bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma next-generation sequencing (NGS) in advanced non-small cell lung cancer (aNSCLC) patients (pts) treated with immune checkpoint inhibitors (ICIs): Impact of STK11 and TP53 mutations on outcome.
Authors: Pavan Alberto , Zulato Elisabetta , Calvetti Lorenzo , Ferro Alessandra , Nardo Giorgia , Boscolo Alice , Attili Ilaria , Frega Stefano , Dal Maso Alessandro , Pasello Giulia , Guarneri Valentina , Aprile Giuseppe , Conte Pier Franco , Indraccolo Stefano , Bonanno Laura 
Published: May 2020

3046 Background: ICIs revolutionized aNSCLC treatment. The next challenge lays on the search for predictive markers. Detection of multiple tumor-related genetic alterations through NGS in cell free DNA is a promising tool, provided the limited availability of tumor tissue in most cases. Methods: Between January 2017 and October 2019, aNSCLC pts consecutively referring to our Institution were prospectively screened with plasma NGS while included in two clinical trials: VISION (NCT02864992) and MAGIC trial, an observational study. In VISION trial NGS was performed in plasma (Guardant360 test) and tissue (Oncomine Focus Assay). In MAGIC Myriapod NGS-IL 56G Assay was used. Aim of the study was to evaluate the impact of STK11, KRAS and TP53 mutations (muts) on outcome of ICI-treated pts, with overall survival (OS) as primary endpoint. A control group of pts not receiving ICIs was also analyzed. Results: A total of 235 NSCLC pts were enrolled and received ICIs. 93 pts were analyzed in plasma at the time of beginning ICIs: median OS was 18.9 m (95% CI: 13.7-24.1) and median immune-related progression free disease (irPFS) 3.8 m (95% CI: 2.5-5.1). 49 (52.7%), 22 (23.7%) and 8 (8.6%) pts carried TP53, KRAS and STK11 pathogenic alterations, respectively. STK11 mutated pts showed a trend for worse OS compared with wildtype counterpart (14.9 m, 95% CI: 6.5-23.3, versus 20.3, 95% CI: 13.4-27.2, p = 0.192) KRAS muts had no impact on outcome. Pts with TP53 or STK11/KRAS co-mut (n = 3) had worse OS (12.3 m, 95% CI: 9.2-15.4; HR = 3, 95% CI: 1.6-5.8, p = 0.001 and 5.9 m, 95% CI: 1.4-7.6; HR = 2.9, 95% CI: 1.4-6.3, p = 0.007) and worse irPFS (2.8 m, 95% CI: 1.7-3.9, HR = 1.8 95% CI: 1.1-3.1, p = 0.03 and 1.2 m, 95% CI: 0.9-1.5, HR = 2.2 95% CI: 1.2-4.1, p = 0.01). Number of muts negatively impacts pts’ OS (HR = 1.2, 95% CI: 1.1-1.3, p = 0.02) and was higher among TP53 mutated pts (p < 0.001, Mann-Whitney test). In multivariate analysis, TP53 and STK11/KRAS retained significance. A control group of pts not receiving ICIs was analyzed (n = 101): median OS was 16.8 m (95% CI: 13-20.6). Nor STK11 (n = 10), nor STK11/KRAS (n = 6) had impact on OS (HR = 1.8, 95% CI: 0.7-4.7, p = 0.267 and 1.4, 95% CI: 0.7-3.0, p = 0.293) while the presence of TP53 muts (n = 41) was associated with shorter OS (11.4 m, 95% CI: 7.3-15.5; HR = 2.2, 95% CI: 1.2-4.2, p = 0.009). Conclusions: NGS performed in plasma might be used to detect predictive markers. TP53 muts in plasma at baseline had prognostic value, while STK11/KRAS muts were associated with worse outcome to ICIs.
TCR clonality and Treg frequency as predictors of outcome in stage III NSCLC treated with durvalumab.
Authors: Lau Sally CM , Soleimani Shirin , Wong Stephanie WY , Pedersen Stephanie , Wang Ben X , Elkrief Arielle , Patel Devalben , Fares Aline Fusco , Jao Kevin , Daaboul Nathalie , Hakozaki Taiki , Bradbury Penelope Ann , Liu Geoffrey , Leighl Natasha B. , Tsao Ming-Sound , Ohashi Pamela S , Pugh Trevor John , Routy Bertrand , Shepherd Frances A. , Sacher Adrian G. 
Published: May 2020

3050 Background: Novel blood-based biomarkers evaluating T-cell receptor (TCR) clonality as well as the frequency/activation of immune populations hold significant potential for predicting response and elucidating the biology of anti-tumor immunity in stage 3 NSCLC treated with durvalumab. In this study, we sought to characterize clinical and immunologic predictors of durable response to therapy with a specific focus on TCR clonality and peripheral immune populations. Methods: Stage 3 NSCLC patients undergoing chemoradiation (CRT) and durvalumab were prospectively recruited and underwent baseline and serial blood collections. TCR repertoire analysis was performed on cfDNA using hybrid-capture TCR sequencing and TCR diversity estimated using Shannon’s entropy index. Viably preserved 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. Correlations between cell populations were examined using linear and cox regression. Results: 134 stage 3 NSCLC patients who received durvalumab had a median PFS was 15.4 months, with worse PFS in patients with PD-L1 1-49% (HR 2.4, p = 0.03) and PD-L1 < 1% (HR 2.6, p = 0.03). Smoking and EGFR/ALK mutations were not predictors of PFS. Immune profiling was performed in a pilot of 19 patients. Baseline TCR diversity did not associate with clinical factors or outcome. However, lack of clonal expansion after CRT indicated by a higher Shannon’s index was significantly associated with increased frequency of Tregs after durvalumab (p < 0.05). In turn, this elevation in Tregs was associated with significantly reduced PFS in EGFR/ALK wt patients (p = 0.03) and a trend towards reduced PFS in the overall cohort (HR 5.2, p = 0.1). Conclusions: Clonal expansion of T cells after CRT may influence the likelihood of an anti-tumor immune response following PD-L1 blockade in stage 3 NSCLC. Similarly, expansion of peripheral Treg populations is associated with increased likelihood of disease recurrence. Further characterization of TCR clonality, minimal residual disease and T cell subpopulations using serially collected blood is ongoing.
Phase Ib clinical study of CBP501, cisplatin, and nivolumab administered every three weeks in patients with advanced refractory tumors: Efficacy in dose-escalation and expansion cohorts.
Authors: Matrana Marc Ryan , Tsai Frank , Cleary James M. , Satti Suma , Borazanci Erkut , Estes Jacob , Moser Justin , Do Khanh Tu , Du Lingling , Sharma Sunil , Khemka Vivek , Kolmakov Valentin , Kawabe Takumi , Shapiro Geoffrey 
Published: May 2020

3059 Background: CBP501 is a 12-amino acid G2 checkpoint abrogator and calmodulin-modulating peptide that increases platinum influx into tumor cells and induces tumor immunogenic cell death. CBP501 also suppresses platinum-induced release of cytokines by macrophages, lowers cancer stem cell populations, and reduces migration, invasion, and epithelial-mesenchymal transition of tumor cells. We report safety and efficacy outcomes from dose-escalation and expansion cohorts of a Phase Ib study of CBP501 combined with cisplatin and nivolumab (NCT03113188). Methods: An open-label Phase I trial was conducted using a 3+3 design: CBP501 and cisplatin were dosed simultaneously by 1h infusion Q3W at 4 different combined dose levels (CBP501: 16 or 25 mg/m2; cisplatin: 60 or 75 mg/m2) in the dose-escalation cohort. Nivolumab (240 mg) was dosed on the same day as a 1h infusion following CBP501/cisplatin. CBP501 and cisplatin were fixed at 25 and 60 mg/m2, respectively, in the expansion cohort. Eligible patients had pathologically confirmed, locally advanced or metastatic solid tumors, age ≥18 years, ECOG PS 0-1, life expectancy > 3 months. The dose-expansion cohort had pretreated metastatic exocrine pancreatic cancer or microsatellite stable colorectal cancer (CRC). Scans were performed every 6 weeks while on study, then every 3 months. Results: The most common related adverse events (AEs) were infusion-related reaction (rash, itching, hives; n = 32/37 [Gr 1, n = 4; Gr 2, n = 28]; 86%) and anemia (n = 19/37 [Gr 1/2, n = 10; Gr 3, n = 9]; 51%). There were no additional safety signals other than those known for each agent. At January 9, 2020 (interim analysis), efficacy was evaluable in 17/19 patients in the dose-escalation cohort. Unconfirmed partial response was seen in 18% (3/17; 1 pancreatic, 1 colorectal, 1 cholangiocarcinoma), with > 3 months stable disease (SD) in 41% (7/17), disease control in 41% (7/17), and > 8 months overall survival (OS) in 53% (9/17). In the expansion cohort, efficacy was evaluable in 8/13 patients with pancreatic cancer: > 4 months SD was 50% (4/8), median progression-free survival 4.2 months, and median OS 5.9 months (6/8 ≥3rd line). The CRC cohort median OS for all CRC patients (n = 10) including the dose-escalation cohort (n = 5) was 17.5 months (10/10 ≥3rd line). Conclusions: The triple-drug combination is reasonably tolerable with preliminary signs of efficacy in refractory solid tumors, including those in which cisplatin and nivolumab have limited single-agent activity. Clinical trial information: NCT03113188 .
Safety of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors.
Authors: Johnson Melissa Lynne , Patel Manish R. , Cherry Mohamad , Kang Yoon-Koo , Yamaguchi Kensei , Oh Do-Youn , Hussein Maen A. , Kitano Shigehisa , Kondo Shunsuke , Hansen Aaron Richard , Percent Ivor John , George Ben , Arrowsmith Edward , Morimoto Manabu , Duffy Christine , Ge Miaomiao , Rohrbacher Maren , Elgadi Mabrouk M. , Bendell Johanna C. 
Published: May 2020

3063 Background: LAG-3, an immune checkpoint receptor involved in T-cell regulation, is frequently co-expressed with PD-1. LAG-3 and PD-1 signaling contributes to immune cell exhaustion and reduces the immune response to tumor cells. Dual inhibition of PD-1 and LAG-3 may reactivate the T-cell response better than blockade of either individual pathway. Here, we report combined safety data from 4 trials investigating BI 754111, an anti-LAG-3 mAb, in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: Data from 2 phase I dose-escalation/expansion trials, 1 phase I imaging trial, and 1 phase II trial were included. Eligible patients had advanced and/or metastatic solid tumors with measurable disease and an Eastern Cooperative Oncology Group performance status ≤1. Patients received BI 754111 (intravenously [iv], 4–800 mg) in combination with BI 754091 (iv, 240 mg fixed dose) every 3 weeks (q3w). Patients remained on treatment until progressive disease or unacceptable toxicity. In each trial, safety was assessed by incidence and severity of adverse events (AEs), and graded according to Common Terminology Criteria for AEs, version 5. Results: Overall, 321 patients were treated with BI 754111 in combination with BI 754091 (200 [62%] male; median age, 63 years [range 18–88]). Median treatment exposure was 85 days (range 9–625). Of these patients, 282 (87.9%) had any AE (G≥3 in 99 [30.8%]). 285 patients received the 600 mg recommended phase II dose of BI 754111 plus BI 754091 240 mg q3w. Median treatment exposure in these patients was 74 days (range, 8–590). The table shows the 3 most common AEs and 4 most common immune-related AEs, and their frequency. 21 (7.4%) patients had AEs leading to study drug discontinuation, most commonly infusion-related reactions (IRRs) in 6 (2.1%) patients. Serious AEs (all-cause) occurred in 77 patients (27.0%), most commonly pleural effusion in 6 (2.1%) and deep vein thrombosis in 4 (1.4%) patients. 2 patients (0.7%) experienced an AE resulting in death (cardiac tamponade and acute kidney injury, both related to underlying diseases). Conclusions: The combination of BI 754111 and BI 754091 had a manageable safety profile, similar to other checkpoint inhibitors. Clinical trial information: NCT03156114, NCT03433898, NCT03697304, NCT03780725 . [Table: see text]
Fecal microbiota transplantation (FMT) for immune checkpoint inhibitor induced–colitis (IMC) refractory to immunosuppressive therapy.
Authors: Wang Yinghong , Ma Weijie , Abu-Sbeih Hamzah , Jiang Zhi-Dong , DuPont Herbert L. 
Published: May 2020

3067 Background: ICIs are efficacious treatment for several advanced malignancies. IMC can limit their use, and can be refractory to medical treatment (immunosuppression) with significant morbidity. Gut microbiome alteration affects IMC development. We sought FMT as a novel therapy for IMC refractory to immunosuppressive therapy. Methods: 15 patients who received FMT for IMC after failure of immunosuppressive therapy were included (6/2017-1/2020). FMT was performed via colonoscopy with healthy donor’s stool. Results: Median age was 55 years with 67% males. 5 patients received PD(L)-1, one CTLA-4 and 9 on combination. Majority had genitourinary cancers followed by melanoma. Median time from ICI to IMC was 75 days. 14 patients had grade 3-4 diarrhea and 9 had grade 3-4 colitis. Endoscopy showed mucosal inflammation in 12 patients and normal mucosa in 3 patients. IMC was refractory to 2-3 doses of infliximab or vedolizumab after corticosteroids prior to FMT. Median time from IMC onset to FMT was 75 days. 13 patients received one . 11 patients achieved clinical response within 10 days of FMT (7-14). Symptom remission was maintained for a median follow-up of 13 months. 6 patients resumed non ICI cancer treatments after FMT. 4 patients had persistent symptoms; 2 continued on vedolizumab, 1 had total colectomy, and 1 transferred to hospice. 4-8 weeks after FMT, endoscopic remission was achieved in 64% of the 11 patients who responded to FMT. No adverse events were reported. Conclusions: FMT treatment was successful in 73% of patients with for IMC refractory to immunosuppressive therapy. Controlled clinical trials are warranted to confirm our conclusion. [Table: see text]
Interrogation of neoantigen-specific CD8 T cells in peripheral blood following PD-L1 blockade in patients with metastatic urothelial carcinoma (mUC).
Authors: Holm Jeppe Sejerø , Funt Samuel Aaron , Bjerregaard Anne-Mette , Reading James L. , Maher Colleen Anne , Regazzi Ashley Marie , Wong Phillip , Al-Ahmadie Hikmat , Overgaard Nana Haahr , Tamhane Tripti , Bentzen Amalie Kai , Snyder Alexandra , Merghoub Taha , Wolchok Jedd D. , Nielsen Morten , Rosenberg Jonathan E. , Bajorin Dean F. , Hadrup Sine Reker 
Published: May 2020

3075 Background: Proliferation of CD8 T cells can be detected in the blood of cancer patients (pts) following a single dose of immune checkpoint blockade (ICB) and tends to be more robust in responding pts. Furthermore, tumor mutational burden (TMB) is seen to predict outcome to ICB across cancers. Mutation-derived neoepitopes presented on the tumor cell surface is believed to be recognized by T cells and are thus critical for tumor clearance. However, the capacity to mount a neoantigen T cell response and the kinetics in relation to ICB remain poorly understood. Methods: 24 pts with mUC were treated with atezolizumab (anti-PD-L1) 1200mg q3w on IMVigor 210 at MSKCC and included in here. Pt-specific neoepitopes were predicted based on whole-exome and RNA sequencing of pre-treatment archival tumors using the MuPeXI platform. Using DNA-barcode labelled pMHC multimers, we investigated CD8 T cell recognition of mutation-derived neoepitopes by screening pt PBMC samples pre- and post-treatment with atezolizumab (n = 85 PBMC samples). The kinetics of neoepitope-specific CD8 T cells were assessed for association with durable clinical benefit (DCB; defined as progression free survival > 6 mo). Results: Neoepitope peptide libraries of between 200-587 peptides were generated per pt (mean = 260 peptides per pt). 31 out of a combined 56 possible pt HLA types across the cohort were utilized for T cell analyses (mean four HLAs per pt). MHC multimer-based screening of pt PBMCs revealed detection of neoepitope-specific CD8 T cells in 22 of 24 pts pre-treatment (range one to 14 neoepitope responses) and 21 of 22 pts post-treatment (up to 273 weeks after trial start; one to 19 neoepitope responses). There were large inter- and intra-patient variations of neoepitope-specific CD8 T cell responses during treatment with the largest increases occurring at the 3-wk, post-treatment initiation timepoint. We observed that pts with DCB tend to raise a broader neoantigen T cell response than patients without DCB. 38% of pts without DCB and 67% of pts with DCB exhibited an increase in neoepitope-specific CD8 T cell responses within 3 wks of treatment initiation. Conclusions: Using high-throughput screening, pt-specific neoepitope reactive CD8 T cells could be detected pre- and post-treatment in pts with mUC treated with atezolizumab. Phenotypic characterization of neoepitope reactive CD8 T cells is ongoing. These data may help elucidate the dynamics and characteristics of the T cells of highest relevance to the ICB-induced, anti-tumor immune response.
Preliminary results of sintilimab plus different dose of IBI305 (anti-VEGF monoclonal antibody) in patients with advanced hepatocellular carcinoma: A phase Ib study.
Authors: Zhang Wen , Bi Xinyu , Sun Yongkun , Yu Yue , Zhou Jian-guo , Zeng Huiying , Wu Fan , Luo Yang , Yang Yong , Chen Mingxia , Wang Yan , Zhou Hui , Cai Jianqiang , Zhao Hong , Zhou Aiping 
Published: May 2020

3079 Background: The study aimed to evaluate the safety and efficacy of sintilimab, a PD-1 blockade, plus IBI305, a biosimilar candidate of bevacizumab, in patients (pts) with advanced hepatocellular carcinoma (HCC). Methods: Adults with histocytologically confirmed advanced or metastatic HCC were enrolled in this two-part study. Part 1 was dose escalation trial, with initial dose of sintilimab 200 mg plus IBI305 7.5 mg/kg, q3w (low-dose group). If tolerable, IBI305 was escalated to 15 mg/kg (high-dose group). In part 2 for extension, at least 20 pts were enrolled to each tolerable dose group. Results: As data cutoff (Jan. 7, 2020), 50 pts were enrolled, 29 in low-dose group and 21 in high-dose group. 41 patients were systemic treatment naïve. The median treatment cycle was 4 (range: 1-19) in low-dose group and 11 (range: 1-16) in high-dose group. Most TRAEs were G1-2 with the most common being hypertension (28.0%) and pyrexia (26.0%). Totally, the grade 3 or more TRAEs were occurred in 6 (12.0%) pts, including hypertension occurred in 2 (4%) pts. The objective response rate (ORR) per RECIST v1.1 was 24.1% (95%CI: 10.3 - 43.5) in low-dose group, and 33.3% (95% CI:13.3 - 59.0) in high-dose group. As with the cutoff date, the median PFS has not been reached and the 6-month PFS rates were 60.5% (95%CI 36.1, 78.0) and 75.8% (95% CI: 47.3, 90.2), respectively. Conclusions: The combination of sintilimab and IBI305 showed promising efficacy and favourable safety profile in advanced HCC in both low-dose and high-dose groups. The preliminary result of this study warrant further exploration of dose selection for anti-VEGF/VEGFR agent when combined with PD-1/PD-L1 antibody. Clinical trial information: NCT04072679 . [Table: see text]
Impact of relacorilant, a selective glucocorticoid receptor antagonist, on the immunosuppressive effects of endogenous cortisol.
Authors: Greenstein Andrew , Munster Pamela N. , Sachdev Jasgit C. , Fleming Gini F. , Grauer Andreas , Shepherd Stacie Peacock 
Published: May 2020

3091 Background: Cortisol, an endogenous glucocorticoid receptor (GR) agonist, controls a broad transcriptional program that affects T-cell activation, pro-inflammatory cytokine secretion, and immune cell trafficking. By selectively antagonizing GR, relacorilant may reverse the immunosuppressive effects of cortisol in solid tumor cancers. Methods: Immune cells and GR expression were assessed by IHC and calculated based on The Cancer Genome Atlas (TCGA) data. Human PBMCs were stimulated with αCD3+IL-12 +/- cortisol or cortisol + relacorilant. EG7 tumor-bearing mice were treated with anti-PD1 (RMP1-14) ip Q5D +/- relacorilant QD. Whole blood mRNA was measured via Nanostring, hematology was performed using standard complete blood count assays, and cytokines were assessed by immunoassays in study NCT02762981. Results: GR expression was observed in human tumor and immune cells. Its abundance was positively correlated with tumor infiltration of TH2, Treg, and PDL1+ cells ( P< .001) and negatively correlated with TH1 cells ( P< .001). In PBMCs, cortisol inhibited, and relacorilant restored, CD8+ T-cell activation ( P< .001) and pro-inflammatory cytokine secretion (TNFα P= .006, IFNγ P< .05). In the EG7 syngeneic model, relacorilant increased αPD1 efficacy ( P= .007) and decreased circulating IL-10 ( P< .002). In patients with advanced solid tumors, relacorilant + nab-paclitaxel systemically suppressed the expression of canonical GR-controlled genes ( ptgs2 P< .001) and genes encoding candidate-immunomodulatory drug targets ( cxcl8, ptger4, ido1; P< .001). In a small subset of patients (n = 11), sustained clinical response was associated with increased T-cell count ( P= .06) and IFNγ ( P= .03), as well as decreased Tregs ( P= .06) and IL-10 ( P= .03). Conclusions: Evidence of T-cell activation by relacorilant was observed in PBMCs, syngeneic mouse tumors, and patients with sustained response in a Phase 1 study. This supports the hypothesis that relacorilant can reverse immune suppression by endogenous cortisol in solid tumor cancers. Clinical studies with immune checkpoint inhibitors and relacorilant are planned.
A phase I dose-escalation and expansion study of intratumoral CV8102 as single-agent or in combination with anti-PD-1 antibodies in patients with advanced solid tumors.
Authors: Eigentler Thomas , Bauernfeind Franz G , Becker Jürgen C. , Brossart Peter , Fluck Michael , Heinzerling Lucie , Krauss Jürgen , Mohr Peter , Ochsenreither Sebastian , Schreiber Jutta Sylvina , Terheyden Patrick , Weide Benjamin , Weishaupt Carsten , Funkner Fatma , Muth Anke , Kays Sarah-Katharina , Stosnach Claudia , Daehling Angelika , Quintini Gianluca , Gnad-Vogt Senta Ulrike 
Published: May 2020

3096 Background: CV8102 is a non-coding, non-capped RNA that activates the innate (via TLR7/8, RIG-I) and adaptive immunity dose-dependently. CV8102 injected intratumorally (i.t.), as a single agent or combined with systemic anti-PD-1 antibody (Ab) led to tumor growth inhibition in animal models and showed synergism with PD-1 blockade. Methods: An open-label, cohort-based, dose escalation and expansion study in patients with advanced cutaneous melanoma (cMEL), cutaneous squamous cell carcinoma (cSCC), head and neck squamous cell carcinoma (hnSCC) or adenoid cystic carcinoma (ACC) is ongoing investigating i.t. CV8102 as single agent and in combination with anti-PD-1 antibodies. [NCT03291002]. Results: As of December 2019, 23 patients in the cohort A (single agent) and 13 patients in cohort C (combination with anti-PD-1 Ab) were exposed to at least one dose of CV8102 at dose levels of 25-600 µg (single agent) and 25-450 µg (combination). No dose limiting toxicities (DLTs) were observed within the first two weeks of study drug treatment. Most frequent TEAEs were G1/2 fatigue, fever, chills and headache. 4 (17%) patients (pts) in cohort A and 3 (23%) pts in cohort C experienced related G3 TEAEs that were manageable with supportive treatment (liver enzyme increases (3), abscess at injection site (1), hypertension (1), asymptomatic elevation of pancreatic enzymes (2)). In cohort A, 2 cMEL patients experienced an objective response according to RECIST 1.1 (1 CR in a PD-1 naïve pt and 1 PR in a PD-1 refractory pt) and 2 further pts (cMEL, hnSCC) showed SD with shrinkage of tumor lesions. Conclusions: CV8102 i.t. was well tolerated without dose limiting toxicities to date and showed evidence of single agent activity. Updated results on safety, efficacy and serum biomarkers will be presented. Clinical trial information: NCT03291002 .