bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab (nivo) + nab-paclitaxel (nab-P) + carboplatin (C) in patients (pts) with non-small cell lung cancer (NSCLC): Interim results from a multicenter phase I study.
Authors: Waterhouse David Michael , Goldman Jonathan Wade , George Ben , O'Dwyer Peter J. , Ye Moncy , Chen Tianlei , Trunova Nataliya , Kelly Karen 
Published: September 2018

9095 Background: Despite success of single-agent immune checkpoint inhibitors, an unmet therapeutic need remains in pts with NSCLC. Chemotherapy and immunotherapy may have synergistic antitumor activity, but safety and efficacy need to be established. Here, we present interim results for pts with NSCLC (Arm C) from the phase I safety trial of nivo + nab-P in pancreatic cancer (± gemcitabine), NSCLC (+ C), and metastatic breast cancer. Methods: Part 1 evaluated potential dose-limiting toxicities (DLTs) before Part 2 expansion. Chemotherapy-naive pts with histologically/cytologically confirmed stage IIIB/IV NSCLC received 4 cycles of nab-P 100 mg/m2d 1, 8, 15 + C AUC 6 d 1 + nivo 5 mg/kg d 15 of each 21-d cycle; in cycles 5+, nivo was continued as maintenance monotherapy. Primary endpoints: number of pts with DLTs (Part 1) and percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (Parts 1 and 2). DLT-evaluable pts included those who received ≥ 2 complete nivo cycles and remained on study for 14 d after the last nivo dose in cycle 2, received ≥ 1 nivo dose and discontinued due to DLT before completing 2 nivo cycles, or experienced equivocal DLT after ≥ 1 nivo dose. Secondary endpoints included safety, PFS, OS, DCR, ORR, and DOR. Results: All pts (n = 22) received nab-P/C; results for nivo-treated pts (n = 20) are presented. Of the nivo-treated pts, the median age was 66 y (55% ≥ 65 y), 75% were female, 80% were white, and 70% had ECOG PS 1. More pts had adenocarcinoma (50%) than squamous cell carcinoma (35%; 10% other, 5% data pending). No DLTs reported (5 DLT-evaluable pts). Most common grade 3/4 TEAEs were neutropenia (45%) and anemia (35%). No grade 3/4 immune-related colitis or pneumonitis reported. Best ORR (RECIST v1.1) was 50% (1 CR [unconfirmed, 5%] and 9 PRs [45%]; 6 pts had SD [30%]; 4 pts had PD [20%]). Best ORR by histology: squamous, 71%; nonsquamous, 54%. Median PFS was 10.5 months (squamous, 10.5 months; nonsquamous, not evaluable). Conclusions: Results demonstrated safety of the nivo + nab-P/C combination in NSCLC with no unexpected safety signals. Preliminary efficacy results are promising. (NCT02309177) Clinical trial information: NCT02309177.
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 Lynne , Brana Irene , Gil-Martin Marta , Perez Raymond P. , Moreno Victor , Salama April K. , Calvo Emiliano , Yee Nelson S. , Safran Howard , González-Martín Antonio , Aljumaily Raid , Mahadevan Daruka , Mohan Kosalai Kal , Qin Rui , Stankevich Elizabeth , Lowy Israel , Fury Matthew G. , Homsi Jade 
Published: September 2018

9503 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 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 3 mg/kg REGN2810 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 REGN2810 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 REGN2810 treatment after initial response. Correlative studies are in process, including PD-L1 status and whole exome tumor DNA sequencing. Conclusions: REGN2810 is well tolerated and produces antitumor activity in patients with advanced CSCC. A pivotal trial of REGN2810 for patients with advanced CSCC is enrolling patients (NCT02760498). Clinical trial information: NCT02383212.
COMBI-MB: A phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant (mut) melanoma brain metastases (MBM).
Authors: Davies Michael A. , Robert Caroline , Long Georgina V. , Grob Jean Jacques , Flaherty Keith T. , Arance Ana , Chiarion-Sileni Vanna , Thomas Luc , Lesimple Thierry , Mortier Laurent , Moschos Stergios J. , Hogg David , Marquez Rodas Ivan , Del Vecchio Michele , Lebbe Celeste , Meyer Nicolas , Zhang Ying , Huang Yingjie , Mookerjee Bijoyesh , Saiag Philippe 
Published: September 2018

9506 Background: CNS metastases are common and associated with very poor prognosis in pts with metastatic melanoma (MM). In the phase II BREAK-MB trial, D had clinical activity in BRAF V600–mut MBM. D + T has shown superiority over D alone in pts with BRAF V600–mut mm without MBM; however, efficacy of this regimen on MBM has not been characterized. Here, we report results from a phase II trial of D + T in BRAFV600–mut MBM (COMBI-MB; NCT02039947). Methods: This open-label, phase II study evaluated D 150 mg BID + T 2 mg QD in 4 MBM cohorts: (A) BRAFV600E, asymptomatic MBM, no prior local treatment (Tx); (B) BRAFV600E, asymptomatic MBM, prior local Tx; (C) BRAFV600D/K/R, asymptomatic MBM, with or without prior local Tx; and (D) BRAFV600D/E/K/R, symptomatic MBM, with or without prior local Tx. The primary objective was intracranial response rate (IRR) in cohort A (null hypothesis, IRR ≤ 35%). Secondary endpoints included IRR in cohorts B, C, and D; extracranial (ERR) and overall (ORR) response rates; intracranial (IDCR), extracranial (EDCR), and overall (ODCR) disease control rates; duration of IR, ER, and OR; PFS; OS; and safety. Results: 125 pts were enrolled (A, n = 76; B, n = 16; C, n = 16; D, n = 17). In cohort A, median age was 52, 53% were male, and 37% had LDH > ULN. At data cutoff (28 Nov 2016; median f/u, 9.0 mo), in cohort A, investigator-assessed IRR was 58% (IDCR, 78%), ERR was 55% (EDCR, 80%), and ORR was 58% (ODCR, 80%). Median duration of IR, ER, and OR was 6.5 mo (95% CI, 4.9-10.3), 10.2 mo (95% CI, 6.5-13.0), and 6.5 mo (95% CI, 4.9-10.3), respectively. Median PFS was 5.6 mo (95% CI, 5.3-7.4). Independent review supported these results. 6-mo OS was 79%; with 31 pts (41%) still in f/u, preliminary median OS was 10.8 mo (95% CI, 8.7-19.6). Efficacy in cohorts B, C, and D will be reported. AEs across cohorts (any, 98%; grade 3/4, 48%) were consistent with prior D + T studies; 10% of pts (8% in cohort A) discontinued due to AEs. Conclusions: In this first report of a phase II trial evaluating a BRAF and MEK inhibitor combination in BRAFV600–mut MBM, the primary endpoint was met. Promising IRR and IDCR were seen with D + T, but responses appear less durable than reported for mm without MBMs. No unexpected safety issues were observed. Clinical trial information: NCT02039947.
Metagenomic shotgun sequencing to identify specific human gut microbes associated with immune checkpoint therapy efficacy in melanoma patients.
Authors: Frankel Arthur E. , Froehlich Thomas W. , Kim Jiwoong , Coughlin Laura A. , Xie Yang , Frenkel Eugene P. , Koh Andrew Y. 
Published: September 2018

9516 Background: Immune checkpoint inhibitor therapy, ICT, achieves durable remissions in 30-50% of patients (pts) with metastatic melanoma (Larkin et al. NEJM 2015). It is still unclear what host factors modulate response to ICT. Preclinical mouse studies with B16 melanoma demonstrated that ICT response was dependent on the presence of specific commensal gut bacteria (Vetizou et al. Science 2015; Sivan et al. Science2015). These specific gut bacteria induced the maturation of dendritic cells (DCs) and T-cells needed for effective ICT. We sought to determine whether specific gut microbiota are associated with improved response to ICT in melanoma patients. Methods: 37 melanoma pts treated with ICT (nivolumab plus ipilimumab or pembrolizumab alone) at UTSW Medical Center were enrolled. Fecal samples were collected prior to ICT. Genomic DNA was extracted, and metagenomic shotgun sequencing (MSS) performed on an Illumina HiSeq 2500 PE-100. Taxonomic (MetaPhlAn) and functional (HUMAnN) analysis was performed on MSS data. Disease status was assessed by CT scans and physical exams every two months. Results: Among the 23 evaluable pts, 8 were classified as RECIST responders, 5 with stable disease and 10 with progression. RECIST responder microbiomes were significantly enriched with Methanobrevibacter smithii(p = 0.03; LDA coupled with effect size measurements, LEfSe; Kruskal-Wallis test) , Bacteroides thetaiotamicron(p = 0.03) , Lactobacillus plantarum(p = 0.04), and Eubacterium limosum(p = 0.01) compared to those with progressive disease. Conclusions: MSS identified 4 specific gut microbiota associated with improved response to ICT therapy in melanoma pts. All of these bacteria have been shown to modulate host immune response (Bang PLoS One 2014; Hickey Cell Host Microbe 2016; Rigaux Allergy 2009; Kaunachi World J Gastroentertol 2006). To gain mechanistic insight and confirm causality, shotgun metabolomics on the same fecal specimens used for MSS, in vitroimmune cell assays using the gut microbiota identified, and preclinical modeling in a mouse melanoma model with ICT are underway. These studies may lay the foundation for optimizing the host response to ICT.
Targeting EZH2 in acral lentiginous melanoma (ALM).
Authors: Izsak Allison , Giles Keith Michael , Lui Kevin Paul , Weiss Sarah A. , Moran Una , Vega-Saenz de Miera Eleazar , Stein Jennifer , Lee Ann Yeelin , Darvishian Farbod , Shapiro Richard L. , Berman Russell S. , Pavlick Anna C. , Wilson Melissa , Osman Iman 
Published: September 2018

9534 Background: Efforts to identify targeted therapies that can improve treatment outcome in metastatic ALM have been unsuccessful. In a previous genomic screening, we identified copy number amplification of the histone methyltransferase EZH2 in 47% of ALM cases, a higher frequency than previously reported in cutaneous melanomas (CM) (5%). Here, we tested the hypothesis that increased EZH2 expression contributes to ALM progression and may confer selective sensitivity to EZH2 inhibition. Methods: EZH2 expression was examined by immunohistochemistry (IHC) in 51 primary (21 stage I, 13 Stage II and 17 Stage III) and 23 metastatic (11 in transit, 8 nodal and 4 visceral) ALM cases with extensive clinicopathological data and protocol-driven follow up. Colony formation and cell proliferation was assessed following treatment of ALM and CM cell lines with three EZH2 inhibitors, including GSK126, currently in clinical trials. The effect of GSK126 on H3K27me3 and downstream EZH2 targets was analyzed by western blotting. Results: EZH2 is commonly overexpressed in both primary (30/51; 65%) and metastatic (20/23; 87%) ALM cases, with a significant increase in mean IHC score between primary and metastatic tumors (1.9 vs. 2.7, respectively, p = 0.047). EZH2 expression increased in 6/10 metastatic ALM tumors compared to their matched primary tumors. ALM tumors with EZH2 gene amplification showed increased EZH2 protein expression; however more cases showed overexpression with no amplification suggesting a potential epigenetic component of EZH2 regulation. GSK126 significantly suppressed ALM colony formation at lower doses compared to CM (1 µM vs. 5 µM, respectively). EZH2 inhibition also increased expression of the downstream tumor suppressor E-cadherin in ALM but not in CM cell lines. Finally, ALM cell lines had significantly lower basal H3K27me3 levels than CM cell lines, suggesting an additional, histone methyltransferase-independent function of EZH2 in ALM. Conclusions: Our data demonstrate thatEZH2 upregulation is common in ALM, and suggest that it may play a role in ALM’s metastatic progression that requires further investigation. Selective sensitivity of ALM cell lines to EZH2 inhibitors supports the therapeutic potential of EZH2-targeted therapy in ALM.
Exploratory biomarker analysis in avelumab-treated patients with metastatic Merkel cell carcinoma progressed after chemotherapy.
Authors: Shapiro Irina , Grote Hans Juergen , D'Urso Vittorio , von Heydebreck Anja , Mahnke Lisa , Kaufman Howard , Nghiem Paul , Cai Ti 
Published: September 2018

9557 Background: Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer. Tumor oncogenesis is linked to Merkel cell polyomavirus (MCPyV) integration and UV exposure. PD-L1 is often expressed in MCC tumors, suggesting that patients with MCC could benefit from anti-PD-L1 therapy. Avelumab is a fully human anti-PD-L1 IgG1 monoclonal antibody that has demonstrated clinical efficacy in patients (pts) with metastatic MCC (mMCC) in a Phase 2 trial with an objective response rate (ORR) of 31.8% in the primary analysis. Assessment of candidate predictive biomarkers may help to identify patients with a greater probability of response to avelumab and to improve understanding of MCC biology. Methods: Patients in a Phase 2 trial (NCT02155647) with mMCC and tumor progression on prior chemotherapy received avelumab at 10 mg/kg Q2W. PD-L1 expression, MCPyV status and CD8+ T-cell infiltration in pretreatment tumor samples were evaluated by immunohistochemistry (IHC). MCPyV status was also evaluated by real-time PCR. Results: Tumor PD-L1 expression was evaluable in 74 of 88 (84.1%) pts with mMCC treated with avelumab, of which 58 (65.9%) and 19 (21.6%) pts were positive at 1% and 5% cut-offs. ORR was 34.5% and 18.8% for PD-L1 positive and negative pts at 1% cutoff, and 52.6% and 23.6% for PD-L1 positive and negative pts at 5% cutoff. MCPyV status was positive in 60% (46/77) pts evaluable by IHC and 63% (45/71) pts evaluable by PCR; of 66 pts tested by both IHC and PCR, concordance was 90.9%. MCPyV+ and MCPyV– pts had similar frequencies of PD-L1+ tumors (80% and 73%) with an ORR of 26.1% and 35.5% respectively. Baseline CD8+ T-cell infiltration was assessed at tumor invasive margin and tumor center in 53 pts, ORR was 44.4% vs 19.2% and 32.1% vs 28% for pts with high or low CD8+ T-cell density at respective locations. Conclusions: In an international cohort of pts with mMCC, avelumab had clinical activity among biomarker subgroups analyzed, including PD-L1 expression, MCPyV status and density of CD8+ tumor-infiltrating T-cells. The current biomarkers were not predictive of response but further research into understanding how avelumab mediates anti-tumor activity in MCC may identify novel biomarkers. Clinical trial information: NCT02155647.
Validation, in silico and in vitro, of a gene-signature based risk score in cutaneous melanoma.
Authors: Brunner Georg , Falk Thomas M. , Ertas Beyhan , Berking Carola , Schulze Hans-Joachim , Blödorn-Schlicht Norbert 
Published: September 2018

9560 Background: Melanoma staging, as defined by the American Joint Committee on Cancer (AJCC), is limited in its ability to predict outcome. We have previously identified and validated a prognostic gene signature expressed in primary cutaneous melanoma and adjacent stroma. The signature comprises seven protective genes (down-regulated with tumor progression) and one risk-associated gene (up-regulated). A signature-based risk score independently predicts patient survival, across AJCC stages IA-IIIC, in formalin-fixed, paraffin-embedded (FFPE) melanomas (training cohort, n = 125; p = 0.0003, hazard ratio 1.85). The score has been validated in 206 melanomas, selected to be significantly mis-prognosticated by AJCC staging regarding patient survival (40.8% mis-prognostication). In this cohort, the score outperforms AJCC staging (p = 0.0005, hazard ratio 1.41 vs. p = n.s.), correcting 34.9% of AJCC-based mis-prognostications. Methods: Here, we report twofold external validation of the risk score, (i) prognostic performance in silico using the SurvExpress web tool (Aguirre-Gamboa et al., 2013), and (ii) technical performance in vitro(Dermatologikum Hamburg; IMGM Munich) . Results: (i) Kaplan Meier analysis and log-rank testing demonstrated that all signature genes combined predicted survival in four different cohorts of metastatic melanoma (from GEO Expression Omnibus or Cancer Genome Atlas; cohorts dichotomized at the median): see table. (ii) The risk score was re-analyzed in melanomas of the training cohort (n=69). The overall concordance of duplicate determinations was 90% (average scores of 1.12 ± 0.14 and 0.97 ± 0.14). Conclusions: In conclusion, we have validated a signature-based FFPE melanoma risk score, complementary to AJCC staging in predicting outcome: (i) Signature genes predicted patient survival in silico(n=449) (ii) The risk score proved to be reproducible and technically robust in vitro. The score improves risk stratification and decision making in melanoma, particularly regarding new adjuvant therapies. [Table: see text]
Multidimensional spatial characterization of the tumor microenvironment (TME) in synchronous melanoma metastases (SMM) to yield insights into mixed responses to therapy in metastatic melanoma (MM) patients (pts).
Authors: Reuben Alexandre , Tetzlaff Michael T. , Spencer Christine , Ong Giang , Barker Kristi , Prieto Peter A. , Vellano Christopher , Lee Jinho , Hudgens Courtney , McKean Meredith Ann , Gopalakrishnan Vancheswaran , Szczepaniak Sloane Robert , Reddy Sangeetha , Merritt Chris , Warren Sarah , Beechem Joseph M , Davies Michael A. , Hwu Patrick , Mills Gordon B. , Wargo Jennifer Ann 
Published: September 2018

9575 Background: Although both targeted and immune therapies have significantly improved outcomes for mm pts, only a minority of pts experience durable responses with many pts with multiple SMM demonstrating differential responses to therapy. We performed multidimensional spatial characterization of immune markers in SMM from mm patients treated with targeted and immune therapies to improve our understanding of correlations and determinants of response. Methods: NanoString's Digital Spatial Profiling research platform was used on 6 SMM from 3 pts (treatment-naïve; BRAF + MEK targeted therapy treated; anti-PD-1 immunotherapy treated) for 30 immune and signaling proteins. For analysis, we selected and compared immune-rich (CD45+) and tumor-rich (S100B+) regions across SMM. Results were compared to lesion-specific clinical responses. Results: Striking differences in patterns of expression across SMM from individual pts were detected, including in Ki67, CD68 myeloid cells, and the potent immunosuppressor B7-H3. SMM progressing after targeted therapy demonstrated higher pAKT and PD-L1 expression, consistent with described resistance mechanisms. Large differences in expression of PD-L1 were noted following anti-PD-1 therapy, which could contribute to heterogeneous responses. Differential expression patterns in the TME associated with response were also detected, including in increases in CD4 and CD14 cells in progressing lesions. Conclusions: Striking differences in responding and non-responding SMM were observed, providing potential explanations for the heterogeneous clinical responses frequently observed in mm pts. Studies are ongoing to further characterize interactions and spatial distribution of cell types, as well as integrate these findings with previous molecular and immune profiling data (whole exome sequencing, gene expression profiling, flow cytometry, IHC, TCR sequencing) in these and additional SMM to identify actionable strategies to homogenize responses across metastases in mm pts.
Use of circulating tumor DNA to predict survival in patients with resected high-risk stage II/III melanoma.
Authors: Lee Rebecca , Gremel Gabriela , Marshall Andrea , Myers Kevin A , Fisher Nita , Corrie Philippa , Dunn Janet , Dhomen Nathalie , Middleton Mark R. , Marais Richard , Lorigan Paul 
Published: September 2018

9583 Background: Patients with high-risk stage II/III resected melanoma commonly develop metastatic disease. Adjuvant high dose interferon and ipilimumab 10mg/kg are associated with survival benefit, but at the expense of toxicity. At present, we cannot differentiate between patients who will progress to stage IV disease or those cured by surgery. Circulating tumor DNA (ctDNA) is a biomarker of disease progression in many cancers including stage IV melanoma, however its utility in the adjuvant setting has not been investigated. Methods: We performed droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma of 161 stage IIB, IIC/III high-risk melanoma patients enrolled in AVAST-M; a randomized study of bevacizumab vs. observation. Baseline plasma samples were collected within 12 weeks of surgery for both arms. Results: Mutant BRAF or NRASctDNA was detectable ( > 1 copy of mutant ctDNA) in 12% (19/161) of patients. Patients with detectable ctDNA had a decreased disease free interval (DFI; hazard ratio [HR] 3.12; 95% confidence interval [CI] 1.79-5.47; p < 0.0001) and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80-5.79; p < 0.0001) vs. those with undetectable ctDNA. One year DFI rate for patients with detectable ctDNA was 26% (95% CI 10-47%) vs. 74% (95% CI 66-81%) for those with undetectable ctDNA. One year DMFI rate for patients with detectable ctDNA was 37% (95% CI 17-57%) vs. 84% (95% CI 77-89%) with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for N classification and performance status (PS) (DFI HR 3.48; 95% CI 1.95-6.19, p < 0.0001; DMFI HR 3.41, 95% CI 1.88-6.20, p < 0.0001). Five year overall survival (OS) rate for patients with detectable ctDNA was 33% (95% CI 14-55%) vs. 65% (95% CI 56-72%) for those with undetectable ctDNA. OS was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.4-4.96); p = 0.003) and remained significant after adjustment for PS (HR 2.5, 95% CI 1.32-4.74, p = 0.005). Conclusions: CtDNA is predictive of relapse and survival in high-risk, resected melanoma and can potentially aid stratification of patients for adjuvant therapy.