bluuebunny/crossref_metadata_2025_split huggingface dataset:
Performance verification of a plasma-based PD-L1 test that reliably measures mRNA expression from patients with NCSLC.
Authors: Mellert Hestia S. , Jackson Leisa , Pestano Gary Anthony 
Published: February 2018

156 Background: The detection of circulating nucleic acids using non-invasive blood-draws has become highly relevant to clinical testing. In this study we report on the development of a blood-based PD-L1 test for immunotherapy selection. Methods: We have previously reported on the analytic performance of a droplet digital™ PCR (ddPCR) assay for circulating cytokeratin 19 and PD-L1. Using a variable threshold based on a logistic regression score for the blood assay and a 1% IHC (immunohistochemistry) tissue cut-off, concordance was 80% (n = 16). Positive calls for the blood-based PD-L1 assay ranged from 2 to 124 copies. In this study we focused on variables that could impact concordance of the blood assay and tissue results. Criteria included droplet counts for tissue and blood mRNA transcripts and tumor proportion score (TPS) for the tissue IHC assay (22C3 pharmDx). Results: We examined the correlation between PD-L1 in formalin-fixed paraffin-embedded (FFPE) tissue by IHC, mRNA expression in serial cut FFPE sections, and in matched plasma samples collected at the time of tissue resection. Five cases were assayed to confirm PD-L1 positivity by tissue. We successfully recovered RNA from serial tissue sections for each case and detected PD-L1 levels ranging from 6 to 1272 copies. Plasma samples were available for four of the cases for circulating RNA evaluation, and we were successful in detecting PD-L1 in all cases (copy range 32-138). While all four cases contained detectible PD-L1 mRNA in tissue and circulation, we observed little concordance between these levels in tissue and blood. Conclusions: We have developed methods to measure the dynamic range of PD-L1 from plasma. We have shown feasibility of these methods by evaluating key immune and cancer-specific RNAs. The current study demonstrates that although the development of quantitative assays for mRNA in blood is possible, concordance with traditional clinical tissue assays such as IHC may not be a useful validation measure. We have initiated prospective validation studies that will continue to evaluate PD-L1 expression by IHC and in the blood-based assay, and will also monitor patient performance measures in response to immunotherapy.
Pan-Cancer assessment of tumor mutational burden using a comprehensive genomic profiling assay.
Authors: Nichol Donna , Jones Siân , Angiouli Samuel V. , Keefer Laurel , Nesselbush Monica , Sengamalay Naomi , White James , Simmons John , Diaz Luis A. , Velculescu Victor E. , Sausen Mark 
Published: February 2018

157 Background: Checkpoint inhibitors (CPIs) have been approved for frontline or subsequent therapies in several indications over the last few years. While patient response can be remarkably durable, many patients do not benefit. Current clinical biomarkers of response to CPIs include microsatellite instability (MSI) and PD-L1 expression. While a proportion of many solid tumors display microsatellite instability, the prevalence is often very low. Similarly, while clinically informative, PD-L1 expression alone is not sufficient to predict therapeutic outcomes with high accuracy. The lack of predictive biomarkers for response highlights the need for improved biomarkers with greater prevalence across tumor types to predict response to CPIs. Multiple clinical studies have revealed that high tumor mutational burden (TMB) is associated with improved clinical response. Methods: Here, we describe the development of a method that can be used to accurately infer mutational burden from a discrete set of targeted regions of interest across the exome. Initially, we performed an assessment of the accuracy across multiple bioinformatics methods for identification of individual sequence mutations (SBS/indels) using orthogonally validated data together with publicly available TCGA whole-exome sequencing data. The targeted regions were then isolated from these datasets to demonstrate analytical performance across several different solid tumor types. Finally, we evaluated independent non-small cell lung cancer (NSCLC) and colorectal carcinoma (CRC) cohorts to demonstrate the analytical accuracy of the assay and bioinformatics approach for determination of mutational burden when compared to whole exome sequencing. Results: In summary, high concordance was observed across a large dynamic range of mutations per megabase of coding sequence. Conclusions: Our data indicate that the assay can be used to accurately determine mutational burden in a range of tumor types, across a spectra of potential mutational burden cut-offs using automated, complex mutation identification algorithms.
Clinical significance of humoral immunity against XAGE1 cancer-testis antigen in lung adenocarcinoma.
Authors: Oka Mikio , Kurose Koji , Isobe Midori , Fukuda Minoru , Ohue Yoshihiro 
Published: February 2018

162 Background: Cancer-testis antigens (CTAs) are expressed predominantly in the testis and various types of cancer. Some of CTAs are highly immunogenic and attractive targets for cancer immunotherapy. We identified XAGE1 as a dominant CTA in lung adenocarcinoma (LAD). In this study, we examined immune responses to XAGE1 and the clinical significance in LAD patients. Methods: Expression of XAGE1 and immune checkpoint molecules in LAD tissues was determined by immunohistochemistry. The XAGE1 antibody and T cell immune responses were analyzed in blood samples. Then, overall survival (OS) of the XAGE1 antigen-positive and -negative, and XAGE1 antibody-positive and -negative patients was analyzed. Results: The XAGE1 antigen was expressed in approximately 40% of LAD, and the expression reflected shortened OS of pStage I-IIIA LAD in two japanese cohorts. In addition, expression profiles of XAGE1 and immune checkpoint molecules of PD-L1 and galectin-9 on tumor cells efficiently predicted OS of pStage I-IIIA LAD patients. The XAGE1 antibody response was observed in 6% (9/155) of our pStage I-IIIA, and 20% (34/167) of cStage IIIB-IV LAD, respectively, showing a higher antibody response rate in more advanced stages. In the antibody-positive patients, CD4 and CD8 T cell responses were frequently elicited, and phenotypic and functional analyses of T cells indicated immune activation. Furthermore, the OS of antibody-positive patients significantly prolonged as compared with that of antibody-negative patients with either XAGE1 antigen-positive EGFRwt (31.5 vs 15.6 months, P = 0.05) or EGFRmt (34.7 vs 11.1 months, P = 0.001) LAD. Multivariate analysis showed that the XAGE1 antigen expression was a worse predictor in EGFRmt LAD (HR: 5.23). On the other hand, the presence of the XAGE1 antibody was a strong predictor for prolonged OS in XAGE1 antigen positive LAD (HR: 0.18) and in either EGFRwt or EGFRmt LAD. Conclusions: The XAGE1 antigen induced strong immune responses in LAD patients with more advanced stages, and the production of XAGE1 antibody in these patients showed good prognosis. Our results indicate that the XAGE1 immunity is probably a good prognostic biomarker in LAD and a promising target for immunotherapy of LAD.
Efficacy of checkpoint inhibitors, tumor vaccines, and cellular immunotherapies in patients with advanced non-small cell lung cancer.
Authors: Yu Yunfang , Ou Qiyun , Wang Ying , Liu Zhifeng , Fu Tuping , Gao Quanlong , Lin Dagui , Yao Herui 
Published: February 2018

165 Background: Checkpoint inhibitors, tumor vaccines or cellular immunotherapies demonstrated prolonged survival versus placebo or observation in several randomized clinical trials (RCTs) of patients with advanced non-small-cell lung cancer (NSCLC). We aimed to clarify the benefits of imunotherapy by a meta-analysis of RCTs data. Methods: We searched for RCTs investigating immunotherapy versus placebo or observation in patients with advanced NSCLC. Overall survival (OS) and progression-free survival (PFS) were calculated as combined hazard ratios (HRs). The quality of the evidence was evaluated with the GRADE framework. Results: Overall, 23 RCTs including a total of 8,956 patients were identified (5,142 patients in the immunotherapy group and 3,814 in the placebo or observation group). High- to moderate-quality evidence indicated that immunotherapy prolonged OS (HR = 0.79, 95% confidence interval (CI) 0.75 to 0.84, P < 0.0001) and PFS (HR = 0.80, 95% CI 0.73 to 0.88, P < 0.0001). In subgroup analysis, high- to moderate-quality evidence revealed immunotherapy extended NSCLC survival and PFS in tumor vaccines (HR, 0.84, 95% CI 0.76 to 0.92 and 0.86, 95% CI 0.78 to 0.94 for OS and PFS, respectively), checkpoint inhibitors (0.77, 95% CI 0.72 to 0.83 and 0.78, 95% CI 0.68 to 0.90, respectively), maintenance therapy (0.77, 95% CI 0.71 to 0.83 and 0.78, 95% CI 0.66 to 0.91, respectively), first-line therapy (0.89, 95% CI 0.80 to 0.98 and 0.76, 95% CI 0.64 to 0.91, respectively), previous definitive chemotherapy (0.72, 95% CI 0.67 to 0.78 and 0.87, 95% CI 0.79 to 0.95, respectively), and concurrent chemotherapy (0.87, 95% CI 0.80 to 0.95 and 0.84, 95% CI 0.77 to 0.91, respectively). There was a benefit of immunotherapy in previous definitive chemotherapy compared with chemoradiotherapy and with concurrent administration of chemotherapy (OS as HR: P = 0.002 and P = 0.006, respectively). Conclusions: This analysis provides strong evidence for OS and PFS benefit of immunotherapy in patients with advanced NSCLC, particularly in those receiving tumor vaccines, checkpoint inhibitors, maintenance and first-line therapy, previous definitive chemotherapy, and with concurrent chemotherapy.
Comprehensive immune and mutational profile of melanoma.
Authors: Conroy Jeffrey M. , Pabla Sarabjot , Ernstoff Marc S. , Puzanov Igor , Nesline Mary , Glenn Sean T. , Papanicolau-Sengos Antonios , Burgher Blake , Andreas Jonathan , Giamo Vincent , Qin Maochun , Lenzo Felicia L. , Gardner Mark , Morrison Carl 
Published: February 2018

182 Background: The association between tumor mutational profiles and immune signatures has not been well-characterized. Methods: 306 melanoma samples were tested by NGS using a comprehensive cancer panel for mutational status and an immune response panel which interrogates the expression profile of 54 validated immune-related genes. The ranking of gene expression, mutational burden and 7 immune phenotypes was compared to a reference population. 38% cases were positive for activating BRAF mutations, 12% for RAS, and 6% for NF1. The remaining 44% were considered triple wild type. Principal component analysis (PCA) followed by hierarchical clustering was performed to determine association of BRAF/RAS/NF1 mutations and triple wild type with immune phenotypes, mutational burden and gene expression as measured by the NGS panels. Results: PCA showed that the first and second dimension explain 86% of the variation in the mutation profiles of the 306 melanomas. The first principal component highly correlated with BRAF positive status (pval < 0.001), the second highly correlated with RAS positive status (pval < 0.001), and the third principal component, although not informative, highly correlated with NF1 status (pval < 0.001) and Mutation Burden (pval < 0.001). Hierarchical clustering of the samples resulted in 4 distinct clusters: RAS positive, BRAF Positive, NF1 positive and triple wild type. The RAS positive cluster demonstrated significantly lower expression of ICOSLG, ICOS, CD4, C10orf54, CD40 and CD244 genes. Similarly, the BRAF positive cluster under-expresses immune escape and proinflammatory immune phenotypes, but over-expressed OX40L. The NF1 positive cluster had significantly higher mutational burden than other clusters. On the contrary, the triple wild type cluster over-expressed 6 out of 7 immune phenotypes. Conclusions: BRAF/RAS/NF1 mutation status are immunophenotypically distinct and do not associate with a typical immune phenotype in the tumor microenvironment. Triple wild type samples present with an overall activated immune phenotype, representative of an inflamed tumor. Additional studies are necessary to include additional activating or loss of function mutations to expand these findings.
Intralesional anti-PD1 treatment in patients with metastatic melanoma: The pilot study.
Authors: Samoylenko Igor , Korotkova Olga V. , Zabotina Tatiana , Demidov Lev V. 
Published: February 2018

188 Background: Systemic anti-PD1 treatment is major advantage for metastatic melanoma patients over the last five years. Nevertheless up to the moment there are no solid predictive factors discovered. On the other hand immune related adverse events develop quite frequent and sometimes could be dangerous. Methods: Patient with advanced cutaneous melanoma with known BRAF status and at least one superficial lesion (suitable for injection) are eligible. One of two commercially available anti-PD1 drugs (nivolumab or pembrolizumab) is administered intralesionaly to patients every 2 weeks with total daily dose not more than 50 mg (5 ml) using a scale-base approach depending on lesions size. Clinical and immunological outcomes assessed every 12 weeks. For assessing lymphoid infiltrate tumor biopsy performed before treatment and on week 12. To detect a systemic objective response rate of 50% with sensitivity of 80% and error type alfa 5% at least 25 patients to be included. Interim analysis was preplanned when 3 (25%) of events occurred. Results: Among 7 pts OR was detected in 4 (54.7%), PD in 3 (42.9%). Bystander effect was seen in 2 of 4 patients (50%). Among 3 non-responders 2 failed to salvage systemic anti-PD1 treatment and one is now on anti-CTLA4. The most common adverse event was injection site pain, which was self-limiting. Baseline immune phenotype of tumor infiltrating lymphocytes (TILs) was available for 5 of 7 pts included. Baseline percent of TILs, CD3+CD8+ and CD8+CD279+ was higher in responders vs non-responders (3.6±4.08% vs 0.8±0, NS, 75.1±20.6% vs 54.8±1.13, NS; 36.75±18.7% vs 42.8±13.1, NS respectively ). Baseline difference in CD11b+CD28- between responders (7.06±7.768) and non-responders (25.0 ±0.00) was statistically significant. Conclusions: these results demonstrates feasibility, tolerability and potential clinical efficacy of intralesional anti-PD1 in melanoma patients. Further study are needed to determine if unsuccessful intralesional administration could predict failure to systemic treatment as well as TILs phenotype could predict intralesional or systemic anti-PD1 clincal benefit Clinical trial information: MEL004IL.
18-month efficacy and safety update from JAVELIN Merkel 200 part A: A phase II study of avelumab in metastatic Merkel cell carcinoma progressed on chemotherapy.
Authors: D'Angelo Sandra P. , Russell Jeffery Scott , Bhatia Shailender , Hamid Omid , Mehnert Janice M. , Terheyden Patrick , Shih Kent C. , Brownell Isaac , Lebbé Celeste , Lewis Karl D. , Linette Gerald P. , Milella Michele , Hennessy Meliessa , Bajars Marcis , Zwiener Isabella , Nghiem Paul 
Published: February 2018

192 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. Avelumab, a human anti–PD-L1 monoclonal antibody, is FDA and EMA approved for the treatment of metastatic MCC (mMCC). Here, we report efficacy and safety data for avelumab in patients (pts) with mMCC at ≥18-mo of follow-up. Methods: Pts with mMCC and progression on prior chemotherapy received avelumab 10 mg/kg IV Q2W. Objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) were evaluated by independent review committee (RECIST v1.1) with tumor assessment every 6 wks; overall survival (OS) and adverse events (AEs; NCI CTCAE v4.0) were also evaluated. Results: As of Mar 24, 2017, 88 pts were treated and followed for a median of 23.0 mo (range 18.7–32.0). Median treatment duration was 17 wks (range 2–132; mean 35 wks ±37). Treatment was ongoing in 15 pts (17%); 7 pts (8%) voluntarily discontinued with continuing responses (5 complete responses [CR] and 2 partial responses). Other reasons for discontinuation were disease progression (n = 42; 48%), death (n = 10; 11%), AE (n = 8; 9%), or consent withdrawal/other (n = 6; 7%). Confirmed ORR of 33% (95% CI 23.3–43.8; CR in 11.4%) remained unchanged from previous analysis and median DOR has not been reached (range 2.8–24.9 mo; 95% CI 18.0–not estimable). Responses were ongoing in 20/29 pts (69%), including 5 pts with > 2 y of follow-up. PFS curve showed a plateau with identical 12- and 18-mo rates of 29% (95% CI 19–39). Median OS was 12.6 mo (95% CI 7.5-19.0) and the 12- and 18-mo OS rates were 51% (95% CI 40–61) and 40% (95% CI 29–50), respectively. 66 pts (75%) had a treatment-related (TR)AE, most commonly ( > 10%) fatigue (25%), infusion-related reaction (15%; all grade 1/2), nausea (11%), and diarrhea (11%); 8 (9%) had a grade ≥3 TRAE. 17 pts (19%) had an immune-related AE, which was grade ≥3 in 4 pts (4.5%). No treatment-related deaths occurred. Conclusions: Updated results demonstrate continued durable antitumor activity of avelumab in pts with mMCC, beyond that expected with cytotoxic chemotherapy. The median OS exceeding 1 y and manageable safety profile of avelumab signify a clinically meaningful benefit in pts with mMCC. Clinical trial information: NCT02155647.
Cemiplimab (REGN2810): A fully human anti-PD-1 monoclonal antibody for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC)—Initial safety and efficacy from expansion cohorts (ECs) of phase I study.
Authors: Papadopoulos Kyriakos P , Owonikoko Taofeek Kunle , Johnson Melissa , Brana Irene , Gil Martin Marta , Perez Raymond P. , Moreno Victor , Salama April K. , Calvo Emiliano , Yee Nelson S , Safran Howard , Gonzalez Martin Antonio , Aljumaily Raid , Mahadevan Daruka , Mohan Kosalai Kal , Li Jingjin , Stankevich Elizabeth , Lowy Israel , Fury Matthew G. , Homsi Jade 
Published: February 2018

195 Background: There is no established standard of care for unresectable locally advanced or metastatic CSCC. UV-induced DNA damage causes hypermutation in most CSCCs. Therefore, these tumors may be responsive to PD-1 checkpoint blockade. In the dose escalation portion of the phase 1 study of cemiplimab (REGN2810), a durable (19 + months) radiologic complete response was observed in a patient (pt) with metastatic CSCC (ASCO 2015, #3024). Methods: ECs enrolled pts with distantly metastatic (EC 7) and locally advanced (EC 8) CSCC. All patients received cemiplimab 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks for up to 48 weeks. Research biopsies were performed at baseline and Day 29 (and at progression, if possible). Tumor measurements were performed every 8 weeks according to RECIST 1.1 to determine overall response rate (ORR). Data cutoff date was 31 Jan 2017. Results: 26 pts were enrolled (10 in EC 7 and 16 in EC 8): median age, 72.5 y (range, 56–88y); median PS 1 (range, 0–1); 21M:5F; median number of prior systemic therapy regimens, 1 (range, 0–2). Median exposure to cemiplimab was 7 doses (range, 1–22). The most common treatment-related adverse event of any grade was fatigue (19.2%). Each of the following ≥ Grade 3 related AEs occurred once: AST elevation, ALT elevation, arthralgia, and rash. ORR (PR + CR, including unconfirmed) and disease control rate (ORR+SD) were 52% (12/23; 4uPR, 5 PR, 2CR, 1 uCR) and 70% (16/23, including 4SD), respectively. Three patients are not yet evaluable. Median PFS and OS have not been reached, and only one patient has experienced PD during cemiplimab treatment after initial response. Correlative studies are in process, including PD-L1 status and whole exome tumor DNA sequencing. Conclusions: Cemiplimab is well tolerated and produces antitumor activity in patients with advanced CSCC. A pivotal trial of cemiplimab for patients with advanced CSCC is enrolling patients. Clinical trial information: NCT02383212.
Real world treatment patterns of first-line combination therapies among BRAF+ metastatic melanoma patients stratified by tumor burden.
Authors: Ghate Sameer , Tang Jackson , Li Zhiyi , Nakasato Antonio Reis 
Published: February 2018

198 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), stratified by tumor burden. Methods: A retrospective observational analysis used Flatiron Health’s electronic health record-derived database from Oct ’15 - Jul ’16. Pts were aged ≥18 years with a MM diagnosis, tested BRAF+ prior to therapy, and treated with ipilimumab+nivolumab (I+N) or dabrafenib+trametinib (D+T) as 1L therapy. Low tumor burden was defined as low/normal LDH (≤ 333 IU/L) and no brain metastasis. High tumor burden was defined as high LDH ( > 333 IU/L) or brain metastasis. Baseline characteristics and treatment patterns were descriptively assessed. Kaplan-Meier (KM) analysis measured time to discontinuation. Results: Among 76 BRAF+ pts, 38% (29) were treated with I+N as 1L, and 62% (47) were treated with D+T as 1L. Of these, 45% (13/29) of I+N vs. 32% (15/47) of D+T had low tumor burden, while 41% (12/29) of I+N vs. 49% (23/47) of D+T had high tumor burden. The two cohorts did not differ by age or gender. Treatment patterns are summarized below. Conclusions: Among pts with low tumor burden, I+N demonstrated shorter time to discontinuation and higher discontinuation rate relative to D+T. Treatment toxicity and progression was the main reason for discontinuation of I+N and D+T, respectively. Among pts with high tumor burden, I+N demonstrated longer time to discontinuation but higher discontinuation rate relative to D+T. Progression was the main reason for discontinuation of both I+N and D+T. [Table: see text]