bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ipilimumab versus placebo after complete resection of stage III melanoma: Long-term follow-up results the EORTC 18071 double-blind phase 3 randomized trial.
Authors: Eggermont Alexander M. M. , Chiarion-Sileni Vanna , Grob Jean Jacques , Dummer Reinhard , Wolchok Jedd D. , Schmidt Henrik , Hamid Omid , Robert Caroline , Ascierto Paolo Antonio , Richards Jon M. , Lebbe Celeste , Ferraresi Virginia , Smylie Michael , Weber Jeffrey S. , Maio Michele , Hosein Fareeda , de Pril Veerle , Kicinski Michal , Suciu Stefan , Testori Alessandro 
Published: May 2019

2512 Background: Since 2015, ipilimumab (Ipi) is an approved treatment for stage III melanoma based on a significantly (P=0.0013) prolonged recurrence-free survival (RFS) (Eggermont et al, Lancet Oncology, 2015). At a median follow-up of 5.3 years, RFS (HR=0.76) and distant metastasis-free survival (DMFS) (HR=0.76), assessed by an IRC, and overall survival (OS) (HR=0.72) were prolonged in the Ipi group as compared to the placebo (Pbo) group (Eggermont et al, NEJM, 2016), despite a 53.3% (Ipi) vs 4.6% (Pbo) treatment discontinuation rate due to adverse events. Methods: In this randomized double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. Here, we report the comparison between the Ipi and Pbo groups regarding the long-term efficacy outcomes using the local investigator assessments. Results: Overall, 20%/44%/36% of pts had AJCC-7 stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. Median follow-up was 6.9 yrs. The RFS, DMFS and OS benefit observed in the Ipi group was long-lasting (almost 10% difference at 7 years) and consistent across subgroups: no significant predictive factors could be detected. Conclusions: In this phase III trial, Ipi, administered at 10 mg/kg, as adjuvant therapy provided, at a 6.9 yr median follow-up, a sustained improvement in the RFS, DMFS, and OS long-term results in patients with high-risk stage III melanoma. Clinical trial information: NCT00636168. [Table: see text]
Prognostic and predictive value of an immune-related adverse event among stage III melanoma patients included in the EORTC 1325/KEYNOTE-054 pembrolizumab versus placebo trial.
Authors: Eggermont Alexander M. M. , Kicinski Michal , Blank Christian U. , Mandalà Mario , Long Georgina V. , Atkinson Victoria , Dalle Stéphane , Haydon Andrew Mark , Lichinitser Mikhail , Khattak Muhammad , Carlino Matteo S. , Sandhu Shahneen Kaur , Puig Susana , Ascierto Paolo Antonio , Krepler Clemens , Ibrahim Nageatte , Marreaud Sandrine , Van Akkooi Alexander Christopher Jonathan , Robert Caroline , Suciu Stefan 
Published: May 2019

2517 Background: Several studies suggested that patients (pts) with an immune-related adverse event (irAE) during immunotherapy have better outcomes than those without. It remains uncertain whether these observations can be explained by guarantee-time bias or the role of irAE as an indicator of drug activity. Here, we investigated the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 trial that compared pembrolizumab and placebo in high-risk stage III melanoma pts. Methods: Eligible pts included adults with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA (lymph node metastasis > 1 mm), IIIB or IIIC (without in-transit metastasis) and with no active autoimmune disease that required systemic treatment in past 2 years. We used a Cox model adjusted for sex, age, and stage with a time-varying covariate taking a value zero before the irAE onset and a value one afterwards to estimate the association between the occurrence of irAEs and RFS. Results: Consistent with the main analysis in the ITT population (n = 1019, Eggermont et al, NEJM, 2018), RFS was longer in the pembrolizumab than in the placebo arm (HR = 0.56, 98.4% CI: 0.43-074) among pts who started the treatment (n = 1011). The incidence of irAE on study was 37.3% in the pembrolizumab (n = 509) and 9.0% in the placebo arm (n = 502) and, in each treatment group, it was similar in males and females. The occurrence of an irAE was significantly associated with a longer RFS in the pembrolizumab arm (HR = 0.61, 95% CI: 0.39-0.95, P = 0.03). This was true for both males and females. However, in the placebo arm, no association was observed (HR = 1.39, 95% CI: 0.83-2.32, P = 0.21). Compared to the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater (P = 0.028) after an onset of an irAE (HR = 0.37, 95% CI: 0.24-0.57) than without/before an irAE (HR = 0.61, 95% CI: 0.49-0.77). Conclusions: In the EORTC 1325/KEYNOTE-054 study conducted in high-risk stage III melanoma pts, the occurrence of an irAE was strongly associated with a longer RFS in those treated with pembrolizumab, but not with placebo. Clinical trial information: NCT02362594.
Phase I study of OKT3 x hu3F8 bispecific antibody (GD2Bi) armed T cells (GD2BATs) in GD2-positive tumors.
Authors: Yankelevich Maxim , Modak Shakeel , Chu Roland , Lee Daniel W. , Thakur Archana , Cheung Nai-Kong V. , Lum Lawrence G. 
Published: May 2019

2533 Background: With the proven success of anti-GD2 monoclonal antibodies in eradicating minimal residual disease in neuroblastoma (NB), exploiting antibody based anti-GD2 in T cell mediated strategies has potential to combat higher disease burden and improve patient outcome. We hypothesized that arming of ex vivo expanded and activated, autologous, blood derived T cells (ATC) with chemically heteroconjugated GD2Bi should redirect them to target NB. In vitro, ATC coated (armed) with 50 ng/106 cells of GD2Bi exhibited specific killing of NB and osteosarcoma (OS) cell lines. Methods: In this phase I study (NCT02173093), patients with GD2-positive tumors received 8, biweekly infusions of GD2BATs + daily low-dose IL-2 and biweekly granulocyte-macrophage colony stimulating factor (GM-CSF). The study followed the standard 3+3 design with dose levels of 40, 80, and 160 x 106 GD2BATs/kg/infusion. Results: Twelve patients (NB = 7, OS = 3, Desmoplastic Small Round Cell Tumor = 2) were enrolled from 11/2013 to 12/2017 and 9 completed therapy. Adequate ATCs could not be grown in one patient and two patients did not complete 8 infusions because of rapid disease progression. Infusions were given in outpatient settings. All patients developed a mild, dose-independent and manageable form of cytokine release syndrome with grades 2-3 fevers/chills, headaches and occasional hypotension for up to 48 hours after infusion. No patients developed significant pain. Maximum tolerated dose was not reached. Evidence of activity was seen in several patients including one patient with OS who had a PET response, one patient with NB who had complete bone marrow response (this patient had remained progression free for 2.5 years after completion of infusions), and another NB patient who had a minor response on MIBG scan. Four patients with NB are currently alive after additional therapies at 12, 14, 18, and 47 months post BAT infusions. Conclusions: Autologous T cells from heavily pretreated patients could be expanded ex vivo to large numbers, armed with GD2Bi, cryopreserved and thawed for safe IV administration up to total dose of 1.28x109/kg. Ongoing phase II arm of the trial will focus on evaluation of clinical activity of GD2BATs in patients with NB. Clinical trial information: NCT02173093.
Phase 1 trial of anti-CD19 chimeric antigen receptor T (CAR-T) cells with tumor necrosis alfa receptor superfamily 19 (TNFRSF19) transmembrane domain.
Authors: Caimi Paolo Fabrizio , Reese Jane , Otegbeye Folashade , Schneider Dina , Chamoun Kamal , Boughan Kirsten M , Cooper Brenda W. , Galloway Erin , Gallogly Molly , Kruger Winfried , Worden Andrew , Kadan Michael , Malek Ehsan , Metheny Leland L. , Tomlinson Benjamin K. , Sekaly Rafick-Pierre , Wald David , Orentas Rimas , Dropulic Boro , De Lima Marcos J.G. 
Published: May 2019

2539 Background: AntiCD19 CAR-T cells have shown encouraging anti-lymphoma activity. Decreasing the time from apheresis to CAR-T infusion can make this therapy available to pts with rapid progression. We present the interim results of a phase I clinical trial using on-site CAR-T manufacture. Methods: Adult pts with r/r CD19+ B cell lymphomas who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc,LTG1563) encoding an antiCD19 binding motif, CD8 linker and TNFRSF19 transmembrane region, and 4-lBB/CD3z domains. GMP-compliant manufacture was done using CliniMACS Prodigy, in a 12-day culture. Dose levels were 0.5, 1 and 2 x 106 CAR-T cells/kg. Lymphodepletion was done with cyclophosphamide (60mg/kg x 1) and fludarabine (25mg/m2/d x 3). Results: 7 pts (4 women, 3 men) were enrolled. Median age was 60y [range 43-69]. Diagnoses were DLBCL (n = 3) PMBCL, follicular lymphoma (FL), transformed FL, and transformed lymphoplasmacytic lymphoma; with a median of 4 previous treatments. Six pts had symptomatic refractory disease. CAR-T cell product manufacture was successful in all pts. Mean transduction rate was 44% [range 29-57]. CAR-T cell doses were 0.5 x 106/kg (n = 3) and 1 x 106/kg (n = 4). Median apheresis to infusion time was 13 days [range 13–20], 5 products were infused fresh. CAR-T persistence based on vector sequence, peaked in peripheral blood MNCs between days 14-21. Five pts are evaluable for safety. CRS grade 1 - 2 (Lee) occurred in 4 pts; with 3 requiring treatment. Grade 4 CRES (CARTOX-10) occurred in 1 pt, with resolution after corticosteroids; considered a DLT as it lasted more than 72 hours. No treatment-related mortality has occurred. 4/5 evaluable pts have achieved complete response. One pt did not respond and died. After a median follow up 3 months, all responding pts are alive and 1 relapsed 6 mo after treatment. Conclusions: Second generation antiCD19 CAR-T cells with TNFRS19 transmembrane domain have clinical activity against refractory NHL. Short manufacture time achieved by local CAR-T cell manufacture with the CliniMACS Prodigy enables treatment of a very high risk NHL population. Clinical trial information: NCT03434769.
Phase 1 study of LY3022855, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in patients with metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (MCRPC).
Authors: Autio Karen A. , Klebanoff Christopher Austin , Schaer David , Kauh John S. , Slovin Susan F. , Blinder Victoria Susana , Comen Elizabeth Anne , Danila Daniel Costin , Hoffman David M. J. , Kang Suhyun , McAndrew Philomena , Modi Shanu , Morris Michael J. , Rathkopf Dana E. , Sanford Rachel Ann , Tate Sonya C. , Yu Danni , McArthur Heather L. 
Published: May 2019

2548 Background: Tumor-associated macrophages (TAM) correlate with increased invasiveness, growth, and immunosuppression. Activation of CSF-1R results in proliferation, differentiation, and migration of monocytes/macrophages. CSF-1R inhibition with LY3022855 (LY), a human immunoglobulin G subclass 1 (IgG1) monoclonal antibody (mAB), may have favorable anti-tumor effects. We evaluated the safety and clinical response of LY monotherapy. Methods: Patients (pts) with advanced refractory MBC and MCRPC received LY intravenously in 6-week cycles in cohorts: A) 1.25 mg/kg every 2 weeks [Q2W]; B) 1.0 mg/kg on Weeks 1, 2, 4, and 5; C) 100 mg once weekly; D)100 mg Q2W. MCRPC pts were enrolled in cohorts A and B; MBC pts were enrolled in all cohorts. Anti-tumor activity was assessed using RECIST v1.1 by radiological imaging every 6 weeks. Results: Thirty-four pts (22 MBC; 12 MCRPC) received ≥1 dose of LY. Median age was 57.0 years (range: 32.0–81.0) for MBC pts and 72.5 years (range: 58.0–84.0) for MCRPC pts. Baseline Eastern Cooperative Oncology Group performance status was 0 (n = 13, 38.2%), 1 (n = 18, 52.9%), or 2 (n = 3, 8.8%). MBC pts were hormone receptor (HR) positive (n = 20), HR negative (n = 1), or unknown (n = 1); 3 MBC pts received concurrent hormone therapy. Common treatment-related adverse events of any grade were fatigue (38.2%), decreased appetite (26.5%), nausea (26.5%), increased lipase (23.5%), and increased creatine phosphokinase (20.6%). No complete or partial response was observed. Stable disease (SD) was observed in 5/22 MBC pts (duration 82–302 days) and 3/7 evaluable MCPRC pts (duration 50–124 days). Two MBC pts (9%; Cohort A) had durable SD > 9 months and 1 pt had palpable reduction in a nontarget neck mass. Circulating CSF1 and IL-34 increased at Day 8 suggestive of target engagement. Pharmacokinetics of LY were consistent with other IgG1 mAbs. Conclusions: LY3022855 was well tolerated and showed evidence of target engagement. Clinically meaningful SD > 9 months was observed in 2 MBC pts. Tumor biomarker analyses are underway. Clinical trial information: NCT02265536.
An open label, multicenter phase II study combining imprime PGG (PGG) with pembrolizumab (P) in previously treated metastatic triple-negative breast cancer (mTNBC).
Authors: O'Day Steven , Borges Virginia F. , Chmielowski Bartosz , Rao Ruta D. , Abu-Khalaf Maysa M. , Stopeck Alison , Nikolinakos Petros , Telli Melinda L. , Xie Bin , Shaheen Montaser F. , Mattson Paulette , Gargano Michele Anne , Cox Joanna , Karantza Vassiliki , Chisamore Michael Jon , Osterwalder Bruno , Bose Nandita , Uhlik Mark T. , Graff Jeremy 
Published: May 2019

2550 Background: Checkpoint inhibitor (CPI) monotherapy shows limited clinical response in previously treated mTNBC patients (pts) (Table). Agents are needed that extend this benefit to more mTNBC pts. PGG is a novel, IV administered PAMP that, in pts with 20ug/ml anti-beta glucan antibody (ABA+), activates innate immune cells. Preclinically, PGG reprograms myeloid cells to repolarize the immunosuppressive tumor microenvironment & enhance antigen presentation, driving T cell activation- the mechanistic basis to explore PGG + P in mTNBC patients. Methods: 44 mTNBC pts ( 1 line of chemotherapy [Tx] for metastatic disease, ABA) received PGG (4 mpk IV weekly) + P (200 mg IV q3w) until PD or intolerable toxicity. 1° endpoints were ORR by RECIST v1.1 & safety. 2° endpoints included OS & DCR. CT scans (q6 wks) were reviewed locally. Tumor biopsies (pre & 6 wks on Tx) & blood samples were assessed for PGG-mediated immune activation. Results: Table shows IMPRIME 1 clinical response data (Keynote086, PCD4989g shown for context). Confirmed response was also evident in pts with liver or visceral metastases, high LDH. 10 IMPRIME 1 pts were originally ER/PR+, received hormonal Tx and progressed to TNBC. Of these, 5 are confirmed PR, 4 SD (3 still on Tx), 1 PD. No unexpected safety signals were observed. Conclusions: These are the first clinical data to suggest that PGG provides added clinical benefit for pts with previously treated mTNBC and support further development of PGG + P for mTNBC. Clinical trial information: NCT02981303. [Table: see text]
Assessment of the Fanconi anemia repair pathway as a predictor of clinical activity of pembrolizumab (PEM).
Authors: Villalona-Calero Miguel Angel , Diaz John Paul , Diaz Zuanel , Duan Wenrui , Schroeder Eric Douglas , Aparo Santiago , Gatcliffe Troy Antony , Alonso Alfredo Pedro , Cuitiva Sebastian , Albrecht Federico , Venkatappa Siddhartha A. , Guardiola Victor , Troner Michael B. , Garrido Sara M. , Walker Gail , Rubens Muni , De Zarraga Fernando I. , Vuong Hao 
Published: May 2019

2555 Background: Given the activity of immune checkpoint inhibitors (ICI) in mismatch repair deficient tumors, we evaluated if homologous recombination repair deficiency associates with solid tumor response to ICI. Methods: We conducted a phase 2 trial (NCT03274661) of PEM in metastatic solid tumor patients progressing on standard of care and for whom PEM had no FDA approved indication. We evaluated a triple stain (FANCD2foci/DAPI/Ki67) immunofluorescence functional assay of the Fanconi Anemia pathway (FATSI) in treated patients’ archived tumors as a correlative biomarker. Patients with microsatellite unstable tumors were not eligible. The primary objective was objective response rate (iORR, CR+PR) by Immune Response Criteria, with the hypothesis that patients with FATSI negative tumors will have better clinical outcome. Secondary objectives were progression free survival (PFS), 6 months PFS and survival. PEM was given every 3 weeks and computed tomography scans were performed every 6 weeks. We utilized a two-stage phase II trial design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%. If ≥ 2 of the first 20 evaluable patients had an objective response the trial proceeded to full accrual of 39 evaluable patients. Outcomes were evaluated according to FATSI staining. Results: 42 patients (40 evaluable) (35F,7M; median age 62[36-83]) enrolled. Median # of prior regimens was 2[1-7]. Primary Dx included ovarian/fallopian (13), endometrial (10), colorectal (3), cervix (2), pancreatic(2), vaginal (2) and 1 each of various others. No unexpected toxicities occurred. Response evaluation showed 2 CR, 5 PR, 11 SD, 22 PD and 2 NE (iORR 18%). FATSI tumor analyses results are available in 34 patients; 25 FATSI positive, 9 negative. 2 PR, 8 SD, 14 PD, 1 NE occurred among the FATSI (+) (iORR 8%) and 2 CR, 2 PR, 2 SD, 3 PD among the FATSI (-) patients (iORR 44%). mPFS and 6m-PFS were 54 days and 12% (3/25) in FATSI (+), versus 248 days and 56% (5/9) in FATSI (-) patients; p = 0.017. Conclusions: PEM has meaningful antitumor activity in non MSI-high malignancies with no current FDA approved indications. Evaluation of FATSI as a biomarker supports a biomarker selected population approach. Clinical trial information: NCT03274661.
Fatal adverse events associated with pembrolizumab in cancer patients: A meta-analysis.
Authors: Golshani Gol Minoo , Sher Amna Falak , Wu Shenhong 
Published: May 2019

2561 Background: Pembrolizumab, an immune checkpoint inhibitor (ICI) against programmed cell death-1(PD-1) protein has emerged as an effective treatment for many cancers. Although better tolerated than chemotherapy, it has unique immune related adverse event and little is known about its risk of fatal adverse events (FAE). Therefore, we conducted a meta-analysis of clinical trials to determine the incidence and risk of fatal adverse events with pembrolizumab. Methods: A systematic search for phase I-III clinical trials of pembrolizumab was conducted using databases from PUBMED, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October 2018. Eligible studies included prospective clinical trials of pembrolizumab with available data on FAE. Data on FAE was extracted from each study and pooled for calculations. Incidence, relative risk (RR) and 95% confidence intervals (CI) were calculated by employing fixed or random-effects models. Results: A total of 11 clinical trials of pembrolizumab, with 3713 patients were included for analysis. The overall incidence of FAE with pembrolizumab was 1.2% (95% CI: 0.5-2.8%).The incidence of FAE significantly varied among different tumor types (P=0.02), ranging from 0.2% in melanoma to 3.1% in breast cancer.The incidence of FAE was significantly higher (P<0.001) with chemotherapy plus pembrolizumab (7.0%, 95%CI: 4.9-10%) as compared to pembrolizumab alone (0.7%, 95% CI: 0.4-1.2, p=<0.001). There was no significant difference in the risk of FAEs when pembrolizumab was compared with chemotherapy with RR=1.24 (95% CI: 0.8-1.89, P=0.31). Conclusions: Pembrolizumab is similar to chemotherapy in the risk of fatal adverse events in cancer patients. Combination of pembrolizumab with chemotherapy increased the risk of FAE in comparison with pembrolizumab alone. Further studies are needed to identify risk factors. [Table: see text]
Characteristics of patients receiving immune checkpoint inhibitors (ICI) in ASCO’s CancerLinQ.
Authors: Rubinstein Wendy S. , Chen Li , Komatsoulis George Anthony , Stepanski Edward , Jun Monika , Zhi Jizu , Lau Denise , Roberts Jeremy , Miller Robert S. , Walker Mark S. , Fukushima Ryan , Hyde Brigham , Khozin Sean 
Published: May 2019

2566 Background: ICI’s have demonstrated significant clinical benefit since the first FDA approval in 2011 of ipilimumab for metastatic melanoma. Five additional ICI therapies have since been approved across several indications. The objectives of this study were to describe the clinical and demographic features of patients receiving ICI treatment along with utilization patterns in real-world settings. Methods: We conducted a retrospective, observational cohort study using statistically de-identified data from January 2011 to November 2018 in CancerLinQ, ASCO’s real-world oncology database, which now contains EHR data from 49 diverse oncology practices in the U.S. Adult patients diagnosed with any cancer type who received ≥1 dose of an ICI (see Table) and had ≥2 clinical visits were eligible for inclusion. Patients were excluded if they received an ICI prior to its first FDA approval date to avoid inclusion of clinical trial patients. Descriptive statistics were used to examine treatment patterns and clinical characteristics of patients receiving ICIs. Results: This analysis included 12,712 patients who received an ICI. Median patient age was 67.4 years [IQR 59.3, 75.3]; 58% were male. White race made up the highest percent (83%) of ICI patients, followed by Black race (9%) and Other (8%). The most common primary cancers at the start of treatment were lung cancer (36%), melanoma (8%), urothelial cancer (2%) and renal cell carcinoma (2%). Of the 8,444 patients with known disease stage, 5,446 (64%) had Stage IV cancer. Breakdown of ICI treatment patterns can be found in the accompanying table. Uptake of ICIs was the most rapid for nivolumab, which had the highest use (49%), followed by pembrolizumab for rapid adoption and use (30%). Conclusions: This analysis gives insights into patient characteristics and real-world treatment patterns for ICIs. ICIs were used most widely in males, lung cancer patients and patients with advanced disease. These baseline characteristics inform our analyses of ICI use in patients with autoimmune disease, also reported herein.[Table: see text]