bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time to first-line (1L) therapy discontinuation in metastatic melanoma (MM).
Authors: Luke Jason J. , Ghate Sameer , Ionescu-Ittu Raluca , Ndife Briana , Burne Rebecca , Laliberté François , Duh Mei Sheng 
Published: February 2018

196 Background: Nivolumab or pembrolizumab monotherapy (N/P) and dabrafenib+trametinib combination therapy (D+T) are currently the most commonly used regimens for the treatment of MM in anti-PD1 and BRAF inhibitor classes, respectively. We describe time to discontinuation of 1L therapy with N/P or D+T in patients (pts) with MM in a real-world setting. Methods: Adults with MM initiated on N/P or D+T in 1L were identified in Truven MarketScan databases (Q1/2014 - Q2/2016; n = 443). Outcomes included (a) distribution of time to 1L discontinuation among pts who discontinued 1L therapy during the study follow-up (reported by year of 1L start) and (b) rates of pts still on 1L therapy at different time points after 1L therapy start ("on treatment" rates) estimated from Kaplan-Meier analyses. Results: Of 443 pts, 243 (55%) were initiated on N/P and 200 (45%) on D+T. Pts initiated on D+T appeared to be younger, with more brain metastases, and higher use of emergency care in the 6 mo prior to 1L therapy start as compared to those initiated on N/P (Table). Time to 1L discontinuation and "on treatment" rates were similar between the treatment groups, with a tendency towards longer time to 1L discontinuation for D+T (Table). Conclusions: This real-world data study showed numerically longer time to 1L discontinuation for pts treated with D+T as compared to N/P, despite higher comorbidity burden. [Table: see text]
Real world treatment patterns of first-line combination therapies among BRAF+ metastatic melanoma patients.
Authors: Ghate Sameer , Tang Jackson , Li Zhiyi , Nakasato Antonio Reis 
Published: February 2018

197 Background: For patients (pts) with metastatic melanoma (MM) and BRAF V600 mutation (BRAF+), options for first-line (1L) systemic combination therapy include immunotherapy (IO) or targeted therapy (TT). This study describes real world treatment patterns among BRAF+ MM pts treated with 1L ipilimumab+nivolumab (I+N) or dabrafenib+trametinib (D+T). Methods: This retrospective observational analysis used Flatiron Health’s electronic health record-derived database from Oct 2015 - Jul 2016. Oct 2015 was chosen as the start date as both combo use of I+N and D+T had been approved by the FDA. Pts were aged ≥18 years with a MM diagnosis, tested BRAF+ prior to therapy, and treated with either I+N or D+T as 1L therapy. Baseline demographic and clinical characteristics, and treatment patterns were collected from structured data and unstructured data in physician notes, and were descriptively assessed. Kaplan-Meier (KM) analysis measured time to discontinuation. Statistical inferences were not planned in this study. Results: Among 76 BRAF+ pts, 62% (47) were treated with D+T as 1L, and 38% (29) were treated with I+N as 1L. Compared to D+T pts, lower proportion of I+N pts had a history of brain metastases (31% vs. 34%) and elevated ( > 333 IU/L) lactate dehydrogenase (10% vs. 19%), while a higher proportion of I+N pts reported ECOG performance status score of zero (38% vs. 23%). The two cohorts were similar in age, gender and baseline comorbidities. Discontinuation among D+T and I+N was 43% (20) and 48% (14) respectively. The primary reason for discontinuation was progression among D+T pts (10/20) vs. toxic effects of therapy among I+N pts (8/14). KM median time to discontinuation was 213 days for D+T pts vs. 196 days for I+N pts. 55% of I+N pts did not complete full induction of 4 doses of ipilimumab, citing toxic effects of therapy. Conclusions: 1L D+T patients had higher tumor burden, elevated LDH levels, and higher ECOG performance status score, but lower discontinuation rate and longer time to treatment discontinuation relative to BRAF+ 1L I+N pts.
Immune checkpoint inhibitor responses in KIT-mutated metastatic melanoma.
Authors: McKean Meredith Ann , Oba Junna , Ma Junsheng , Haydu Lauren Elaine , Bassett Roland L. , Woodman Scott Eric 
Published: February 2018

199 Background: KIT-mutated MM is a rare melanoma entity. Response rates of KIT-mutated MM to anti CTLA-4 and anti PD-1 have not previously been reported. Methods: A single-institution retrospective review identified patients (pts) with KIT-mutated MM treated with at least two doses of anti CTLA-4 or anti PD-1 between 2008-2017 with response determined by immune-related response criteria (irRC). Overall survival (OS) was from ICI start to death or last follow-up date, and progression-free-survival (PFS) was from ICI start to date of progression or death if pts deceased without disease progression. Results: Thirty-five pts treated with ipilimumab were identified. Median follow-up was 63.7 months. Median age at MM diagnosis was 65.4 years (range 26-81) and 54.3% were male. Subtypes were 51.4% mucosal, 22.9% acral-lentiginous, 22.9% cutaneous, and 2.9% unknown primary. KIT mutations were 57.1% exon 11, 25.7% exon 17, 11.4% exon 13, and 5.7% exon 2. Anatomical M stage at treatment initiation was 11.4% M1a, 34.3% M1b, and 54.3% M1c. Median OS was 11.8 months (8.4-35.6) and PFS was 3.0 months (2.8-5.8). Responses to ipilimumab were 8.6% complete response (CR), 11.4% partial response (PR), 28.6% stable disease (SD), and 51.4% progressive disease (PD) for a 48.6% clinical response rate (CRR). Twenty pts treated with anti PD-1 were identified. Median follow-up was 7.9 months. Median age at MM diagnosis was 66.7 years (range 42.6-86.8) and 70% were male. Subtypes were 40% mucosal, 30% cutaneous, 20% acral-lentiginous, and 10% unknown primary. KIT mutations were 45% exon 11, 35% exon 17, 10% exon 2, 5% exon 13 and and 5% exon 10. Anatomical M stage at treatment initiation was 10% M1a, 15% M1b, and 75% M1c. Median OS was 22.5 months (7.4-NA ) and PFS was 3.2 months (2.7-NA). Responses to anti PD-1 were 10.0% CR, 25.0% PR, 20.0% SD, and 45.0% PD for a 55.0% CRR. For both anti CTLA-4 and anti PD-1 treated cohorts, univariate analysis demonstrated no statistical significance between tumor response to ICI and clinical pt characteristics or KIT mutation exon. Conclusions: KIT-mutated MM demonstrated CRR of 48.6-55.0% to ICI. There was no correlation between pt characteristics or KIT exon mutation and response to therapy; however, analysis was limited by sample size.
Safety and clinical activity of pembrolizumab immunotherapy and multi-organ site ablative stereotactic body radiotherapy (iMOSART) in patients with advanced solid tumors.
Authors: Lemons Jeffrey , Luke Jason J. , Karrison Theodore , Pitroda Sean , Melotek James , Zha Yuanyuan , Al-Hallaq Hania A , Arina Ainhoa , Janisch Linda A. , Chang Paul J , Patel Jyoti D. , Fleming Gini F. , Moroney John William , Sharma Manish , White Julia R. , Ratain Mark J. , Gajewski Thomas , Weichselbaum Ralph R. , Chmura Steven J. 
Published: February 2018

20 Background: Clinical responses to PD1 blockade have been linked to IFN-γ associated gene expression in the tumor microenvironment. Stereotactic body radiotherapy (SBRT) can stimulate innate and adaptive immunity to potentially augment immunotherapy. Anti-PD1 treatment outcomes are improved with lower disease burden and multi-site radiation is an emerging paradigm for eradicating metastatic disease. Methods: We conducted a phase I study for patients with metastatic solid tumors who progressed on standard treatment. The primary aim was to evaluate the safety of pembrolizumab Immunotherapy with Multi-Organ Site Ablative stereotactic body Radiation Therapy (iMOSART). Two to four metastases were chosen for each patient and not all sites of disease were targeted with SBRT. Metastases > 65cc were partially irradiated. Pembrolizumab was initiated within 7 days after the final SBRT treatment. Results: 79 patients were enrolled, three patients did not receive any treatment and three patients only received SBRT. The 73 patients included in the analysis were treated with SBRT and at least 1 cycle of pembrolizumab. 94.5% of patients had two lesions treated with SBRT. Median follow-up for toxicity was 5.5 months (IQR 3.3-8.1). Six patients experienced dose-limiting toxicity (DLT) with no radiation dose reductions. RECIST overall objective response rate was 13.5% in the 68 patients with imaging follow-up. Superior control of irradiated lesions was observed compared to non-irradiated target lesions for the 52 patients with paired data (p = 0·0005) with a mean percent tumor burden change -21·7% (SD 24·3%) for irradiated lesions vs. 1·7% (SD 46·3%) for non-irradiated lesions (p = 0·0008). While abscopal response defined by 30% reduction in any single non-irradiated measurable lesion was present in 26·9% of patients, abscopal response was 13·2% when defined by 30% reduction in aggregate diameter of non-irradiated measurable lesions. Conclusions: iMOSART was well tolerated with acceptable toxicity. Further randomized studies are warranted to investigate the potential clinical benefit of this combination approach. Clinical trial information: NCT02608385.
Association of the neutrophil-to-lymphocyte ratio prior to checkpoint blockade immunotherapy (CBI) or radiation plus CBI with overall survival in melanoma patients.
Authors: Rhodes Terence Duane , Fulde Gail , Romero Robin , Abraham Tyler , Moulton Bryce , Van Meter Margaret , Thota Ramya , Lewis Mark Andrew , Haslem Derrick S. , Nadauld Lincoln , Barker Tyler 
Published: February 2018

200 Background: Studies in certain cancer types have indicated that radiation therapy prior to the use of CBI provides a survival benefit. This benefit has not been clearly defined for patients with metastatic melanoma. Additionally, the neutrophil-to-lymphocyte ratio (NLR) may be a potential biomarker. Methods: This retrospective study was performed in patients diagnosed with melanoma between January 2007 and August 2016 who received CBI with or without previous radiation treatment at Intermountain Healthcare (Utah, USA). Cases were identified from electronic medical records and data was manually extracted through August of 2017. The neutrophil-to-lymphocyte ratio (NLR) was calculated from the absolute neutrophil and lymphocyte counts of a complete blood cell count with differentials performed as a routine standard of care procedure in melanoma patients prior to therapy initiation. Overall survival was defined as the length of time (d) from start of CBI to death as of August, 2017. Results: Forty-six melanoma patients were initially identified. Of these, thirteen patients were excluded due to lack of follow-up data (n = 9), radiation performed after CBI (n = 3), or concurrent radiation and CBI (n = 1). The final analysis consisted of 33 subjects separated below (NLR < 3.12, n = 16) and above (NLR ≥ 3.12, n = 17) the NLR median. Age, height, body mass, and body mass index were not significantly different between groups (p-range: 0.11-0.60). Results from the Kaplan-Meier curve indicate that a NLR above the median associates with lower overall survival (Mantel, p = 0.04) in melanoma patients receiving CBI with or without previous radiation treatment. In a separate analysis of this cohort, overall survival was not significantly influenced by radiation therapy prior to CBI. Conclusions: Although prior radiation therapy offered no survival advantage for patients receiving CBI, NLR less than 3.12 was associated with an increase in overall survival. Further studies are need to explore NLR as a biomarker.
Efficacy of PD-1/PD-L1 therapy: Do proton pump inhibitors affect the outcome?
Authors: Mukherjee Sarbajit , Khalid Bilal , Ibrahimi Sami , Morton Jordan Malie , Roman Darwin , Zhao Yan D , Aljumaily Raid 
Published: February 2018

208 Background: Recent studies have shown that manipulating the gut microbiome modulates the efficacy of anti-PD1/PD-L1 directed therapy leading to increase in the activity of CD8+ T-cells. Proton Pump inhibitors (PPIs) affect the gut microbiome. The objective of this study was to investigate the effects of PPIs use on agents that target the PD-1/PD-L1 pathway in patients treated with these agents. Methods: We looked at the outcomes of 158 patients aged 18 years or older, treated at the University of Oklahoma Health Sciences Center between 2014 and 2016. The primary aim of this study was to investigate whether survival of patients treated with agents that target PD-1/PD-L1 pathway was affected by PPI use. The secondary objective was to identify if there is any difference in the immune related side effect profile between PPI users and non-users. The overall survival (OS) and progression free survival (PFS) were compared between PPI users and nonusers using the log-rank tests. Survival curves were generated using the Kaplan-Meyer method. The proportions of Grade 3 or 4 colitis or pneumonitis were compared between PPI users and nonusers using the Fisher’s exact test. SAS 9.4 was used for the statistical analysis and a 0.05 significance level was used. Results: The majority of patients were females (57%). The median age was 63 years. Lung cancer was the most common diagnosis (20%) followed by melanoma (20%) and ovarian cancer (12%). Nivolumab was the most commonly used agent (47%) followed by Pembrolizumab (22%), other investigational agents (22%) and Atezolizumab (7%). The median follow-up time from the date of first PPI dose was 7 months. There was no statistically significant difference in OS or PFS between PPI users and nonusers (p = 0.77). There were no significant differences in proportions of Grade 3 or 4 colitis between PPI users and nonusers (5% vs. 5.26%, p > .99). Similarly, there were no significant differences in proportions of Grade 3 or 4 pneumonitis between PPI users and nonusers (6.25% vs. 1.75%, p = 0.40). Conclusions: Use of PPI does not affect the outcome of patients receiving agents that target PD1/PD-L1 pathway. The incidence of important immune related side effects was similar between PPI users and non-users.
Association of PD-L1 mRNA levels in plasma-derived exosomes with response to nivolumab and pembrolizumab in melanoma and NSCLC.
Authors: Del Re Marzia , Marconcini Riccardo , Pasquini Giulia , Rofi Eleonora , Vivaldi Caterina , Bloise Francesco , Restante Giuliana , Arrigoni Elena , Bianco Mariagrazia , Caparello Chiara , Crucitta Stefania , Petrini Iacopo , Vasile Enrico , Morganti Riccardo , Falcone Alfredo , Danesi Romano 
Published: February 2018

210 Background: The anti-PD-1 monoclonal antibodies (moAb) nivolumab and pembrolizumab have improved the survival of melanoma and non-small cell lung cancer (NSCLC) patients. However, treatment selection is based on tumor PD-L1 expression by immuno-histochemistry and no specific approaches are available to monitor treatment response. The aim of this study was to investigate the association between PD-L1 mRNA levels in plasma-derived exosomes and response to nivolumab and pembrolizumab in patients affected by melanoma (n = 18) and NSCLC (n = 8). Methods: Blood (6 ml) was obtained at 1) baseline (before initiation of anti-PD1 moAb or at the time of last available radiological evaluation of disease response) and 2) after two months of treatment (at the time of first response evaluation or disease re-assessment). Exosomes were extracted from plasma and PD-L1 mRNA expression was measured by digital PCR and expressed as copies/ml. Results: Overall, the number of copies of mRNA PD-L1/ml plasma varied according to tumor response; in particular, an increase was found in patients with PD and a decrease was observed in patients who achieved a CR/PR. The mean±SEM values of PD-L1 in patients responding to treatment (CR+PR) were 830.4±231.3 and 242.5±82.5 copies/ml (baseline vs. 2 months, p = 0.016), respectively. In patients with stable disease the mean±SEM values were as expected 298.8±97.2 vs. 247.5±29.8 copies/ml (p = 0.586), while in progressive disease PD-L1 expression levels were 204.0±68.8 vs. 416.0±87.8 copies/ml (p = 0.001), respectively. Conclusions: In the present study, we demonstrate for the first time that changes in exosomal PD-L1 expression occur in melanoma and NSCLC patients treated with nivolumab or pembrolizumab and may correlate with the radiological tumor response. This proof-of-concept study demonstrates the feasibility of detecting PD-L1 in plasma and its relationship with response to treatment.
Efficacy of immune checkpoint inhibitors in patients with brain metastasis from NSCLC, RCC, and melanoma.
Authors: Lauko Adam , Thapa Bicky , Jia Xuefei , Ahluwalia Manmeet Singh 
Published: February 2018

214 Background: Immune checkpoint inhibitors are revolutionizing the treatment of multiple advanced malignancies, however, there is limited data on the efficacy of immune checkpoint blockade in brain metastasis. We conducted a study to analyze the overall survival (OS) and progression-free survival (PFS) among patients with brain metastasis from Non-Small Cell Lung Carcinoma (NSCLC), Renal Cell Carcinoma (RCC), and Melanoma treated with either Nivolumab, Pembrolizumab, Ipilimumab or a combination. Methods: After IRB approval, we retrospectively evaluated patients with brain metastasis treated at our tertiary care institution from 2011-2017 who underwent immunotherapy and one or more of the following; whole brain radiation therapy (WBRT), surgery, stereotactic radiosurgery (SRS) or systemic chemotherapy. Univariable and multivariable analysis was utilized to analyze OS and PFS. Volumetric analysis to assess treatment response is ongoing. Results: A total of 128 patients were identified with a median age of 60.6 years. 49% of patients were male; 77% of patients had a good (0 or 1) ECOG performance scores at the time of the brain metastasis; 83 patients had supratentorial brain metastasis, 11 had infratentorial and 24 had both. The prevalence of mutations was 34% in NSCLC patients, 58% in melanoma, and 0% in RCC. The median OS from the start of immunotherapy was not reached for RCC and was 17.1 and 28.9 months for Melanoma and NSCLC respectively. Median PFS was 5.9, 6.7 and 3.6 months for RCC, Melanoma, and NSCLC respectively. On multivariable analysis, SRS, sex and the number of cycles of immunotherapy had statistically significant hazard ratios. Conclusions: Immune checkpoint inhibitors are efficacious in the treatment of brain metastasis. Further analysis including response criteria using volumetric analysis is ongoing and final results will be presented at the meeting. [Table: see text]
Immune deserts: Correlation of low CD8 gene expression with non-response to checkpoint inhibition.
Authors: Gardner Mark , Pabla Sarabjot , Ernstoff Marc S. , Puzanov Igor , Conroy Jeffrey M. , Nesline Mary , Glenn Sean T. , Papanicolau-Sengos Antonios , Burgher Blake , Andreas Jonathan , Giamo Vincent , Qin Maochun , Lenzo Felicia L. , Morrison Carl 
Published: February 2018

23 Background: Associations between presence and density of effector T-cells (CD8+) and response to checkpoint inhibitors (CPIs) has been established for protein biomarkers using immunohistochemistry but less work has been done to characterize this relationship through gene expression. Methods: We collected clinical response data (RECIST v1.1) for 184 patients who had been treated with CPIs across tumor types with FDA indications. We tested formalin-fixed paraffin embedded (FFPE) samples by NGS with a comprehensive immune response panel which interrogates the gene expression profile of 54 validated immune-related genes. Ranked gene expression was compared to a reference population. 85/184 (46%) cases were considered “responders” after six months, and 66/184 cases (36%) were considered responders after twelve months on treatment. We hypothesized that patients with in the bottom quartile of CD8 expression, as measured by the rank of the sum of normalized CD8A and CD8B transcripts compared to a reference population, would be unlikely to respond to checkpoint therapy (immune deserts), and that “hot” tumor environments (TME) with the highest quartile of expression would be most likely to respond. Results: After six months of therapy, 13/40 (32.5%) patients with immune desert tumors responded to therapy, whereas 39/82 patients (47.6%) in the middle 50% of expression responded, and 33/62 (53.2%) of patients with “hot” TME responded to treatment. The two-tailed p-value of the null hypothesis, that TME status does not correlate with response, was 0.018 and could be rejected. After twelve months of observation, 9/40 (22.5%) immune desert patients were considered “responders”. 28/82 (34.2%) of the middle 50% of expression were classified as responders, and 29/62 (46.8%) of top quartile samples came from responders. The two-tailed p-value of the null hypothesis was 0.005 and could be rejected. Conclusions: Gene expression of CD8 as measured by RNA-seq from FFPE samples can be used to compare these samples versus a reference population to predict an increase or decrease in likelihood of response to CPIs. Patients in the lowest quartile of CD8 expression were the least likely to respond to these promising therapies.
The coupling of MDSCs with a computational analytic method to detect solid tumors.
Authors: Dominguez George , Sholevar Cyrus , Polo Alexander , Roop John , Campisi Anthony , Gabrilovich Dmitry , Rauscher Frank J. , Kumar Amit 
Published: February 2018

24 Background: Myeloid-derived suppressor cells (MDSCs) are key contributors in supporting tumor progression and tumor escape through their ability to suppress anti-tumor responses mediated through T cell and natural killer (NK) cell activity. Several studies have demonstrated their utility as indicators of tumor progression and possible predictors of clinical outcomes, but there is significant overlap with healthy individuals preventing discrete and accurate calls. The objective of our study was to create a non-invasive cancer detection assay that analyzes flow cytometry data in an objective method using an artificial neural network (NN) to distinguish between cancer patients (CPs) and healthy donors (HDs) based upon the flow cytometry profiles of MDSCs and other leukocytes. Methods: We used standard multiparametric flow cytometry techniques to immunophenotype MDSCs and other leukocytes found in the peripheral blood of 52 biopsy-confirmed CPs with solid tumors and 70 HDs. A series of NNs utilizing pattern recognition computational algorithms are then created using three data sets: 1) the training set - this ‘teaches’ the two output categories of cancer and not cancer, 2) the validation set – this uses backpropagation to improve the accuracy of the trained networks, and 3) the testing set – this is used to rank the trained networks against each other. Finally, a naïve testing set is then used to determine the overall sensitivity and specificity for the top-ranking networks. Results: Using traditional flow cytometry gating methods to analyze MDSCs as a biomarker for cancer detection, it is difficult to achieve both high sensitivity and specificity due to the substantial overlap with healthy individuals. Here, we incorporated a standard 12 marker flow cytometry assay with NN technology to achieve a sensitivity of 92.3% and a specificity of 90.0% with an area under the ROC curve (AUC) of 0.9477. Conclusions: Pairing the advanced analytical capabilities of our NN with surface biomarker based analysis of MDSCs and certain leukocytes measured in peripheral blood has enabled us the ability to objectively identify patterns indicative for the existence of a solid tumor.