs). We sought to determine if ml-BBNs could describe the biological system and if we could use the model to identify new cases with higher risk of recurrence. Methods: Our study cohort consisted of 89 patients (42 of which recurred) with a median follow up time of 118 months, that were examined for 869 miRNAs. Prior to modeling we segmented the data into training data (72 cases/80%) and testing data (17 cases/20%) at random. We recursively trained ml-BBNs on the training set, using all miRNAs. We used the directed graph structure of the ml-BBNs to identify miRNAs that consistently had more connectivity and goodness of fit as determined by Bayesian Information Criteria (BIC) scoring. MiRNAs that were in the top 50 BIC-scoring nodes across all models were selected for use to train the recurrence BBSMs. To compensate for a small number, bootstrapping was used to increase the sample to 100 records. We then compared our test set cases to our recurrence model, and used a similarity scoring algorithm to evaluate the similarity of values in each test instance to our biological models. For comparison we also trained an ml-BBN using clinical data from the same cohort. We then evaluated the scores against known recurrence outcome using Receiver Operating Characteristic (ROC) curve analysis. Results: BIC-scoring analysis selected 35 miRNAs for use in BBSM modeling. Area Under the Curve (AUC) for detection of recurrence is 0.76 in the training set and 0.62 in the testing set, while the clinical data yielded an AUC of 0.5 in this cohort. Conclusions: Our data suggest that ml-BBNs can be used to describe a biological model of melanoma recurrence. Additional data and refinement need to be made using independent datasets to be of a level that is clinically useful.
Relationship of bleeding to pathologic ulceration in a primary melanoma lesion.
Authors: Kang Paul T , Baker Amy Louise , Warneke James , Curiel Clara N , Jeter Joanne M. , Hersh Evan , Cranmer Lee D. 
Published: March 2020

9102 Background: Lesion bleeding (BL) is a catalyst symptom leading to melanoma (MEL) diagnosis and is associated with adverse outcomes. The pathophysiologic significance of BL has not been elucidated. We hypothesize that BL reflects pathologic ulceration (UL). Methods: This retrospective cohort study was conducted using data from 850 patients seen 2005-2009 at our center. Eligible patients reported the pre-diagnosis BL status of their primary lesion; determination of its UL status was also required. Demographic, clinical, pathologic and outcomes data were abstracted from records. Χ2 and independent t-tests were used for univariate comparisons. Predictors of UL were analyzed with multiple logistic regression. Survival indices were analyzed by the Kaplan-Meier, log-rank, and Cox proportional hazards. Results: 190 patients with 193 MEL lesions were eligible. Median follow-up was 5.3 yr. 67 lesions bled prior to diagnosis; 68 demonstrated UL. BL and UL were associated with each other and with Breslow depth in univariate analyses; UL was also associated with age at diagnosis. Neither was associated with gender, lesion site, use of BL-associated drugs or Clark’s level. A logistic model was developed using BL, gender, lesion site, use of BL-associated drugs, and age at diagnosis. Only BL and age at diagnosis were associated with UL probability (OR=10.6/p<0.001 and OR=1.04/p=0.006, respectively). BL was associated with worsened median relapse-free (RFS) and overall survival (OS) (median 1.16y vs. 1.96y, p=0.001 and 3.06 y vs. 3.41y, p=0.001), as was ulceration. When status of BL and UL were considered together, only UL predicted outcomes. A Cox model of clinical factors (BL, gender, age at diagnosis, lesion site) confirmed the association of BL with RFS and OS (HR 1.82/p=0.006 and HR 2.36/p=0.001). Addition of UL to the model abrogated BL’s predictive value. Conclusions: BL of primary MEL lesions is strongly associated with pathologic UL. When clinical parameters are considered, BL significantly predicts RFS and OS, although this value is lost once UL status is known. Our data are consistent with BL’s reflecting the ulceration status of a primary lesion. When UL status is unknown, BL may be able to serve as its surrogate marker.