bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictable early onset high-dose-glucocorticoid-associated-irAE and its predictive role in anti-PD-1 monotherapy treated advanced melanoma patients.
Authors: Bai Xue , Kim Michelle S. , Kasumova Gyulnara , Chen Tianqi , Cohen Justine Vanessa , Lawrence Donald P. , Freedman Christine , Fadden Riley , Rubin Krista M. , Sharova Tatyana , Frederick Dennie T. , Flaherty Keith , Sullivan Ryan J. , Boland Genevieve Marie 
Published: May 2019

9544 Background: Though uncommon, a subgroup of patients with melanoma develop early-onset severe immune-related adverse effects (irAEs) that require immunosuppressive treatment with high-dose glucocorticoids (HD-GCCs). We aimed to examine the impact of early onset HD-GCC-associated-irAE (EO-HGA-irAE) in the setting of anti-PD-1 monotherapy initiation on prognosis and to develop a predictive scoring system. Methods: Clinical data was collected retrospectively from advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital from Sept 2009 to Dec 2017. The relationship between EO-HGA-irAE and PFS (defined as time from anti-PD-1 monotherapy initiation to PD) was assessed using 8-week conditional landmark analysis (Kaplan-Meier curves, log-rank test) and time-dependent COX regression model (multivariate analysis). Demographic characteristics and baseline routine laboratory variables were collected and correlated with occurrence of EO-HGA-irAE using logistic regression modeling. Best cutoff values were identified using ROC curve (Youden index) to dichotomize continuous variables. Results: Among 146 patients, 13 (8.9%) developed EO-HGA-irAE. In 8-week landmark analysis, median PFS was 2.9 (95% CI, 2.8-3.0) and 17.5 (95% CI, 10.8-24.2) months (P = .001) for patients with and without EO-HGA-irAE, respectively. Multivariate analysis revealed that EO-HGA-irAE was independently correlated with significantly higher risk of disease progression with hazard ratio of 2.4 (95% CI 1.4-4.0) (P = .001). Potential predictive variables (P < .25 for continuous variables, P < .1 for dichotomous variables) in favor of the occurrence of EO-HGA-irAE included age, baseline glucose, and neutrophil, eosinophil, and WBC count. After dichotomization and further validation using a logistic regression model, a scoring system (score range 0-3) composed of 3 dichotomized predictors, including age, baseline glucose, and baseline neutrophil count was developed with odds ratio of 3.4 (95% CI, 1.6-8.8) (P = .001). The probabilities of patients scoring 0,1,2,3 of developing EO-HGA-irAE were 1.1%, 3.5%, 11.1%, and 29.9%, respectively. Conclusions: Development of EO-HGA-irAE is correlated with shorter PFS in advanced melanoma patients treated with anti-PD-1 monotherapy. A scoring system based on age and simple, easily accessible, routinely tested biomarkers can be used to help predict the risk of EO-HGA-irAE occurrence. Validation with a larger sample size is required.
Phase I-II open label multicenter study of PD0332991 in BRAFV600mut metastatic melanoma patients harboring CDKN2A loss and RB1 expression and treated with vemurafenib.
Authors: Louveau Baptiste , Resche-Rigon Matthieu , Lesimple Thierry , Pracht Marc , Baroudjian Barouyr , Delyon Julie , Jouenne Fanelie , Amini-Adle Mona , Dutriaux Caroline , Da Meda Laetitia , Ghrieb Zineb , Bouton Didier , Tibi Annick , Huguet Samuel , Rezai Keyvan , Battistella Maxime , Mourah Samia , Lebbe Celeste 
Published: May 2019

9545 Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAFV600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.
Phase II trial (BCD-100-2/MIRACULUM) of the novel PD-1 inhibitor (BCD-100) in patients with advanced melanoma.
Authors: Fogt Sergey , Shustova Mariia , Demidov Lev V. , Moiseyenko Vladimir , Tjulandin Sergei , Semiglazova Tatiana , Protsenko Svetlana , Odintsova Svetlana , Zukov Ruslan , Lazarev Sergey , Makarova Yuliya , Nechaeva Marina , Sakaeva Dina , Andreev Aleksey , Tarasova Anna , Fadeeva Natalia , Gavrilova Olesya , Ivanov Roman 
Published: May 2019

9549 Background: MIRACULUM (NCT03269565) is a multicenter open-label parallel-arm phase II study investigating the antitumor activity of BCD-100, an IgG1 anti-PD-1 monoclonal antibody with Fc silencing “LALA” mutation, in patients with advanced melanoma. Interim analysis at 6-months is presented. Methods: Patients (pts) with unresectable or metastatic melanoma, without autoimmune disease, and no prior anti-PD-1 or anti-CTLA-4 therapy were eligible. Pts received BCD-100 1 mg/kg Q2W (arm 1) or BCD-100 3 mg/kg Q3W (arm 2) until disease progression or intolerable toxicity. Primary endpoint was ORR assessed per irRECIST by independent central radiology review. A statistical hypothesis that BCD-100 has significant anti-tumor effect (ORR more than 28% in per protocol population) was tested for each study arm with alpha 0.05 and 80% power. Results: 126 pts were treated and 114 were evaluable for the primary endpoint (9 pts dropped out before their first efficacy assessment and 3 pts had major protocol deviations). In arm 1 and arm 2, 17 (27%) and 16 (25%) pts received prior treatment for advanced disease, respectively. The study met its primary endpoint in both study arms. In arm 1, 34% ORR was achieved among 59 response-evaluable patients, including 4 CR and 16 PR, and the disease control rate (DCR) was 68%. In arm 2, 29% ORR was achieved among 55 response-evaluable pts, including 2 CR and 14 PR, and the DCR was 55%. All responses were durable; only one patient in arm 1 presented disease progression, and median PFS and OS were not reached in either study arms at 6 months follow-up. Treatment-related AEs (TRAEs) occurred in 48% of pts in each study arm, including 6% and 5% with grade 3/4 TRAEs in arm 1 and 2, respectively. Immune-related AEs (irAEs) occurred in 29% of pts in arm 1 and 30% of pts in arm 2, including 3% of pts with grade 3/4 irAEs in each arm. Conclusions: Both dosing regimens of BCD-100 (1 mg/kg Q2W and 3 mg/kg Q3W) have durable antitumor activity and a manageable safety profile in patients with advanced melanoma. Clinical trial information: NCT03269565.
Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced/metastatic melanoma resistant to anti-PD-1/PD-L1 therapy.
Authors: Amin Asim , Milhem Mohammed M. , Long Georgina V. , Hoimes Christopher J. , Medina Theresa Michelle , Conry Robert Martin , Lao Christopher D. , Daniels Gregory A. , Reddy Sunil A. , Andtbacka Robert Hans Ingemar , Barve Minal A. , Shaheen Montaser F. , Tueting Thomas , Chisamore Michael Jon , Schmidt Emmett V. , Candia Albert , Obiozor Cynthia Chinedu , Gamelin Erick , Janssen Robert , Ribas Antoni 
Published: May 2019

9555 Background: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in melanoma. SYNERGY-001/KEYNOTE-184 study assesses the safety and preliminary efficacy of the combination of intratumoral SD-101 and intravenous pembrolizumab in PD1/PDL 1 resistant unresectable stage IIIC- IV melanoma. A prior phase 2 study with SD-101 at 8 mg per injection resulted in a 21.4% ORR in this population (Abstract 3781, ESMO 2018). We report preliminary data in this ongoing phase 2 trial evaluating efficacy at a lower SD-101 dose of 2 mg per injection. Methods: PD1/PDL 1 resistant melanoma patients received 2 mg of SD-101 intratumorally per lesion in 1-4 lesions (weekly x 4 doses followed by Q3W x 7). Pembrolizumab was administered at a dose of 200 mg intravenously Q3W. Scans were performed Q9W. Responses were assessed per RECIST v1.1. Results: 23 patients have been enrolled with baseline characteristics: median age 65 years; male: 77%; stage at screening: IIIC = 26%; IV = 57%, unknown = 17%; LDH > ULN: 36%. Lines of prior therapy: 1: 52%; 2: 22%; > 2: 26%. Prior anti CTL-A4 therapy: 39%. Best overall response on prior antiPD-1/PD-L1: PD: 88%, PR/CR: 8%, SD: 4%. Safety: Grade ≥3 treatment-related AEs: pneumonia and constipation (8%). No immune-related AEs reported. 2 non-treatment related SAEs reported from 2 patients: pneumonia and intussusception. 4 patients discontinued treatment early: 1 post SAE, per patient’s request, 3 due to PD. 1 patient died due to malignant pleural effusion after 1 dose of SD 101 and Pembrolizumab. No treatment related deaths. Efficacy: Mean duration on treatment: 39 days (1 - 169). mITT population: six patients at time of first CT scan at day 64: PR: 1, SD: 1, PD:3; non-evaluable: 1. 17 patients on study have not yet had first CT scan. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab is well tolerated. Mature efficacy data, with additional first and second follow-up CT scans, will be presented at the meeting. Clinical trial information: NCT02521870.
The relationship between obesity and immunotherapy: It's complicated.
Authors: Donnelly Douglas MacArthur , Bajaj Shirin , Zhong Judy , Weber Jeffrey S. , Pavlick Anna C. , Balar Arjun Vasant , Hsu Miles , Osman Iman 
Published: May 2019

9562 Background: Obesity is a poor prognostic factor in primary melanoma, and preclinical data has linked it to an immunosuppressive phenotype. Paradoxically, recent reports suggest that obesity may confer a survival benefit in patients with metastatic melanoma (MM) who received immune checkpoint inhibition (ICI). Herein we tested the hypothesis that the relationship between body mass index (BMI) and response to ICI depends on type of ICI and tumor type. Methods: We examined 2 cohorts (MM patients [n = 423] and metastatic bladder cancer [MBC] patients [n = 42]). We tested the associations between BMI and PFS, stratified by first vs. second or greater-line of treatment and treatment type (anti-CTLA4, anti-PD1, combination therapy), adjusting for age, gender, stage, LDH level, ECOG status, number of metastatic sites, and BMI classification changes in the MM cohort. Results: We observed a moderate but insignificant association between being overweight (BMI 25.0-29.9 kg/m2) or obese (BMI > 30kg/m2) and better PFS in patients who received first line ICI therapy (aHR 0·77 [95% CI 0·50-1·20]), and an association with worse PFS in patients who received non-first line ICI therapy (aHR 1.31 [0·74-2.33], P interaction = 0.11). Overweight and obese patients receiving combination ICI had a statistically significant survival benefit (aHR 0.27 [0·10-0.70]), p = 0.007), whereas patients receiving the other treatment types showed heterogeneous trends (P interaction = .005). In the MBC cohort, being overweight conferred the greatest PFS benefit, followed by normal BMI, with obesity being associated with the worst PFS (p = 0.035). Conclusions: Stratifying by clinical features including treatment type, treatment line, and tumor type demonstrated vastly different results and reversal of trends, which underpins the complexity of the relationship between BMI and response to ICI. The lack of consistency amongst our data and published reports highlights the need for a thorough investigation, on a significantly larger scale, to truly elucidate obesity's impact on clinical outcomes in cancer. The scientific community must consider this complexity as well as the known detrimental health effects of obesity when counseling patients.
Molecular profiling of melanoma brain metastases (MBM) compared to primary cutaneous melanoma (CM).
Authors: In Gino Kim , Poorman Kelsey Anne , Saul Michelle , O'Day Steven , Farma Jeffrey M. , Daveluy Steven , Olszanski Anthony J. , Gordon Michael S. , Thomas Jacob Stephen , Eisenberg Burton Larry , Flaherty Lawrence E. , Gibney Geoffrey Thomas , Atkins Michael B. , Vanderwalde Ari M. 
Published: May 2019

9565 Background: Nearly 50% of metastatic melanoma patients develop brain metastases, warranting further investigation into the biology of this event. Methods: We analyzed 132 MBM and 745 CM submitted to Caris Life Sciences from 2015-2018, using next generation sequencing of a 44 or 592 cancer-related gene panel, tumor mutational burden (TMB), and PD-L1 expression by IHC. Genomic alterations (GA), including somatic mutations or CNA, were reported. High TMB (TMB-H) was defined as ≥17 mut/Mb. Comparison of molecular profiles, including cancer-related genes and recurrently altered pathways, between tumor sites and by genomic subgroup (BRAF, NRAS, KIT, NF1), was performed using Fisher’s exact test. Results: Among 132 MBM, 72.7% were male, with median age 62 yo (range 25-83). The most common GAs among MBM were: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Compared to CM, MBM were more often TMB-H (53.7% v 38%, p = .025), with higher PD-L1 expression, using both a ≥1% (54.4% v 35.6%, p = .002) and ≥5% cut-off (32.9% v 15.9%, p = .0006). MBM showed higher rates of GAs among: SETD2 (11.9% v 1.9%, p = .0008), BRAF (52.4% v 35.6%, p = .017), PBRM1 (7.5% v 1.6%, p = .018), KRAS (4% v 1%, p = .026), CCND1 (2.9% v 0%, p = .03), and DICER1 (4.4% v 0.6%, p = .04), compared to CM. Alterations of the MAPK (87.9% v 77.8%, p = .015) and SWI/SNF (22.1% v 11.6%, p = .036) pathway were more frequent in MBM, than CM. When analyzed by genomic subgroup, BRAF+ MBM had more GAs involving the PI3K pathway (20% v 5.1%, p = .027), compared to BRAF WT MBM. NRAS+ MBM had higher PD-L1 expression at the ≥1% cutoff (66.7% v 38.6%, p = .05), but not ≥5%, compared to NRAS WT MBM. NF1+ MBM had more GAs involving the SWI/SNF (60% v 11.6%, p = .003) pathway, as opposed to NF1 WT MBM. No significant associations were seen between KIT status, TMB, PD-L1 or other pathways among MBM. Conclusions: In this cross-sectional study, MBM demonstrated higher PD-L1 expression and were more often TMB-H, compared to CM. MBM also featured more GAs involving BRAF and the MAPK pathway. We identified two novel genes, PBRM1 and SETD2, as well as recurrent alterations of the SWI/SNF pathway, supporting future studies of chromatin remodeling pathways in MBM.
Quality of life (QoL) and symptom burden in patients (pts) with advanced melanoma during the treatment-free interval (TFI) after discontinuation of nivolumab (NIVO) or NIVO plus ipilimumab (IPI).
Authors: Taylor Fiona , Regan Meredith M. , Schadendorf Dirk , Atkins Michael B. , Lawrance Rachael , Moreno-Koehler Alejandro , Moshyk Andriy , Rao Sumati , Ritchings Corey , KOTAPATI SRIVIDYA , Lord-Bessen Jennifer , Rizzo Jasmine I. , McDermott David F. , Middleton Mark R. 
Published: May 2019

9568 Background: The TFI after discontinuation of study therapy has been reported to be longer with NIVO+IPI compared to NIVO or IPI alone, but QoL during the TFI has not been reported in advanced melanoma (MEL) studies. 1-y data from CheckMate (CM) 067 showed maintenance of QoL after treatment (tx) discontinuation with NIVO or NIVO+IPI. Here, we present long-term QoL results from CM 067 during the TFI (period off study tx and free of subsequent therapy), based on an updated 4-y dataset. Methods: In CM 067, 945 pts were randomized 1:1:1 to receive NIVO 3 mg/kg + placebo; NIVO 1 mg/kg + IPI 3 mg/kg × 4, then NIVO 3 mg/kg; or IPI 3 mg/kg × 4 + placebo. Patient-reported outcomes (PRO) were collected using the EORTC QLQ-C30 (5 functional domains, 9 symptoms, global health status) and EQ-5D-3L (utility index, visual analog scale) at baseline, on-tx visits, and follow-up (FU) visits 1 (FU1; 30 d after last dose) and 2 (FU2; 84 d after FU1). EQ-5D-3L was also collected at survival FU visits every 3 mo after FU2 in the first year and every 6 mo thereafter. Within the PRO analysis population, 480 of 764 pts who discontinued protocol tx (for any reason, including drug toxicity; n = 155) had PRO scores, collected prior to initiation of subsequent anticancer therapy, evaluated. Mean changes in PRO scores from last on-tx visit were reported for each FU visit. Results: Across tx arms, PRO scores were maintained from last on-tx visit to FU1 or FU2 for pts who discontinued for any reason. EORTC QLQ-C30 functional and symptom scales remained stable during the TFI. Among pts who discontinued tx due to toxicity, clinically meaningful deterioration in QoL was observed in a few subscales at FU1, but QoL was restored to the same level as the last on-tx visit in all except one subscale by FU2. PRO scores remained stable beyond FU2 for the EQ-5D-3L, regardless of reason for discontinuation. Data interpretation at later FU visits was limited due to smaller sample sizes. Sensitivity analyses for mean change in PRO scores from randomization to FU visits will be presented. Conclusions: QoL was maintained during the TFI, compared to last on-tx visit, in pts with MEL treated with NIVO or NIVO+IPI.
Association of baseline neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.
Authors: Hemadri Amit , Lin Huang , Lin Yan , Rose Amy , Sander Cindy , Najjar Yana , Zarour Hassane M. , Kirkwood John M. , Davar Diwakar 
Published: May 2019

9571 Background: Inflammation is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR) is an easily derived biomarker of systemic inflammation. Several studies have demonstrated that elevated NLR is linked with adverse prognosis in patients (pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the prognostic utility of NLR, we performed a retrospective evaluation of NLR and other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Baseline NLR was defined based on values at the first treatment date. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mos). Results: 172 pts with advanced MEL were evaluated. Elevated NLR was associated with poorer PFS and OS and ORR at all cutoffs (NLR≥2 to NLR≥5) with NLR≥5 having the greatest discriminative value. ORR steadily declined with increasing NLR: NLR≥1 (ORR 64%), NLR≥2 (ORR 61%), NLR≥3 (ORR 52%), NLR≥4 (ORR 43%), NLR≥5 (ORR 43%). Elevated NLR ( < 5 vs. ≥5) was associated with poorer PFS (median 21.5 mths vs. 5.2 mos; p = 0.00041) and OS (median 35.4 os vs. 10.6 mos; p < 0.0001). In a multivariate model, elevated NLR ( < 5 vs. ≥5) was independently associated with poorer OS/PFS separate from ulceration, performance status and elevated LDH. There was no evidence of an age-related increase or decrease in NLR. Conclusions: Baseline NLR was independently associated with response, PFS and OS in the largest retrospective series of advanced MEL pts treated with PD-1 blockade. NLR independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR≥3 to NLR≥5), although NLR≥5 segregated pts best. NLR is an inexpensive and easily obtained real-world biomarker that has a high value in predicting outcomes to PD-1 blockade.
Association of medication (Med) and antibiotic (Abx) use with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.
Authors: Hemadri Amit , Lin Huang , Lin Yan , Rose Amy , Sander Cindy , Najjar Yana , Zarour Hassane M. , Kirkwood John M. , Davar Diwakar 
Published: May 2019

9572 Background: Retrospective studies suggest that various med could dichotomous effects in regards to immunotherapy. These include adverse (antibiotics) and positive (aspirin, beta-blockers) influences. To evaluate potential additive or detrimental effects of various med in patients (pts) receiving PD-1 immunotherapy, we performed a retrospective evaluation of med intake in 172 pts with stage IV cutaneous MEL focusing on aspirin (asp), antacid (ant), antibiotic (abx), bisphosphonate (bisp), metformin (met) and statin (stat) intake. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Med intake was documented based on chart review in all pts. Intake was confirmed by analyzing at least one other note from a non-oncological provider. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how categorical variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mths). Results: 172 pts with advanced MEL were evaluated. Asp, ant, abx, bisp, met and stat use was documented in 62, 82, 29, 4, 15 and 57 pts respectively. ORR was not significantly related to intake of asp, ant, bisp, met and stat use; although ORR was lower in pts who received abx (p=0.0328). There was no significant difference in PFS and OS in pts who received asp, ant, bisp, met and stat. In patients who received abx compared to those who did not, median PFS (16.6 mths vs. 19.8 mths) and median OS (23.8 mths vs. 35.4) were both lower. Abx use did not interact with other meds. Conclusions: In this retrospective series of advanced MEL pts treated with PD-1 blockade, abx use was adversely associated with response to PD-1 blockade. Abx use was also associated with poorer PFS and OS. Conversely, neither a positive nor negative association with ORR, PFS and/or OS was seen with asp, ant, bisp, met and stat use. These results validate prior studies suggesting that abx use is associated with worse outcomes in pts receiving PD-1 blockade possibly by mediating intestinal dysbiosis.