bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating tumor DNA dynamics as prognostic and predictive biomarkers of response to pembrolizumab in patients with virally-related tumors (VRT) treated within the INSPIRE study.
Authors: Oliva Bernal Marc , Liu Zhihui (Amy) , Iafolla Marco Adelmo James , Spreafico Anna , Jennings Sarah , Abdul Razak Albiruni Ryan , Yang Cindy , Bratman Scott Victor , Torti Dax , Pugh Trevor John , Siu Lillian L. , Hansen Aaron Richard 
Published: May 2020

3068 Background: We previously showed a correlation between circulating tumor DNA (ctDNA) dynamics and response to pembrolizumab in a cohort of mixed tumors treated in the INSPIRE study (Yang et al, ESMO 2019). We investigated the prognostic and predictive value of ctDNA dynamics in patients (pts) with VRT. Methods: Pts with VRT (HPV+ squamous cell carcinoma (SCC), EBER+ nasopharyngeal carcinoma (NPC) and MCPyV+ Merkel carcinoma (MC)) and a control cohort of non-VRT (HPV- head and neck SCC) treated with single-agent pembrolizumab were selected for the analysis. ctDNA was assayed at baseline and start of cycle 3 using a pt-specific amplicon-based NGS assay (Signatera). Samples were considered ctDNA positive if ≥2 of 16 pt-specific targets met the qualifying confidence score threshold. Whole exome sequencing (WES) performed in baseline tumor tissue; presence of HPV, EBV and MCPyV in tumor determined through bioinformatic analysis of WES data (VirusFinder, PMID23717618). Changes in tumor size (mm) and response data using RECIST 1.1 were collected. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Results: Twenty pts with VRT (HPV+ head and neck = 8, cervical = 2 and anal = 2 SCC; EBER+NPC = 2; MC = 6) and 11 pts with non-VRT were included. Median follow-up: 11 months (0,5-11). Treatment response: VRT 6 responders (CR + PR + SD > 18weeks) and 14 non-responders (SD < 18 weeks + PD); non-VRT 3 responders and 8 non-responders. Median OS and PFS for all pts were 10.61 and 3.2 months, respectively. No differences in PFS (p = 0.60) nor OS (p = 0.66) were observed among responders between VRT and non-VRT. Among non-responders, VRT had significantly higher OS but not PFS when compared to non-VRT (HR 0.30, p = 0.01 and HR 0.82 p = 0.62, respectively). VRT had quantitatively higher ctDNA at baseline vs non-VRT (Mean 7.9 vs 0.4 ng, p < 0.001). ΔctDNA (Change in ctDNA between baseline and cycle 3) strongly correlated with changes in tumor measurements and response by RECIST 1.1 (Spearman Rho = 0.75) and was associated with survival regardless of viral status (Table). Conclusions: ΔctDNA strongly correlated with changes in tumor response and survival in both VRT and non-VRT. Higher baseline ctDNA was found in VRT. Correlation with circulating viral DNA and radiomics analyses is on-going. [Table: see text]
Spatial analysis of tumor immune microenvironment (TIME) in patients treated with Bintrafusp alfa.
Authors: Abdul Sater Houssein , Robinson Jeffrey , Strauss Julius , Gatti-Mays Margaret Elena , Redman Jason , Floudas Charalampos S. , Marte Jenn , Cordes Lisa M. , Walter Rodriguez Beatriz , Wiseman Andrew , Zaki George , Karzai Fatima , Bilusic Marijo , Madan Ravi Amrit , Schlom Jeffrey , Rajan Arun , Gulley James L. 
Published: May 2020

3070 Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII receptor (TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In preclinical models, bintrafusp alfa treatment promoted CD8+ T cell and NK cell activation, and both immune cell (IC) populations were required for optimal bintrafusp alfa mediated tumor control. However, the effect of bintrafusp alfa on TIME in humans has not been reported. Methods: In this unplanned interim analysis of a biomarker expansion cohort (NCT 02517398), patients (pts) with advanced non-small cell lung cancer (NSCLC) underwent paired biopsies (bx) before and on treatment with bintrafusp alfa (~ 50 days apart). The objective was to evaluate frequency and localization of tumor infiltrated ICs by IHC. Out of 12 pts, 7 had matched (Pre vs Post) tumor-containing specimens sufficient for multiplex immunofluorescence (MxIF) analysis of TIME. Four pts were excluded as Post bx histology for 3/12 [2 PR (partial response), 1 SD (stable disease)] was negative for tumor (necrosis or fibrosis) and 1/12 did not have a Post bx performed. Results: TIME study shows CD8 T cell infiltrates were increased in Post compared to Pre bx (median 161 vs 62/mm²; interquartile range [IQR] 65–396/mm² vs 31–135/mm²; p = 0·04). While M2 macrophages were also increased (median 800 vs 367/mm²; IQR 776–1131/mm² vs 171–831/mm²; p = 0·04), the ratio of M1/M2 was reversed in pts with SD (↑) compared to pts with PD (↓). Other ICs such as CD4, T-regs, NK cells and M1 macrophages were not changed. On average compared to baseline, M2 macrophages were > 2 fold closer to every other IC in pts with PD, but > 2 fold further from any IC in pts with SD. Tregs were relatively closer to other IC in PD pts. Linear Discriminant Analysis was also performed and results indicate that differential IC densities (mainly M1 macrophages and CD4 T cells) do perform as classifiers between long ( > 5 months) and short ( < 5 months) term responses. Conclusions: This study suggests that bintrafusp alfa not only can enhance intratumoral effector IC infiltrates (CD8) but also has a modulating effect on the spatial distribution of both M1/M2 macrophages within the NSCLC TIME. The differential proximity of M2 macrophages to other IC infiltrates and changes in M1/M2 ratios in association with response suggests that an M1/M2 macrophage balance is directly involved in response and/or resistance to bintrafusp alfa. Given the limited number of patients in this cohort, we intend to study effects of bintrafusp alfa in a larger cohort of patients. Clinical trial information: 02517398 .
Rapid expansion of M-MDSCs and association with high levels of plasma TSLP and primary resistance to PD-1 inhibitors in metastatic NSCLC.
Authors: Lau Sally CM , Wong Stephanie WY , Wang Ben X , Patel Devalben , Fares Aline Fusco , Tsao Ming-Sound , Bradbury Penelope Ann , Liu Geoffrey , Leighl Natasha B. , Shepherd Frances A. , Ohashi Pamela S , Sacher Adrian G. 
Published: May 2020

3084 Background: Elevated frequency of peripheral myeloid cell populations has consistently been associated with poor response to immune checkpoint inhibitors (ICI) in metastatic non-small cell lung cancer (mNSCLC). The mechanisms underlying this relationship remains poorly understood. Thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation, has been implicated in a complex feedback loop leading to tumor growth and expansion of myeloid populations. We hypothesized that TSLP levels directly correlate with the presence and expansion of myeloid derived suppressor cell (MDSC) populations and sought to explore their association with response to PD-1 inhibitors in mNSCLC. Methods: mNSCLC patients treated with ICIs underwent baseline and serial blood collection. Peripheral blood mononuclear cells (PBMC) were analyzed by high-dimensional flow cytometry using validated panels to evaluate T/B/NK-cell, Treg and myeloid populations. Plasma cytokines including TSLP were analyzed using ELISA and Luminex assays. Cox and logistic regressions were utilized to correlate biomarkers with progression-free survival (PFS), overall survival (OS) and radiographic response. Results: 30 mNSCLC patients treated with single-agent ICI were included in the analysis. TSLP level was significantly associated with expansion of monocytic(M)-MDSCs in response to ICI treatment (p=0.02). M-MDSC frequency after a median of 20 days of ICI treatment was significantly associated with progressive disease (PD), reduced PFS and OS (all p<0.05) whereas no correlation was seen with baseline M-MDSC frequency. Patients with a doubling of M-MDSCs (n=11) after treatment had a primary PD rate of 64% vs 24% (OR 7.0, p=0.04) and significantly worse median PFS (2.5 vs 7.8 months, HR 2.6 p=0.04). Conclusions: Early expansion of circulating M-MDSCs after treatment with PD-1 inhibitors is associated with elevated baseline TSLP levels and primary disease progression following ICI therapy in mNSCLC. These findings suggest that elevated TSLP and early expansion of myeloid populations may represent an important mechanism of primary resistance to PD-1 inhibitors in mNSCLC.
Relationship of infusion duration to safety, efficacy, and pharmacodynamics (PD): Second part of a phase I-II study using VSV-IFNβ-NIS (VV1) oncolytic virus in patients with refractory solid tumors.
Authors: Merchan Jaime R. , Patel Manish , Cripe Timothy P. , Old Matthew O. , Strauss James Fredric , Thomassen Amber , Diaz Rosa M , Peng Kah Whye , Russell Stephen J. , Russell Luke , Reckner Monica , Wiegert Erol , Bexon Alice Susannah , Powell Steven Francis 
Published: May 2020

3090 Background: VV1 (Voyager V1) is derived from VSV, an RNA virus with low human seroprevalence, engineered to replicate selectively in and kill human cancer cells. In Part 1 of this study, we demonstrated the safety of intratumoral VV1 and dose-response, using serum IFNβ as a biomarker; we observed viral replication in tumor and concomitant lymphocyte/neutrophil trafficking (SITC 2018). 2 other studies suggested greater efficacy and higher IFNβ levels with IV administration. Longer infusion durations were reported to mitigate infusion reactions (IRRs) for another oncolytic. Methods: We studied 3 different infusion durations of VV1 monotherapy at the recommended phase 2 IV dose (1.7 x 1010 TCID50) in patients with advanced solid tumors. Endpoints included safety, preliminary anti-tumor activity, viral titers, IFNβ PD and shedding. Patients received IV VV1 once on D1 and were monitored for DLT over 21 days with efficacy assessments every 6 weeks. IRRs were classified using Lee 2014 criteria for CRS as either constitutional symptoms only (G1) or involving hypotension (G2). Results: 18 patients were treated at 30, 60 and 180-minute durations (n = 7, 5 and 6, respectively). No DLTs, deaths or G3-4 related IRR AEs were observed. Most pts were female (67%), white (100%), with ECOG PS 0 (61%) and median 4 lines of prior systemic therapy (range 1-14) for colorectal (CRC; 56%), squamous cell carcinoma (11%), pheochromocytoma (11%), sarcoma (11%) or other (11%) cancers. The table shows results (number of patients) by infusion duration. Conclusions: There was no difference in safety between the 3 infusion durations, while efficacy and PD markers suggested better anti-tumor effect with 30-minute infusion. VV1 is safe for caregivers, with no viral shedding. Part 3 of this study will now treat CRC patients with VV1 in combination with a checkpoint inhibitor (avelumab). A 5-arm phase 2 basket study in combination with cemiplimab is proceeding with 30-minute infusions. Clinical trial information: NCT02923466 . [Table: see text]
Clinical activity of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in HER2 amplified metastatic breast cancer (MBC) patients (pts) who had progressed on anti-HER2 ADCs.
Authors: Hamilton Erika Paige , Petit Thierry , Pistilli Barbara , Goncalves Anthony , Ferreira Ana Alexandra , Dalenc Florence , Cardoso Fatima , Mita Monica M. , Dezentjé Vincent O. , Manso Luis , Graff Stephanie L. , Bidard Francois Clement , Aftimos Philippe Georges , Escrivá Santiago , Afonso Noemia , Wasserman Ernesto , Bol Kees , Stalbovskaya Viktoriya , Vliet Anastasia , Bachelot Thomas 
Published: May 2020

3093 Background: MCLA-128 (zenocutuzumab ), a HER3 pathway inhibitor, is a humanized bispecific full-length IgG1 antibody targeting both HER2 and HER3 with enhanced ADCC activity. The unique Dock & Block mechanism inhibits HER3 from interacting with its ligands and targets HER2 at a different epitope than trastuzumab, blocking HER2/HER3 dimerization and downstream PI3K/AKT/mTOR signaling. In MBC, HER3 overexpression and/or HER3 ligand upregulation are important drivers leading to trastuzumab resistance, indicating a role for MCLA-128. Preclinical activity was seen in HER2+ breast models when MCLA-128 was combined with trastuzumab. Furthermore, single agent MCLA-128 showed consistent antitumor activity in heavily pretreated HER2+ MBC pts. A phase 2, open-label study explored the MCLA-128/trastuzumab plus vinorelbine triplet in an MBC population. Methods: This open-label trial planned for up to 40 evaluable women with HER2+/amplified MBC progressing on up to 5 anti-HER2 lines including trastuzumab, pertuzumab and an anti-HER2 ADC. Pts received MCLA-128 (750 mg, 2h IV), trastuzumab (8 mg/kg loading, then 6 mg/kg) and vinorelbine (25 mg/m², D1 and 8), q3w. A safety run-in of MCLA-128 + trastuzumab ± chemotherapy was performed. Disease control rate (DCR; RECIST 1.1, per investigator), best overall response (BOR), overall response rate (ORR), safety, and PK are evaluated. Data cutoff was 14Nov2019. Results: 28 pts with a median 3 lines (range 2-5) of anti-HER2 therapy (metastatic setting) and 3 (range 1-6) metastatic sites, received a median of 5 (range 1-17) MCLA-128 cycles. Among 26 pts evaluable for efficacy, 20 patients had CR/PR/SD as BOR; DCR was 77% (90%CI: 60-89) with 1 confirmed CR and 4 PRs (2 unconfirmed). Common related AEs (all grades; G3-4) were neutropenia/neutrophil count decrease (61%; 46%), diarrhea (61%; 4%), asthenia/fatigue (46%; 0), nausea (29%; 0). No clinically significant LVEF decline was seen. At the end of cycle 1, mean trough levels of MCLA-128 was 19.1 µg/mL, and mean terminal half-life was 112 h (n = 8-11). Data on the primary endpoint, clinical benefit rate at 24 weeks, and biomarkers will be provided. Conclusions: The triplet MCLA-128-based combination is active in heavily pretreated pts with HER2+/amplified MBC. The regimen is safe and well tolerated with a manageable AE profile mostly related to the chemotherapy component. Clinical trial information: NCT03321981 .
A phase I, open-label, multicenter, single-dose escalation and multi-dose study of a monoclonal antibody targeting CEACAM1 in subjects with selected advanced or recurrent malignancies.
Authors: Shapira Roni , Weber Jeffrey S. , Geva Ravit , Sznol Mario , Kluger Harriet M. , Wong Deborah J.L. , Liang Bertrand C. 
Published: May 2020

3094 Background: The carcinomembryonic antigen cell adhesion molecule 1 (CEACAM1, CD66a) is a member of the CEA gene family. CEACAM1 interacts homophilically and heterophilically with CEACAM5, and is involved in various anti-proliferative activities. CEACAM1 is expressed on a variety of epithelial and hematological cells, including multiple types of cancer and activated lymphocytes. High CEACAM1 expression in some tumor types is known to be associated with poor disease prognosis. Recently it was demonstrated CEACAM1 is co-expressed on exhausted lymphocytes with other immune checkpoints such as TIM-3 and may regulate downstream activity. CM24 is a novel humanized α-CEACAM1-specific antibody with nM affinity to the N terminal domain of CEACAM1, which blocks intercellular CEACAM1 interactions. Methods: The primary objective was to test the safety and tolerability of CM24 in adult patients with advanced or recurrent cancer. Secondary objectives included assessment of CM24 PK and PD profiles, anti-tumor response and the recommended Phase 2 dose. Patient received IV infusion of CM24 at 7 dose levels ranging between 0.01 and 10 mg/kg in a cycle of 4 doses administered q2wks followed by a 6-week observation only period and additional 6 cycles. Results: 27 patients (median pretreatment of 4 prior regimens; range 2-8, 11 colorectal, 7 melanoma, 4 ovarian, 3 gastric, 2 NSCLC; 13 males, 14 females, mean age of 60 years), were included. Treatment with CM-24 was overall well-tolerated without DLTs up to 10 mg/kg. The most frequent AE was grade 1-3 increased alanine aminotransferase (7 subjects) and the most severe AE was grade 3/4 increase in gamma-glutamyltransferase (4 subjects). Drug-related AEs were observed in 63% of the subjects with grade 3-5 occurred in 3.7%. Eight subjects (29.6%) had stable disease as the best overall response. Median overall survival was 4 (3.4, 8.0) and 6.2 (2.7, 10.2) months for the 3 and 10 mg/kg doses, suggesting dose response. Cmax, AUC and t1/2 increased with increasing dose with the longest t1/2 of 11.2 days obtained at 10mg/kg. The average target occupancy of CM24 at 3mg/kg and 10mg/kg were 75% and 93%, respectively. Conclusions: PK and target-mediated drug disposition analysis suggest that doses higher than 10mg/kg are needed for target saturation at a q2 week regimen while a q3 week regimen is less optimal. A phase 1/2 clinical trial testing CM24 in combination with anti-PD-1 therapy in patients with NSCLC including assessment of CEACAM1 expression is warranted. Clinical trial information: NCT02346955 .
First-in-class microbial ecosystem therapeutics 4 (MET4) in metastatic solid cancer patients treated with immunotherapy: MET4-IO.
Authors: Araujo Daniel Vilarim , Oliva Bernal Marc , Tan Tira Jing Ying , Heirali Alya Abbas , Schneeberger Pierre H.H. , Pimentel Muniz Thiago , Chen Bo , Stayner Lee-Anne , Xia Kathy , Hansen Aaron Richard , Wang Ben X , Hogg David , Cochrane Kyla , Langer Shawn , Mashiach Nissim , Xu Wei , Siu Lillian L. , Coburn Bryan , Spreafico Anna 
Published: May 2020

3098 Background: Therapeutic augmentation of the intestinal microbiome to improve immunotherapy outcomes is an active area of investigation. Microbial Ecosystem Therapeutics (METs) are consortia of human-derived bacteria designed to be reproducible, scalable and safe alternatives to fecal transplant. MET4 is a first-in-class consortium of taxa associated with immune checkpoint inhibitor (ICI)-responsiveness. Here we describe preliminary results of MET4-IO, an interventional trial assessing the safety and ecological effects of MET4 in ICI recipients. Methods: MET4-IO is a randomized investigator-initiated trial, evaluating MET4 in solid cancer patients treated with ICI. MET4-IO involves 3 cohorts of 65 total patients: Group A, a safety cohort of 5 patients already on ICI; Group B, patients starting ICI, randomized 3:1 to receive MET4 or not; Group C, patients on ICI who experience radiological progression but not clinical deterioration, randomized 1:1 to receive MET4 or not. Stool and blood samples are collected at baseline and 4-5 additional time-points. For this interim analysis, 16S rRNA gene sequencing was performed on fecal specimens. Shannon diversity, relative abundance (RA), number and fold-change of MET4 taxa > RA 0.01 were assessed and compared to controls. Results: As of January 26, 2020, 21 patients were enrolled (A = 5,B = 12,C = 4), and 15 (71%) received MET4. The mean age was 65.9 years, 40% were females, 52% had head and neck cancer and 19% melanoma. Sixteen patients (76%) were treated with an anti-PD1 agent as monotherapy and 5 with a combination of anti-PD1 and anti-CTLA4 antibodies. G3-4 toxicities (CTCAEv5.0) attributed to ICI were observed in 13% vs. 17% of MET4 exposed and control patients, respectively. Three patients (20%) experienced toxicities attributed to MET4, all grade 1 except G2 dyspepsia in 1 patient. A greater number of MET4-associated taxa were detectable in MET4 recipients than controls (p < 0.01), with a trend towards higher cumulative RA (p = 0.10). No significant change in Shannon diversity after MET4 was observed, however controls were more likely to lose diversity overtime than MET4 recipients (p = 0.05). Colonization with MET4 varied by recipient and by taxon. Bifidobacterium, Collinsella and Enterococcus were significantly more common and abundant in MET4 recipients than controls. Conclusions: In this cohort, MET4 treatment was safe and associated with higher MET4-associated taxa in recipients than controls. Further analyses including peripheral blood immunophenotyping are ongoing. Clinical trial information: NCT03686202 .
Initial results from a phase II study (TACTI-002) in metastatic non-small cell lung or head and neck carcinoma patients receiving eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab.
Authors: Felip Enriqueta , Doger Bernard , Majem Margarita , Carcereny Enric , Krebs Matthew , Peguero Julio Antonio , Roxburgh Patricia , Forster Martin , Bajaj Pawan , Clay Timothy Dudley , Triebel Frederic 
Published: May 2020

3100 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and then CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses than observed with pembrolizumab alone. We hereby report initial results of a phase II trial (NCT03625323). Methods: A predefined number of patients (pts) are recruited into this 3-cohort trial irrespective of PD-L1 expression; part A: 1st line, PD-X naïve NSCLC; part B: 2nd line, PD-X refractory NSCLC and part C: 2nd line PD-X naive HNSCC. The study has a Simon's 2-stage design, with objective response rate (ORR) as primary endpoint. Secondary endpoints include disease control rate, progression free and overall survival, PK, PD and immunogenicity. Additional pts (N2) will be recruited for each part if pre-specified thresholds for ORR are met. Up to 109 pts will be enrolled. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). The study was approved by ethic committees and institutional review boards. Results: Between 04 Mar 19 and 31 Jan 2020, 48 pts were enrolled and evaluated for safety and exposure. The median age was 66 yrs (range 48-84) and 73 % were male. The ECOG was 0 in 50 % and 1 in 50 % of pts, respectively. Pts received a median of 5 (7) and in total 311 (413) pembrolizumab (efti) administrations, respectively. Three pts (6.3 %) discontinued study treatment due to AEs. The most common ( > 10%) adverse events (AEs) being cough (31 %), asthenia (23 %), decreased appetite (19 %), fatigue (19 %), dyspnea (17 %), diarrhea (15 %) and constipation 13 %). From part A all pts (n = 17) were evaluated. Eight pts (47 %) had a partial response (iPR) and six (35 %) had stable disease according to iRECIST representing an ORR (DCR) of 47 % (82 %). irPRs were observed in all different PD-L1 groups ( < 1%; ≥ 1 % ≤49 %; ≥ 50 %). Ten (10; 59 %) pts are still on therapy (8+ months). In part C stage 1 15/18 pts are evaluable and six (40 %) had an iPR to date. Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in all comer PD-L1 1st line NSCLC and 2nd line HNSCC. Stage 2 has opened for both parts. Clinical trial information: NCT03625323 .