bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world safety of pemetrexed, carboplatin, and pembrolizumab in U.S. NSCLC patients.
Authors: Muehlenbein Catherine , Kim Sangmi , Ryabko Ekaterina , Oton Ana , Agg Himani , Smolyakova Natalia , Kim Jong Seok 
Published: February 2020

50 Background: A Phase 3 KEYNOTE-189 clinical trial showed improved clinical benefit with acceptable toxicity of pemetrexed combined with pembrolizumab and platinum (Gandhi, 2018). However, the safety data with this combination has not been evaluated in a real-world setting with large number of patients with non-squamous non-small cell lung cancer (NSQ NSCLC). Methods: Flatiron Health’s electronic health record-derived data were used to identify advanced NSQ NSCLC patients (≥18 y) who received pemetrexed, pembrolizumab, and carboplatin (≤6 cycles; Pem+Pembro+Carb) as initial treatment from May 2017 to Oct 2018. Endpoints were overall occurrence of select laboratory adverse events (AEs; any Grade and Grade ≥3), which were described by treatment phase (Pem/Pembro cycles < 5 vs ≥5) and pre-specified subgroups. Results: The study included 1088 patients (median age = 68 y; male, 57%). In patients with maintenance (Pem/Pembro ≥5) cohort (N = 462), the median number of treatment cycles was 9 for Pembro and 6 for Pem. The occurrence rates of neutrophil count decrease and platelet count decrease were numerically higher in the induction phase, whereas those of chronic kidney disease (CKD) showed an opposite trend (Table). Grade ≥3 CKD occurrence rate was higher in patients with mild renal impairment (5.1% vs 2.6%) and elderly (≥75 y) patients (7.5% vs 3.3%). Conclusions: Considering the heterogeneity and vulnerability of real-world population, the laboratory AE occurrence rate with Pem+Pembro+Carb in this study was comparable with those reported in KEYNOTE-189. Various trends were observed for the respective AEs by treatment phase. [Table: see text]
A real-world analysis of non-small cell lung cancer patients treated with pembrolizumab or pembrolizumab in combination with pemetrexed and platinum.
Authors: Agg Himani , Winfree Katherine B. , Zhu Yajun Emily , Muehlenbein Catherine 
Published: February 2020

53 Background: Pembrolizumab (Pembro) is used in first-line treatment of patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) as monotherapy and in combination with pemetrexed and platinum agent (Pembro+Pem+Plat). Pembro monotherapy is approved for patients whose tumors express PD-L1 Tumor Proportion Score (TPS) ≥ 1% while triplet therapy is approved regardless of PD-L1 TPS. These 2 regimens have not been compared in a head-to-head trial, and real world (RW) treatment pattern data are lacking. This study used RW data to describe patients who received Pembro or Pembro+Pem+Plat and associated overall survival (OS). Methods: This retrospective observational study selected adult patients with diagnosis of advanced NSQ NSCLC who started first-line treatment with Pembro or Pembro+Pem+Plat between Mar. 2015- Aug. 2018 in Flatiron Health’s electronic health record-derived database. Patient characteristics were summarized descriptively, and the Kaplan-Meier survival method was used (unadjusted). Results: A total of 1137 patients received Pembro (median age 72 years) and 1068 patients received Pembro+Pem+Plat (median age 67 years). Patient characteristics are shown in the Table. Median OS was 11.9 months for the Pembro cohort and 14.3 months for the Pembro+Pem+Plat cohort. Median OS by PD-L1 TPS was TPS < 1%: 8.8 months for Pembro and 9.5 months for Pembro+Pem+Plat, TPS 1-49%: 8.9 months for Pembro and not reached (NR) for Pembro+Pem+Plat, and TPS ≥50%: 13.4 months for Pembro and NR for Pembro+Pem+Plat. Conclusions: These RW data seem to suggest baseline differences between the population with Pembro and Pembro+Pem+Plat with regard to age, PS, disease stage, as well as PD-L1 status. Those baseline differences may play a role in the clinicians’ choice of the two treatment options for the NSCLC patients. [Table: see text]
Efficacy and toxicities of immune checkpoint inhibitors (ICIs) in advanced melanoma: A single institution experience.
Authors: Welaya Karim , Baran Andrea M. , Lekkala Manidhar Reddy , Sahasrabudhe Deepak M. 
Published: February 2020

59 Background: Historically, the prognosis of advanced melanoma has been poor. Recent landmark studies (KEYNOTE-006, CheckMate 066, CheckMate 037 and CheckMate 067) have shown significant improvement in outcomes of patients with advanced melanoma treated with ICIs. In a single institution retrospective study, we evaluated the efficacy and toxicities of ICIs in patients with advanced melanoma treated in real-world clinical practice. Methods: We included patients who received pembrolizumab (PEMBRO), nivolumab (NIVO), or ipilimumab plus nivolumab (IPI/NIVO) at the University of Rochester Medical Center from June 2015 to December 2018. Patient- and cancer-related characteristics were collected and compared between treatment groups. Outcomes including duration of treatment, response rates, and adverse events (AEs) were captured. Progression free survival (PFS) and overall survival (OS) were summarized using the Kaplan-Meier method. Results: We included 89 patients (55 received PEMBRO, 20 received NIVO, and 14 received IPI/NIVO); median age at ICI initiation was 68 years (range, 28-92) and 29% had Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥2. Forty-five patients (51%) had ≥2 co-morbidities. Nine patients (10%) had autoimmune diseases prior to initiating ICIs and 34 patients (38%) had brain metastasis. ICIs were given as first line in 71 patients (80%). Compared to those who received PEMBRO or NIVO, patients who received IPI/NIVO were younger (median age was 61 vs.71 vs. 70, p=0.003) and had better ECOG PS (ECOG PS ≥2 was 0% vs. 40% vs. 33%, p=0.007). Table shows the outcomes for the three groups. Conclusions: Patients with advanced melanoma treated with ICIs derived similar response rates to those seen in published landmark studies. However, median OS was shorter (range was 38 months to not reached in published studies). [Table: see text]
A phase I/IIa clinical trial investigating the therapeutic cancer vaccine UV1 in combination with ipilimumab in patients with malignant melanoma: Four-year survival update.
Authors: Ellingsen Espen Basmo , Aamdal Elin , Inderberg Else Marit , Rasch Wenche , Brunsvig Paal , Aamdal Steinar , Hovig Eivind , Nyakas Marta , Guren Tormod Kyrre , Gaudernack Gustav 
Published: February 2020

62 Background: Combining checkpoint blockade with a cancer vaccine may induce broader immune responses, leading to better clinical outcomes. UV1 targets the enzyme telomerase (hTERT) which is expressed in almost all cancer types and is essential for the immortality of cancer cells and a hallmark of cancer. UV1 consists of three synthetic long peptides and vaccination induces Th1 responses in most patients irrespective of HLA type. This trial explores the synergistic effect of CTLA-4 blockade and hTERT vaccination, allowing unchecked expansion of hTERT-specific T cell clones. Increased number of tumor-specific T cells is associated with a favorable clinical outcome in patients with metastatic melanoma. We investigated the safety, immunological and clinical responses of UV1 vaccine and ipilimumab in this group of patients. Methods: In a phase I/IIa, single-center trial (NCT02275416) patients with metastatic melanoma received treatment with UV1 (300 µg) + GM-CSF (75 µg) as an adjuvant, combined with ipilimumab (3 mg/kg). Safety was assessed according to CTCAE v. 4.0, and tumor responses according to RECIST v.1.1. Immune responses against UV1 peptides were monitored in peripheral mononuclear blood cells by using 3H-thymidine proliferation and IFN-γ ELISPOT assays. Tumor mutational burden (TMB) estimations were based on whole-exome sequencing. Results: 12 patients were treated from Feb to Nov 2015. Treatment was generally well tolerated. Adverse events mainly included injection site reactions and diarrhea. Immune responses occurred very early and 10/11 evaluable patients showed an immune response. Three patients obtained a partial response, and one patient a complete response. 3-year overall survival (OS) was 67%. 4-year survival outcome will be presented along with baseline characteristics and TMB estimations. Conclusions: Combining UV1 and ipilimumab is safe and induces clinical responses in melanoma. The high proportion of immunological responders and early induction of detectable immune responses suggest synergism. OS compares favorably to historical controls. Clinical trial information: NCT02275416.
Multi-institutional, prospective, randomized, double-blind, placebo-controlled phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine to prevent recurrence in high-risk melanoma patients: A subgroup analysis.
Authors: Chick Robert Connor , Faries Mark B. , Hale Diane F. , Kemp Bohan Phillip M. , Hickerson Annelies , Vreeland Timothy J. , Myers John William , Cindass Jessica L. , Brown Tommy A. , Hyngstrom John Robert , Jakub James W. , Sussman Jeffrey J. , Berger Adam C. , Shaheen Montaser F. , Clifton G. Travis , Wagner Thomas , Peoples George Earl 
Published: February 2020

63 Background: A novel vaccine strategy may prevent recurrence in high-risk melanoma patients (pts). The TLPLDC vaccine uses yeast cell wall particles (YCWP) to load tumor lysate into autologous dendritic cells (DC). In this phase IIb trial of TLPLDC vs. placebo in resected stage III/IV pts, TLPLDC increased 24 month (mo) disease free survival (DFS) in the per treatment (PT) population. Here, we present a 24mo DFS subgroup analysis and estimated overall 36mo DFS. Methods: Disease-free pts were randomized 2:1 to the TLPLDC vaccine vs. unloaded YCWP+DC at 0, 1, 2, 6, 12, and 18mo. The protocol was amended to allow concurrent adjuvant checkpoint inhibitor (CPI) therapy once approved. The pre-specified PT population included only pts completing the primary vaccine/placebo series (PVS) at 6 mo. Kaplan-Meier estimates of DFS were used to compare treatment arms by stage (III or IV) and CPI therapy (yes/no) in the ITT and PT populations. Results: 144 pts were randomized (103 TLPLDC, 41 placebo); 98 pts (66 TLPLDC, 32 placebo) completed the PVS. There were no clinicopathologic differences between treatment groups. There was no difference in 24mo DFS in stage III pts (n = 112), but in stage IV pts (n = 32), the 24mo DFS was 44% vs 0% (TLPLDC vs placebo) (p = 0.41) in ITT and 73.3% vs. 0% (HR 0.14, p = 0.002) in PT. Stage IV pts were more likely to receive CPI than stage III pts (50% vs. 30%, p = 0.003). There was no difference in 24mo DFS for pts who did not receive CPI (n = 102), but in pts who received CPI (n = 42), the 24mo DFS was 49.3% vs. 31.3% (p = 0.71) in ITT and 68.8% vs. 41.7% (HR 0.46, p = 0.28) in PT, showing a trend toward improved DFS in pts who completed the PVS and received CPI (n = 31). Overall, the 36mo estimated DFS was 34.2% vs. 21.6% (p = 0.89) for ITT and 56.9% vs. 27.9% (p = 0.021) for PT. Conclusions: The TLPLDC vaccine improved DFS in patients completing the PVS at 24 and 36 mos, particularly in the resected stage IV subset. The apparent synergistic effect with TLPLDC + CPI will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI vs. CPI alone in resected stage IV melanoma pts. Clinical trial information: NCT02301611.
Plasma PD-L1 levels according to histologic grade and IDH status in patients with gliomas.
Authors: Cabezas-Camarero Santiago , García-Barberán Vanesa , Pérez-Alfayate Rebeca , Gandía María L. , Díaz-Millán Isabel , Pérez-Segura Pedro 
Published: February 2020

69 Background: Plasma immune biomarkers such as soluble plasma PD-L1 (sPD-L1) may serve as surrogates of the immune condition of cancer patients and be potential markers of response to different immunotherapy modalities. Very few data exist regarding sPD-L1 in patients with primary brain tumors. Our aim was to study the levels of sPD-L1 in patients with gliomas according to histologic grade and IDH mutation status. Methods: Patients (pts) with grade II to IV gliomas were prospectively enrolled. Single-time-point plasma samples were obtained prior to adjuvant radiotherapy +/- chemotherapy. sPD-L1 determined using ELISA with a rabbit polyclonal anti-PDL1/CD274 antibody as capture reagent. Results: Between February 2017 and August 2019, 44 patients (pts) with gliomas and 12 healthy controls (HC) were enrolled. N=11 grade II, n=9 grade III, n=24 grade IV; n=26 IDHwt, n=18 IDHmut. Higher sPD-L1 levels in glioma pts compared to HC (60.8 vs 47.8 ng/ml, p=0.05). Higher sPD-L1 levels in grade II vs grades III-IV (73.3 vs 60 ng/ml, p=0.09). Higher sPD-L1 in IDHmut grades II-III vs IDHwt grades II-III + IDHmut/wt grade IV (73 vs 59 ng/ml, p=0.07). Non-significantly higher sPD-L1 in grades II-III vs grade IV (73 vs 59 ng/ml, p=0.46). No difference in sPD-L1 in IDHmut vs IDHwt (63.3 vs 59.1 ng/ml, p=0.496), nor in IDHwt vs HC (59.1 vs 47.8 ng/ml, p=0.109). Trend to significance in IDHmut vs HC (63.3 vs 47.8, p=0.062). Conclusions: sPD-L1 levels were significantly higher in glioma pts compared to HC. A trend was seen towards higher sPD-L1 levels in lower-grade (grades II, III) IDHmut gliomas. These findings may indicate a different systemic immune profile for currently defined glioma groups based on histologic grade and IDH status and merit confirmation in a larger sample.
Targeting the immunosuppressive tumor microenvironment: Synergistic effect of low-dose IL12 in combination with dual immune checkpoint inhibition in a preclinical model of ovarian cancer.
Authors: Pavicic Paul G. , Rayman Patricia A. , Al-Sudani Hussein , Diaz-Montero C. Marcela , Mahdi Haider 
Published: February 2020

7 Background: Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer with ~22,000 women diagnosed annually in the US. The impact of immune checkpoint inhibition (ICI) in the treatment of solid tumors has been significant. However, the response rates for OC are low ranging from 11-15%. It is critical to explore strategies to enhance the efficacy of ICI immunotherapy in OC. Targeting immunosuppressive factors and cells within the tumor microenvironment (TME) represents a feasible approach. The use of IL12 is attractive because induces potent antitumor activity by targeting myeloid cells and lymphocytes. However its clinical application has been hindered by its potential systemic toxicity. Here we explore the use of low dose intraperitoneal IL12 to enhance the antitumor activity of dual ICI in OC. Methods: Mice bearing ID8-VEGF tumors implanted intraperitoneally received either anti-PD1 alone or dual ICI treatment of anti-PD1 plus anti-CTLA4 with or without low dose IL12. Ascites accumulation was used as surrogate for tumor progression and determined by assessing weight increase. Blood and ascites were analyzed by flow cytometry for frequency of PMN-MDSC, M-MDSC, and activated T cells. Results: Low dose IL12 alone induced a significant delay in ascites accumulation when compared to untreated controls or mice treated with PD1 monotherapy or dual ICI. Addition of IL12 to dual ICI resulted in significant tumor regression and extended survival benefit compared to dual ICI alone. A synergistic effect of IL12 was not observed when combined with PD1 monotherapy. Antitumor responses associated with a marked decrease in the frequency of M-MDSC in blood and a decrease in both PMN- and M-MDSC in ascites. Decrease in MDSC associated with elevated levels of activated T cells. Conclusions: Low dose IL12 can induce regression of ID8-VEGF tumors. However, durable responses were only observed when IL12 was added to dual ICI. This suggests that IL12 can induce changes in the TME, particularly on MDSC, that can potentiate the antitumor activity of dual ICI. Our findings also suggest a crucial role of CTLA4 blockade perhaps via Treg targeting.
Effect of plinabulin, a novel late-clinical stage immunotherapeutic agent on the adaptive and innate immune system.
Authors: Mohanlal Ramon W. , Huang Lan 
Published: February 2020

8 Background: Plinabulin (Plin) is a small molecule Dendritic Cell modulator, which in the presence of antigen, increases T-cell proliferation in an antigen-dependent manner marrow. The addition of Plin to Docetaxel (Doc) improved mOS with 4.6 months vs Docetaxel monotherapy, and prolonged DoR with more than 1 year (p < 0.05), which is indicative of an immune-mediated mechanism of action (Mohanlal, ASCO-SITC 2017). Neutrophils are our first line of innate immune defense against foreign invaders. We previously reported that Plinabulin prevents chemotherapy (Chemo) Induced Neutropenia (CIN) in patients receiving Doc or TAC throughout the cycle (Doc, Doxorubicin, Cyclophosphamide) (Blayney ASH 2018, St Gallen 2019). Here we analyzed the onset time of neutrophil increase following Plin administration. In addition, we analyzed the impact of Plin on plasma haptoglobin, which is an acute phase protein with anti-inflammatory effects together with immune-enhancing effects and is an integral part of innate immunity (Kristiansen Nature 2001). Methods: Absolute neutrophil count (ANC) and haptoglobin data were analyzed from Phase 2 study BPI-2358-106 (NCT03294577) with 10 (n = 15), 20 (n = 15) and 30 mg/m2 (n = 12) Plin in Breast Cancer patients receiving TAC. Plin was administered on Day 1. ANC and Haptoglobin were analyzed by a Central Laboratory (Covance), from blood draws at predose, and post-dose Plin at Day 2,3,6,7,8,9,10,11,12,13 and 15, and changes relative to predose value were evaluated. Results: Plin dose-dependently increased ANC within 1 day (P < 0.001) and Haptoglobin within 3 days (P < 0.03) of dosing. Mean haptoglobin (P < 0.0005) and ANC (P < 0.001) levels increased with ~two-fold vs baseline levels. ANC levels remained increased for approximately 1 week and haptoglobin levels for > 3 weeks. Conclusions: Based on Plinabulin’s ability to stimulate the innate system, together with its previously reported evidence as a potent activator of the adaptive immune system (Mohanlal, ASCO-SITC 2017), it is concluded that Plinabulin is a potent stimulator of the adaptive and innate immune system. Clinical trial information: NCT03294577.
Immune-related adverse events (irAE) to cancer immune checkpoint inhibitors (CPI) and survival outcomes: To rechallenge or not—An Appalachian experience.
Authors: Albandar Heidar , Safi Salah Ud Din , Fuqua Jacob Lane , Merrill Samuel , Ma Patrick C. 
Published: February 2020

81 Background: The adoption of immunotherapy has led to a paradigm shift in the treatment of many advanced stage malignancies. Patients with durable long term survival under cancer immunotherapy have begun to emerge. Circulating memory immune T and B-cells play a key role in the anamnestic response to future similar antigen exposure and may contribute to durable cancer immunotherapy response and benefits in patients with irAE. We hypothesized that there is increased median overall survival (mOS) in patients who had irAE under CPI therapy. Methods: We conducted a retrospective analysis with an IRB-approved study protocol of adults treated between 2011-2019 at the West Virginia University Cancer Institute, with a histopathologic diagnosis of melanoma or lung cancer, who had received CPI therapy. We collected data on demographics, histology, stage at diagnosis, immunotherapy type used, irAE and its grade, and days from immunotherapy initiation to death. Patients were stratified by irAE status and CPI rechallenge status following irAE. Results: Demographics were similar between the irAE and non-irAE groups within both cancer types. A total of 229 lung and 114 melanoma cancer patients had received CPI. Overall, there were 105/343 (30.6%) cases of irAE found of any grades: 27.5% of lung and 37.7% of melanoma patients developed irAE. The mOS for the non-irAE cohort group was 299 days, which was significantly worse than the irAE cohort (mOS not met, Log-rank, p < 0.0001). Within the irAE cohort, there was no significant survival difference between the non-rechallenged and rechallenged groups (Log-rank p = 0.6150). Conclusions: Our findings identified significantly improved survival outcomes among lung cancer/melanoma patients treated with CPI who developed irAE, including those who were rechallenged after irAE, compared to those who had no irAE. Patients who were CPI-rechallenged after irAE had comparable survival outcomes compared to those without rechallenge. Further multi-center validation studies and prospective studies are warranted to further confirm these findings and help guide clinical management in patients who experience CPI irAE.
Outcomes for patients with metastatic solid malignancies who achieve a complete response on an immune checkpoint inhibitor.
Authors: Wee Christopher Eing , Molina Julian R. 
Published: February 2020

82 Background: Use of immune checkpoint inhibitors (ICI) in metastatic solid malignancies can occasionally result in a complete response (CR). There is limited long-term data regarding outcomes for patients who achieve a CR on ICIs. Methods: We screened the Mayo Clinic electronic medical record using an institutional database query program to identify patients whose records contained keywords such as “pembrolizumab” and “complete response” or “no evidence of disease.” Patients were included if they had measurable metastatic solid tumor disease prior to initiation of ICI and if they had a CR defined by two consecutive imaging studies at least twelve weeks apart. Exclusion criteria included oligometastatic disease treated with locoregional therapy or presence of a second confounding malignancy. Results: One-hundred four patients with a CR on pembrolizumab met criteria. Most (71.1%) patients had melanoma and 63/103 (61.2%) received had received the ICI during the first line of metastatic systemic therapy. Additional characteristics are in Table. At a median follow-up of 35.8 months (6.1-87.7), patients had received ICI for a median of 12.1 months (1.5-46.7). The vast majority of patients who stopped ICI did so electively (for reasons other than disease progression). Of 88 elective discontinuations, only 7 patients had disease recurrence after a median follow-up from start of ICI of 40.5 months. Conclusions: Patients with a metastatic solid malignancy who achieve a CR to pembrolizumab appear to maintain remissions off therapy, with low rates of relapse. Further outcomes will be explored, including analyzing and characterizing a sub-group of “hyper-responders” and patients receiving other ICI agents. [Table: see text]