bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: Updated results.
Authors: Berdeja Jesus G. , Lin Yi , Raje Noopur S. , Siegel David Samuel DiCapua , Munshi Nikhil C. , Liedtke Michaela , Jagannath Sundar , Maus Marcela Valderrama , Turka Ashley , Lam Lyh Ping , Hege Kristen , Morgan Richard , Quigley M. Travis , Kochenderfer James 
Published: September 2018

3010 Background: To test the safety and efficacy of the CAR T cell modality in relapsed/refractory multiple myeloma (MM), we have designed a second-generation CAR construct targeting B cell maturation antigen (BCMA) to redirect T cells to MM. bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB costimulatory motif and a CD3-zeta T cell activation domain. We will report updated safety and efficacy following initial results (Berdeja et al, ENA 2016). Methods: CRB-401 (NCT02658929) is a multi-center phase 1 dose escalation trial of bb2121 in patients with relapsed and/or refractory MM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥ 50% BCMA expression on plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis. Patients undergo lymphodepletion with Flu (30 mg/m2) / Cy (300 mg/m2) daily for 3 days then receive 1 infusion of bb2121. The study follows a standard 3+3 design with planned dose levels of 5, 15, 45, 80 and 120 x 107 CAR+ T cells. Results: As of November 18, 2016, 11 patients had been infused with bb2121 in the first 4 dose cohorts, and 9 patients had reached at least 1 month of follow-up. As of data cut-off, no dose-limiting toxicities and no > Grade 2 neurotoxicities or cytokine release syndrome (CRS) had been observed. Grade 1-2 CRS had been reported in 8/11 (73%) treated patients. All patients treated with doses of 15.0 x 107or higher remained on study and the overall response rate (ORR) in the 6 evaluable patients at these doses was 100%, including 2 sCRs and 2 MRD-negative responses (1 sC, 1 VGPR). CAR+ T cell expansion has been demonstrated consistently. An additional 6 months of follow up on previously reported results and initial data from an additional ~10 patients will be presented. Conclusions: bb2121 shows promising efficacy at dose levels above 5 x 107 CAR+ T cells, including 2 sCRs and ongoing clinical responses at 6 months, with mild and manageable CRS to date. These initial data support the potential of CAR T therapy with bb2121 as a new treatment paradigm in MM. Study sponsored by bluebird bio. Clinical trial information: NCT02658929.
A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.
Authors: Friedlander Michael , Meniawy Tarek , Markman Ben , Mileshkin Linda R. , Harnett Paul R. , Millward Michael , Lundy Joanne , Freimund Alison E. , Norris Christie , Mu Song , Wu John , Paton Virginia E. , Wang Lai , Gao Bo 
Published: September 2018

3013 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that will potentially increase the efficacy of BGB-A317. A phase 1 study identified 60mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, PK profile, and preliminary anti-tumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6 -12 pts with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1-3, BGB-290 doses ranged between 20-60mg PO BID with BGB-A317 2mg/kg IV Q3W. In DLs 4 - 5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 16 Jan 2017, 38 pts [median age 59 years (34-75)] were treated in DLs 1-4; enrollment to DL5 is ongoing. One DLT of persistent Gr 2 nausea was reported in DL 4. The most common adverse event (AE) considered related to both study drugs was fatigue (10.5%). Immune-related AEs were Gr 3 hypophysitis (n = 1), Gr 3 or 4 autoimmune hepatitis(n = 2), and Gr 2 elevated AST/ALT (n = 1). Decreases in tumor burden have been observed in 16 pts; 7 achieved a PR (5 with ovarian and one each with uterine and pancreatic cancer) and one CR was observed in ovarian cancer. Six pts had SD for > 6 months including 2 pts with pancreatic cancer who received BGB-A317+BGB-290 for 189 and 281 days. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: BGB290 and BGB-A317 can be combined. Dose expansion in multiple tumor types is planned to commence in 2017 once the RP2D is determined. Clinical trial information: NCT02660034.
Antibiotics prescription to decrease progression-free survival (PFS) and overall survival (OS) in patients with advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors.
Authors: Derosa Lisa , Routy Bertrand , Mezquita Laura , Naltet Charles , Enot David , Fidelle Marine , Goubet Anne-Gaëlle , Soria Jean-Charles , Massard Christophe , Goldwasser Francois , Zitvogel Laurence , Brosseau Solenn , Escudier Bernard J. , Loriot Yohann , Zalcman Gerard , Besse Benjamin , Albiges Laurence 
Published: September 2018

3015 Background: Use of antibiotics (ATB) alters the gut microbiota composition and decreases bacterial diversity. Pre-clinical evidences demonstrated the impact of the microbiota in the efficacy of immune checkpoint blockades (ICB) in cancer. Interaction between ATB and ICB has not been extensively investigated in cancer patients (pts). Our study evaluated the effect of ATB in cancer pts treated with PD-1/PD-L1 inhibitors. Methods: We conducted a retrospective analysis of pts treated with PD-1/PD-L1 inhibitors for advanced Renal Cell Carcinoma (RCC), Urothelial Cancer (UC) and Non-Small Cell Lung Cancer (NSCLC) and data on ATB use were collected. ATB(+)/(-) groups were defined as pts treated or not with ATB before (2 months period) or within the first month of ICB. PFS and OS were compared between both groups among all pts and then according to tumor site. Statistical analyses were performed using the Kaplan-Meier method. Cox regression analyses were performed separately for each cancer type adjusting for its specific risk factors. Results: Among 175 pts included, 51 (29%) received ATB (mostly beta-lactamases and fluoroquinolones). ATB(+) group had shorter PFS and OS when compared to ATB(-) group: 3.4 vs. 5.2 months, p < 0.013, and 12.2 vs. 20.8 months, p < 0.001, respectively. According to tumor type, ATB(+) group translated into decrease OS (7.0 vs. 13.8 months, p < 0.038) in NSCLC. In RCC and UC pts, ATB (+) group had shorter PFS when compared to ATB(-) group (4.3 vs. 7.4 months, p < 0.013 and 1.8 vs. 4.3 months, p = 0.048, respectively). The negative impact of ATB was maintained after multivariate analyses adjusting for risk factors in each tumor type. Conclusions: ATB prescription preceding or concomitant to the first injection of PD-1/PD-L1 inhibitors impaired the outcome in patients with advanced cancers. This reduction in efficacy seems to be independent of classical prognostic factors in RCC, UC and NSCLC. These data should be validated in larger cohort. In addition, the role of gut composition to explain this interaction is ongoing, as well as novel diagnosis tools based on microbiota to predict response/resistance to ICB.
Overall survival prognosis of patients in immuno-oncology phase I trials: The Gustave Roussy score.
Authors: Bigot Frederic , Castanon Eduardo , Baldini Capucine , Aspeslagh Sandrine , Marabelle Aurelien , Massard Christophe , Hollebecque Antoine , Postel-Vinay Sophie , Soria Jean-Charles 
Published: September 2018

3029 Background: The evaluation of patient’s life expectancy is crucial to select patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on 3 objective variables (number of metastatic sites, LDH and serum albumin) was validated in patients treated with cytotoxic and targeted therapies. We aimed to determine if those factors were applicable to immunotherapy (IT) phase I trials. Methods: A retrospective analysis for risk factors of survival was conducted in a discovery cohort of 155 patients enrolled into IT phase I trials at our institution. We computed univariate and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in IT phase I trials was used to prospectively re-validate this score. Results: 155 patients receiving an experimental IT between March 2012 and January 2016 were included in the discovery cohort. A MVA assessing the RMH Score variables showed that albumin < 35 g/dL (HR 1.73, 95% CI 1.05-2.86) and LDH > upper normal limit (1.88, 95% CI 1.12-3.15) were independent negative prognostic factors for OS. As opposed to the RMH score, number of metastases was not associated with a poorer outcome for this IT cohort (0.83 95% CI 0.51-1.35). Interestingly, a neutrophil to lymphocyte ratio (N/L) > 6 (1.75, 95% CI 1.04-2.95) was associated with a worse OS. A risk analysis based on the results of the MVA showed that patients presenting a high score (2-3) had a significantly shorter OS (20.4 weeks; 95% CI 5.7-35.2) compared to those with a low score (0-1) (68.9 weeks; 95% CI 50-83.7) (HR = 2.9 95% CI 1.87-4.64). In the validation cohort of 113 patients, the patients presenting a high score showed an inferior OS (HR = 6.3, 95% CI 2.7-14.8). Conclusions: In phase I trials of IT, traditional prognostic variables included in the RMH Score are suboptimal to determine patient’s prognosis. In this context, the N/L ratio, which reflects the immune contexture, is a significant prognostic variable. The new Gustave Roussy Score, based on albumin, LDH and N/L ratio allows to better select patients for IT phase I trials.
Very early molecular marker of tumor response to PD-1 inhibition in plasma of patients with advanced non-small cell lung cancer (NSCLC).
Authors: Hiltermann Thijo Jeroen Nicolaas , Miedema A , Hijmering-Kappelle Lucie , Groen Harry J.M. , Schuuring Ed 
Published: September 2018

3030 Background: Nivolumab shows a durable tumor response in 20 % of advanced NSCLC patients. While a PD-L1 immunohistochemistry complementary diagnostic has been approved, there is a need to identify a predictive biomarker with greater diagnostic accuracy. Methods: In an ongoing study of patients, treated with nivolumab every 2 weeks for advanced recurrent NSCLC and a known KRAS mutation in the primary tumor, liquid biopsies were taken by a simple blood draw at baseline (before treatment), 1, 2, 4, 6 and thereafter every 12 weeks until disease progression. Circulating tumor DNA (ctDNA) was extracted from cell free plasma and tested with a specific digital droplet PCR (ddPCR)-KRAS G12/G13 screenings assay (BIORAD). Mutation levels in plasma were compared with tumor response on CT scans by RECIST v.1.1. CT scans were performed at baseline and thereafter every 6 weeks until disease progression. Results: Patient characteristics are shown in table 1. In this prospective analysis specific patterns could be demonstrated in plasma ctDNA testing of KRAS mutation levels. All 4 responders showed an increase of mutant copies/ml plasma in the first week followed by a clear drop to non-detectable KRAS mutations at all CT evaluated tumor responses. The 2 non-responders however, did not show the increase in mutant copies/ml at one week and showed a gradual increase in mutant copies/ml in the following weeks. Conclusions: Specific plasma ctDNA testing seems a very promising early biomarker (1 week) for tumor response to PD-1 therapy. [Table: see text]
Phase 1 safety of ICOS agonist antibody JTX-2011 alone and with nivolumab (nivo) in advanced solid tumors; predicted vs observed pharmacokinetics (PK) in ICONIC.
Authors: Burris Howard A. , Callahan Margaret K. , Tolcher Anthony W. , Kummar Shivaani , Falchook Gerald Steven , Pachynski Russell Kent , Tykodi Scott S. , Gibney Geoffrey Thomas , Seiwert Tanguy Y. , Gainor Justin F. , LoRusso Patricia , Hilbert James , Apgar Josh F , Hua Fei , Burke John M , Lazaro Manny , Clancy Myles , Ding Baoyu , Trehu Elizabeth G. , Yap Timothy Anthony 
Published: September 2018

3033 Background: JTX-2011 is an agonist monoclonal antibody that targets ICOS, Inducible CO-Stimulator of T cells. A dual mechanism of action is intended to activate antigen-specific CD4 T effector cells and selectively deplete intratumoral T regulatory cells. JTX-2011 is equally potent across human, rodent, and non-human primate species. Methods: A quantitative systems pharmacology (QSP) model describing target binding by JTX-2011 and target mediated drug disposition in blood, tumor and non-tumor tissues was based on preclinical potency and non-linear PK data across species. The model was translated to predict PK and target engagement (TE) in humans to facilitate dose selection. The QSP model predicts > 95% TE for 21 days at the top planned dose. We present safety and actual/predicted PK from a Phase 1 study of JTX-2011 alone (Part A) and safety in combination with nivo (Part B). Results: 25 subjects have been dosed, 19 in 4 cohorts of JTX-2011 alone at .003, .01, .03, and .1 mg/kg IV q 21 days, and 6 in 2 cohorts of JTX-2011 .01 mg/kg and .03 mg/kg IV plus nivo 240 mg IV q21 days. Safety data from ≥ 1 cycle is available for 12 subjects in Part A (7 ≥ 3 cycles), and 3 in Part B (all ≥ 3 cycles). PK data is available for cycle 1 of Part A. Mean age (±SD) is 60 (±10.6). Mean prior systemic therapies is > 5 (range 1-11). Tumor types include endometrial, triple negative breast, melanoma, lung, pancreatic and colorectal cancers. No dose limiting toxicities have been reported. 3 Grade 3 adverse events (AEs) were reported in 2 Part A subjects: anemia and hypoxia (unrelated SAE) at .003 mg/kg and JTX-2011 related diarrhea at .1 mg/kg. Grade 1-2 AEs in ≥2 subjects are chills, pyrexia, neck pain, dizziness, and nausea. 5 subjects had JTX-2011 related Grade 1-2 infusion reactions up to 6 hours post infusion. Non-linear exposure increase was observed. While PK at lower doses is consistent with model predictions, AUC and t1/2at 0.03 and 0.1 mg/kg doses are higher than predicted, suggesting higher than predicted TE. Conclusions: JTX-2011 has been well tolerated up to 0.1 mg/kg and with nivo at .01 mg/kg IV q 21 days. Greater than linear exposure increase was observed and TE may be higher than QSP model prediction. Clinical trial information: NCT02904226.
The scope of possible combination therapy with immunotherapy and targeted therapy.
Authors: Colli Leandro Machado , Machiela Mitchell J , Zhang Han , Myers Timothy A , Jessop Lea , Delattre Olivier , Yu Kai , Chanock Stephen J. 
Published: September 2018

3056 Background: Combination treatment of two recent trends in cancer therapy, namely immunotherapy with checkpoint inhibitors and drugs that target specific gene mutations, could improve cancer survivorship overall. Targeted drugs usually induce rapid tumor death leading to the release of neoantigens, and can affect immune development pathways, which could increase the efficacy of checkpoint inhibitor treatment. Assessment of somatic mutation profiles from large public databases provides an estimate of the prevalence of targetable somatic mutations and the burden of somatic nonsynonymous mutations (NsM), used as a surrogate for overall neoantigen load, which, in turn, correlates with clinical utility of checkpoint inhibitors for melanoma and lung adenocarcinoma. The rational design of these combinations based on somatic genomic profiles offers a prioritization scheme for new clinical trials. Methods: We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents and/or a burden of exome-wide non-synonymous mutations (NsM) that exceeds a recently suggested threshold for response to checkpoint inhibitors. Results: Overall, 8.9% of cases have profiles that could benefit from combination therapy, which corresponds to approximately 11.2% of US annual incident cancer cases; the most commonly targetable mutations were observed in PIK3CA, BRAF, NF1, NRAS, and PTEN genes . Interestingly, cases with mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and/or MET appear to be enriched in those with high burdens of NsM, who have a higher likelihood of responding to immunotherapy. Of the 13,349 cases that could benefit from combination therapy, 50.9% had BRAF, NF1, GNAQ and/or GNA11 mutations which can be targeted by Trametinib ; 26.1% by Taselisib (targets PIK3CA mutations); and 19.8% by Afatinib ( EGFR and ERBB2 mutations). Conclusions: Our results indicate a significant proportion of solid tumor patients are eligible for combination therapy and suggest prioritizing specific cancers for combination trials using target drugs and checkpoint inhibitor therapy.
Immune related adverse events (irAE) with platinum chemotherapy (CT) with durvalumab (D) ± tremelimumab (T): CCTG IND226.
Authors: Daaboul Nathalie , Gauthier Isabelle , Tu Dongsheng , Brown-Walker Pamela , Sun Xiaoqun , Hao Desiree , Juergens Rosalyn A. , Bradbury Penelope Ann , Mates Mihaela , Tehfe Mustapha Ali , Kollmannsberger Christian K. , Ellis Peter Michael , Robinson Andrew George , Wheatley-Price Paul , Laurie Scott Andrew , Seymour Lesley 
Published: September 2018

3058 Background: CT is immunomodulatory and requires corticosteroids (CS) premedication. We hypothesized that the incidence of irAE may be lower when D ± T is given with CT or CS. Methods: Patients (pts) receive CT (pemetrexed, nabpaclitaxel, etoposide or gemcitabine + cisplatin or carboplatin; usual 4-6 cycles) with D ± T, followed by D ± T alone (1 year total); pts with ≥ g2 (selected) or ≥ g3 irAE discontinued D ± T. Cycles were coded as CT + D ± T or D ± T; pts could contribute to both. CS: high (dexamethasone > 10mg/day for 5 days) or low CS. irAE were D ± T related gastrointestinal (GI), skin, endocrine, neurologic, hypersensitivity, pneumonitis (PN) or other immune (nephritis (GN), pancreatitis, hepatitis). Biochemistry (BIO; all causality): creatinine, transaminases/bilirubin (LFTS) and amylase/lipase was summarised. Results: In this ongoing study, 118 pts received 723 cycles. Pts had good performance status (PS 0-1), 78 had thoracic malignancies and 84 no prior CT. 44 pts continue on D ± T alone; 32 pts continue on CT + D ± T while 76 pts discontinued D ± T primarily due to disease progression; 15 discontinued for ≥ g2 irAE [PN (3), hepatitis (1), GN (2), adrenal (1), myocarditis (1), GI (3), thrombocytopenia (1), hyperthyroidism (1), encephalitis (1), pt decision (1)]. 67 pts had high CS cycles while 78 pts had low. 50% pts had irAE and 10% had ≥ g3 irAE, most commonly skin and GI. GI (15 vs 11%), skin (26 vs 20%) and PN (3 vs 0%) were reported in more pts during CT + D ± T cycles (non significant (NS)) ; hypothyroidism was more common with D ± T alone (18 vs 10%; p = NS). IrAE rates and severity were similar between high (67 pts) or low CS (78 pts) except for GI (19 vs 10%; p = NS). BIO were more common during CT + D ± T (74% of pts vs 48% p = 0.003); rates in high CS were similar to low CS. LFTs (ALT/AST - 41% vs 16%; 38% vs 9%; p = 0.005) and amylase/lipase (18 vs 9%; 19 vs 14%; p = NS) were more common in pts with CT + D ± T cycles vs pts with D ± T alone cycles. Conclusions: There is no evidence that CT or CS abrogates irAE in this exploratory analysis. GI, skin, pneumonitis, LFTS and amylase/lipase were more common during CT + D ± T suggesting additive/multifactorial causes; hypothyroidism is more common in D ± T cycles, which may reflect time on treatment. Clinical trial information: NCT02537418.
Molecular characterization of immune-related severe adverse events (irSAE).
Authors: Balko Justin M. , Al-Rohil Rami N , Wang Daniel Ying , Liang Yan , Ong Giang , Barker Kristi , Compton Margaret , Wang Yu , Beechem Joseph M , Xu Yaomin , Sosman Jeffrey Alan , Mobley Bret , Shi Chanjuan , Moslehi Javid J. , Johnson Douglas Buckner 
Published: September 2018

3076 Background: Immune checkpoint inhibitors (ICIs; anti-CTLA-4 and anti-PD-1) have shown clinical success in many cancers, but may cause rare irSAE. The molecular features of irSAE have not been extensively explored. Therefore, we characterized the immune composition of tissue affected by ICI-mediated inflammation with a focus on colitis and neurologic toxicity. Methods: We performed retrospective T-cell receptor (TCRβ) sequencing, RNA-sequencing (HTG EdgeSeq; > 2500 immune-related genes), and digital spatial profiling (NanoString) for 20 protein markers in 10 regions across tissues representing ICI-induced colitis, autoimmune inflammation (e.g. Crohn’s) and normal colon. Matched tumors were also included in a subset. We also analyzed the encephalitic and healthy brain of a unique presentation of anti-PD-1-induced encephalitis. Results: Patient-matched melanoma and colitis biopsies (n = 3) demonstrated shared T cell clones in all samples ranging from several shared clones to several hundred (0.4%, 2.7%, and 3% of rearrangements, respectively), including high-frequency clones. Shared TCRβ sequences were also identified among and between colon-irSAE and Crohn’s specimens. Gene expression patterns of inflammation in colon-irSAE resembled that of Crohn’s disease in principle components and clustering analysis, highlighting likeness between these diseases/SAEs. NanoString digital spatial profiling of regions of inflammation across samples showed higher CD68 and PD-L1 positivity in colon-irSAE specimens versus normal colon or Crohn’s specimens and reduced beta-catenin levels in both Crohn’s and colon-irSAE specimens relative to normal controls. Finally, we detected a high degree of TCR clonality in the encephalitic brain, including a single sequence present in ~20% of > 12,000 T cells, suggesting a distinct antigen-specific response. Conclusions: We report the molecular characteristics of irSAE in colon and brain specimens from patients receiving ICIs. Highly clonal TCRβ sequences were frequently detected, particularly in a unique case of encephalitis-irSAE. Furthermore, we identify molecular distinctions and similarities between autoimmune and colon-irSAEs at the gene expression and proteomic levels.