bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in skeletal muscle mass during PD-1 and PD-L1 checkpoint inhibitor therapy in advanced-stage non-small cell lung cancer patients.
Authors: Multani Maneet , Tarhoni Imad , Fughhi Ibdihaj , Basu Sanjib , Batus Marta , Bonomi Philip D. , Fidler Mary J. , Borgia Jeffrey Allen , Shah Palmi 
Published: May 2019

e14061 Background: Severe skeletal muscle loss (sarcopenia) is a principle property of cancer cachexia and is found to be a hallmark of poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). With the latest advancements of PD-1 and PD-L1 checkpoint immunotherapy, we aim to examine changes in sarcopenia before and after treatment with these agents. Methods: : In this study, patients with stage IIIB/IV NSCLC receiving PD-1 and PD-L1 immune checkpoint inhibitors were evaluated. CT images obtained before and after treatment were used for skeletal muscle analyses with the SliceOmatic software (Tomovision) at the level of the first lumbar vertebra. Skeletal muscle index (SMI) was assessed by measuring the cross-sectional muscle area, normalized to patient height. Height, weight, disease progression status, and overall survival (OS) was extracted from EPIC under an IRB-approved protocol. Data was then compared with baseline and clinical outcome was used for survival analysis. Results: In 100 pre-treatment subjects (48% women, mean age of 68), patients with < 32 cm2/m2 SMI had a significantly lower OS (median OS = 1.41 mo, n = 16) compared to those with SMI > 32 cm2/m2 (median OS = 9.44 mo, n = 84, p = 0.024). In 74 patients with pre- and post-treatment data, (avg 2.66 mo interval) an increase of > 5% SMI from baseline occurred in 17 (23%) patients, while a decrease of > 5% SMI from baseline occurred in 26 (35%) patients. Mean reduction in SMI from pre- to post-immunotherapy was 0.921 cm2/m2 while median reduction in SMI was 1.087 cm2/m2. Conclusions: Patients with high pretreatment SMI had a significantly greater overall survival when compared to those with low pretreatment SMI. Two-thirds of patients experienced stability or increase in SMI during immunotherapy. These results suggest that immune checkpoint inhibitors may dampen mechanisms of cancer cachexia in some patients.
Immune checkpoint inhibitors (ICI): An analysis of FDA’s and EMA’s decision patterns and times for initial approvals and extensions of indication.
Authors: Mayer-Nicolai Christine , Schmitt Elmar , Hartmann Markus , Serrano Philippe 
Published: May 2019

e14062 Background: In certain clinical settings ICI have demonstrated unprecedented patterns of efficacy, resulting since 2011 in regulatory approvals worldwide in a variety of cancer indications. As immuno-oncology (IO) drugs constitute today an intense area of oncology drug development, we sought to analyze and compare the regulatory approval decisions for ICI, issued until end of 2018 by the US FDA and the European Medicines Agency (EMA). Methods: We reviewed the biological license applications (BLA) of the 7 (EU: 6) ICI, for which marketing approval decisions for were granted so far. Together with parallel and extension of indication applications, 43 (FDA) respectively 23 (EMA) approval procedures were finalized between March 2011 and December 2018. We analyzed agency decision outcomes and timeline patterns; approval decisions issued for novel non-IO cancer drugs served as benchmarks. The primary variable for analysis was median approval time (MAT). Results: MAT for initial BLA applications for ICI in the USA were with 189 days [Interquartile range (IQR) 154-209] shorter than MAT for BLA and NDA approvals for non-IO drugs: for the 51 novel oncology drugs approved 2011-2018 by the FDA, MAT was 227 days [IQR 159-303]. With 181 days [IQR 155-184], FDA’s MAT for ICI line extensions did not differ from MAT for initial ICI approvals. For the EU, MAT for initial ICI marketing applications were with 373 days (IQR 326-413) also shorter than MAT for the 51 non-IO drugs approved 2011-18 (422 days [IQR 368-450]); for ICI line extensions, MAT was 254 days [IQR 187-293). Conclusions: For ICI as for novel non-IO cancer drugs, initial regulatory approvals are usually issued in the USA first. Regulatory approval times for initial approvals are shorter in the USA, compared to Europe, the same applies for ICI extensions of indication. FDA’s extensive granting of breakthrough therapy designations (BTD) helped to bring US MAT for initial ICI BLA down to 6 months – i.e. to the same time, FDA requires for its priority review of extensions of indication. For some ICI extensions of indication, the granting of BTD supported approval decisions within 3 months, supporting patients’ rapid access to novel therapies.
Association of efficacy of anti-PD-1 immunotherapy in patients with advanced cancer with immune-related adverse events (irAEs).
Authors: Rogado Revuelta Jacobo , Romero-Laorden Nuria , Sanchez Torres Jose Miguel , Pacheco-Barcia Vilma , Ballesteros Anabel , Ramos-Levi Ana Maria , Arranz Reyes , Lorenzo Alicia , Gullón Pedro , Garrido García Ana , Serra Jose Maria , Donnay Olga , Adrados Magdalena , Costas Pablo , Aspa Javier , Alfranca Arantza , Fenor De La Maza Maria Dolores , Mondejar Rebeca , Colomer Ramon 
Published: May 2019

e14064 Background: Cancer immune therapy has shown benefit in many cancer types, although it may initiate autoimmune-related disorders in some patients. We have attempted to establish whether the incidence of irAEs after the use of nivolumab or pembrolizumab in advanced malignancies is associated with anti-PD-1 treatment efficacy. Methods: We retrospectively reviewed all clinical records of patients treated with single-agent nivolumab or pembrolizumab for advanced cancer from january 2016 until september 2018. IrAEs were identified clinically and graded as per the CTCAE v.4.0. Efficacy was evaluated with objective response rate (ORR, iRECIST criteria), progression-free survival (PFS) and overall survival (OS). Uni and multivariate tests were performed to determine the association between irAEs and ORR, PFS or OS. Results: We identified 110 patients. Primary diagnoses were lung cancer (n = 78), melanoma (n = 10), head and neck carcinoma (n = 7), renal carcinoma (n = 5), Hodgkin's lymphoma (n = 3), urothelial carcinoma (n = 3) and gallbladder adenocarcinoma, hepatocellular carcinoma, gastric adenocarcinoma and Merkel cell carcinoma (n = 1 each). IrAEs were observed in 40 patients (36.4%). The most frequent irAEs were hypothyroidism (n = 15), nephritis (n = 5) and hyperthyroidism (n = 4). Objective response was observed in 45 patients (40.9%), median PFS was 5 months (0.5-32 months) and median overall survival was 24.5 months (3-110 months). Thirty-three of the 40 patients with irAEs had objective response (82.5%) in contrast with 12 of the 70 cases without irAEs (17%) (OR 22.78, 95% CI 5.9-87.0, P < 0.000001). PFS in patients with irAEs was 10 months and 3 months in those without irAEs (HR 2.4, P = 0.004). OS in patients with irAEs was 32 months and 22 in those without irAEs, without statistically significant differences. Conclusions: In advanced cancer treated with nivolumab or pembrolizumab, patients who developed irAEs showed a significantly improved efficacy (ORR of 82.5% and PFS of 10 months) over patients without irAEs (ORR of 17% and PFS of 3 months).
Immunotherapy discontinuation and outcome: A multicenter real-life experience.
Authors: Bassanelli Maria , Giannarelli Diana , Migliorino Maria RITA , Russano Marco , Gelibter Alain , Cecere Fabiana Letizia , Barucca Viola , Giacinti Silvana , Bria Emilio , Ruggeri Enzo , Calabro Fabio , Santini Daniele , Rauco Annamaria , Ceribelli Anna 
Published: May 2019

e14075 Background: Unlike chemotherapy, the optimum treatment duration with Immune checkpoint inhibitors (ICIs) is not clearly established. The aim of this study was to assess the outcome of patients (pts) who discontinued immune-based therapies for any reason except progressive disease. Methods: We conducted an observational, retrospective analysis of 46 consecutive pts with advanced cancer who received ICIs as clinically indicated, at eight Italian institutions. Tumor response to treatment was defined according to RECIST. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan -Meier method. Results: 46 pts (median age 68 years [range 41-86]; male: 65.2%) with advanced cancer (n.39 non-small-cell lung cancer, n.15 renal cell carcinoma and n.2 melanoma) were treated with ICIs: 44 pts received programmed death 1 (PD-1) inhibitors (n.31 nivolumab, n.13 pembrolizumab) and 2 pts programmed death ligand 1 (PD-L1) (n.1 durvalumab, n.1 atezolizumab). A median of 8 cycles were administered [range 1 to 52]. 36 pts discontinued ICIs due to toxicities (diarrhoea, pneumonitis, hepatotoxicity) and 10 pts for reasons non immune-related. The median progression free survival (PFS) from the beginning of ICIs was 12.4 months (mo) [95% CI: 8.2-16.6] and the median OS was 20.0 mo (95% CI: 11.8-28.2). Median PFS from discontinuation of therapy was 5.0 mo [95% CI: 2.7-7.3] and median OS was 16.1 mo (95% CI: 5.4-26.8). Best response achieved according RECIST criteria were: 1 complete response (CR), 18 partial response, 21 stable disease (SD), 2 progressive disease (PR) and 3 non evaluable (NE). During interruption of ICIs 1 pts achieved a PR. Conclusions: This study shows the activity of ICIs, in terms of outcome and durable immune-response, in pts with advanced cancer even after treatment discontinuation.
Proton pump inhibitors and response to immune check-point inhibitors: Single center study.
Authors: Trabolsi Asaad , Winter Megan , Rodriguez Estelamari 
Published: May 2019

e14092 Background: Checkpoint inhibitors (blocking antibodies to PD-1, PD-L1, CTLA-4) have proven effective against several tumor types. While the response is impressive in some patients, we still don’t understand all the patient factors that determine resistance to this class of medication. Studies of host factors have identified composition of the gut microbiome at baseline as a positive predictor of ICI response. Proton pump inhibitors have been reported to interfere with gut microbiome composition. In this single center, retrospective study, we studied the effect of concomitant treatment of proton pump inhibitors on response to ICIs in patients with locally advanced and metastatic cancer. Methods: A retrospective cohort of Non-small cell lung cancer, renal cell carcinoma and Melanoma patients that were treated from January 2016 to May 2018 at the Mount Sinai Medical Center were included in this study. Demographics, prior systemic treatment, performance status, ICI agent, and use of PPI (with in 30 days prior to 30 days after the first dose of ICI administration) were collected. Primary objective of the study was progression free survival (PFS) by utilization of PPIs. PFS was calculated using the log-rank test and survival curve was generated using the Kaplan-Meier method. Information was collected from electronic medical records. Results: Of the 97 patients that met the study criteria, 63 patients had complete data and included in the analysis. 46 patients had Non-small cell lung cancer, 13 had melanoma and 4 renal cancer. Checkpoint inhibitors most commonly prescribed included: Pembrolizumab (29 patients : 46%), Nivolumab (22 patients:35%), Nivolumab + Ipilimumab (9:14 %). 25 patients were taking PPI upon initiation of ICI treatment. In addition, 26 patients received steroids with in 30 days of treatment initiation. There was no statistically significant difference in PFS between patients on PPIs and not on PPIs. The median PFS was 672 days (95% CI: 32, 1311) for PPI users and 341 days (95% CI: 123, 558) for non PPI users. P = 0.244. Conclusions: In this, single-center, retrospective study, we did not detect a significant difference in PFS between patients who used PPI at baseline and patients who did not. Limitations of this study mainly included retrospective analysis, a small sample size, single center population and heterogeneity in disease pathology. We did not collect information on other tumor and treatment related factors like PDL 1 expression, tumor mutation burden, use of antibiotics, and immunotherapy related adverse reactions.
Immunotherapy efficacy and safety of programmed cell death 1 (PD-1) versus programmed death ligand-1 (PD-L1) inhibitors in pan-cancer: A systematic review and meta-analysis.
Authors: Duan Jianchun , Cui Longgang , Wang Guoqiang , Zhao Zhengyi , Chen Shiqing , Song Jia , Yang Lei , Qi Chuang , Fang Zhili , Wang Qing , Zhang Yuzi , Zhao Jing , Bai Yuezong , Cai Shangli , Xiong Lei , Wang Zhijie , Zhao Xiaochen , Wang Jie 
Published: May 2019

e14113 Background: Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) and its ligand (PD-L1) have led to a paradigm shift in cancer treatment, while whether PD-1 and PD-L1 inhibitors deliver different clinical outcomes remains obscure. Here we carried out a systematic review and meta-analysis to compare the efficacy and safety profile of PD-1 and PD-L1 inhibitors in pan-cancer patients. Methods: We systematically searched PubMed, Cochrane library, and Embase from January 2000 to December 2018 for randomized controlled trials that compared PD-1/PD-L1 inhibitors with standard treatment in patients with solid tumors. We also reviewed abstracts and presentations from all major conference proceedings. Retrospective studies and trials that compared anti-PD-1/PD-L1 with other immunotherapies were excluded. The primary outcome was the difference in overall survival (OS). Studies were stratified into comparison groups upon studies mirrored with trial design and patient characteristics. Effect size in each comparison group was pooled first, the difference in overall survival was estimated, and the overall effect sizes was pooled using a random-effects model. Results: A total of 3864 publications were retrieved through initial literature search, 17 randomized controlled trials involving 9549 patients with solid tumors were included for this meta-analysis. PD-1 inhibitors exhibited significantly improved OS over PD-L1 inhibitors either in overall population (HR 0.75, 95% CI 0.64-0.87), as monotherapy (HR 0.79, 95% CI 0.65-0.96), or combination with chemotherapy (HR 0.66, 95% CI 0.53-0.82). PD-1 inhibitors also showed improved progression free survival (PFS) over PD-L1 inhibitors in overall population (HR 0.70, 95% CI 0.53-0.94). No significant difference was observed for safety profile between PD-1 inhibitors and PD-L1 inhibitors as monotherapy. PD-1 inhibitors plus chemotherapy have less Grade 3-5 adverse events than PD-L1 inhibitors plus chemotherapy (overall RR 0.84, 95% CI 0.75-0.93). Sensitivity analysis presented a satisfactory consistency of the overall estimates across these analyses. Conclusions: PD-1 inhibitors exhibited better clinical performance for survival outcome and safety profile over PD-L1 inhibitors. Future studies and explorations of the underlying mechanisms are needed for the further optimization of treatment strategies in clinical practice.
Evaluating the role of the COX2/PGE2 pathway in anti-melanoma immunity.
Authors: Ferreira Michelle , Krykbaeva Irina , Damsky William , Kluger Harriet M. , Bosenberg Marcus 
Published: May 2019

e14114 Background: Checkpoint inhibitors such as anti-PD1 (aPD1) have revolutionized treatment of metastatic melanoma. However, a large subset of patients receiving such treatment fails to respond to aPD1 monotherapy due to mechanisms such as PD-L1 upregulation within the tumor and T cell exhaustion in the tumor microenvironment. The PGE2/COX2 signaling pathway is one of the pathways implicated in T cell exhaustion and PD1/PD-L1 upregulation and thus represents an attractive pharmacologic target to enhance effects of aPD1 therapy due to the availability and safety of inhibitors such as aspirin or NSAIDs. There is evidence that PGE2/COX2 pathway inhibitors act synergistically with aPD1 therapy in murine melanoma and breast cancer models. Here we aimed to further characterize this synergism using the YUMMER (Yale University Mouse Melanoma Exposed to Radiation) 1.7 model, an irradiated, syngeneic cell line originating from BrafV600E; Pten-/-; and Cdkn2a -/- genetically engineered mouse melanomas. YUMMER1.7 cells implanted into the flanks of C57BL6/j mice show reproducible but partial responses to intraperitoneal aPD1 therapy and thus serves as an ideal platform to study whether concurrent PGE2/COX2 pathway blockade may result in additive effects to aPD1 therapy. Methods: 6-7 week old male C57BL6/j mice (n = 20) were injected with 500K YUMMER1.7 cells and treated with aPD1 therapy alone starting on day 7 after tumor implantation (n = 10) or with aPD1 therapy starting on day 7 in addition to ibuprofen dissolved in drinking water at a concentration of 1 mg/mL started on the day of tumor implantation (n = 10). Using an average daily water consumption estimate of 6 mL/day, this translates to a human equivalent of roughly 1200 mg/day, a moderate dose of ibuprofen. Tumor growth was monitored and tracked to an endpoint of 1cm3. Results: Tumor volume at day 17 significantly differed between the two groups (p < 0.0001). Survival curves were significantly different between the two groups (p < 0.0001); all tumors treated with aPD1 alone grew to endpoint by day 32, while all tumors treated with aPD1 + ibuprofen regressed with 8 out of 10 showing complete regression by day 32. Conclusions: We have shown that ibuprofen strongly synergizes with aPD1 therapy in a murine model of melanoma, complementing existing evidence. This suggests that PGE2/COX2 inhibitors such as NSAIDs, which are over-the-counter agents with a well-studied safety profile, may serve as a promising means of enhancing the response to aPD1 therapies such as nivolumab in melanoma patients who initially fail aPD1 monotherapy.
Real-life use of nivolumab and pembrolizumab in four adult university teaching hospitals in Québec, Canada.
Authors: Letarte Nathalie , El Raichani Layal , Guevremont Chantal , Marcotte Nathalie , Berard Ghislain , Michel Marie-Claude , Varin France , Pelletier Elaine , Farand Paul , Deschênes Louise , Froment Daniel , Ovetchkine Philippe , Fournier Marie-Andrée , Blais Normand , Rajan Raghu , Jamal Rahima 
Published: May 2019

e14125 Background: Nivolumab and pembrolizumab, two anti-PD1 agents, were approved and funded in Québec since 2016 for non small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and melanoma. The objectives were to describe and assess the “real-life” use, efficacy and security of nivolumab and pembrolizumab in NSCLC, RCC and melanoma in the general population. Methods: Medical records of every patient who received nivolumab or pembrolizumab between January 1st 2011 and October 31st 2017 were reviewed retrospectively. Data analysis cut-off was Dec 31st 2017. Results: In total, 532 patients received at least one dose of anti-PD1 during the study period. Median number of doses received varied for each indication (medians varied from 4 to 9.5). Adverse events were pooled together by drug. 47.7 % of patients receiving pembrolizumab suffered from any grade immune-related adverse event (IRAE), most of them of grade 1 or 2. 12.2 % of patients reported grade 3-4 IRAE. Most of the patients reported only one type of IRAE. For nivolumab, 44.6% of patients presented with any IRAE, including 8.3% of grade 3-4. Dermatologic IRAE were more frequent in the melanoma patients whereas gastrointestinal and pulmonary IRAE were more frequent in NSCLC patients. Treatment discontinuation due to adverse events varied from 6 to18% depending on indication. Conclusions: Nivolumab and pembrolizumab seemed less effective and caused more IRAE in “real-life” population than in the pivotal clinical trials. Caution and regular follow-up are warranted when using these drugs in general population. Longer follow-up is needed.[Table: see text]
DC-HIL/Gpnmb checkpoint blockade as a synergistic combination for stereotactic ablative radiation (SAbR).
Authors: Ramani Vijay , Chung Jin-Sung , Kobayashi Masato , Schoenhals Jonathan , Cruz Ponciano D , Hannan Raquibul , Ariizumi Kiyoshi 
Published: May 2019

e14129 Background: The combination of radiotherapy (RT)/immunotherapy holds a promise as an innovative cancer treatment. Expansion of myeloid-derived suppressor cells (MDSC) dampens cancer immunity, and DC-HIL receptor is a potent mediator of the suppressor function. We examined whether DC-HIL blockade is useful as a synergistic combination for SAbR using mouse model and human clinical samples. Methods: After tumor-irradiation on mice with subcutaneous (sc) RM9 prostate cancer (PC), tumor-infiltrating lymphocytes were phenotypically analyzed. Mice with sc tumor were injected i.v. with RM9-GFP cells (lung mets); 4 d later tumor-irradiated and treated with Ab (6 x 200 μg/shot). Tumor growth was measured by volume or GFP+ cells. PC (n = 22, stages II-III) patients were treated with SAbR, and blood samples collected at week (w) 0, 2, 8 and assayed for % monocytic (m) and granulocytic (g) MDSC and their expression of DC-HIL vs. PDL1. Suppressor function of MDSC was assayed by fall in T cell IFN-γ response. Results: Tumor-RT increased MDSC by 40% on day 8; the most expanded subset Gr1hiLy6Clo gMDSC expressed DC-HIL highly but PDL1 lowly. Combination of anti-DC-HIL/RT inhibited tumor growth in RT-irradiated sc tumor and non-irradiated lung mets and converted tumor microenvironment from the suppressive to the competent milieu. PC patients (17/22 cases) showed elevated MDSC blood levels at w2, but markedly varied at w8 among individuals (2.7 ± 7.3%). DC-HIL+ MDSC levels were also upregulated. gMDSC showed small changes after RT, and DC-HIL (but not PDL1) expression was markedly upgraded by ~90% (n = 3). SAbR decreased the suppressor ability of both MDSC: ~93% T cell suppression at w0 down to ~56% at w8 by mMDSC; and ~76% to ~49% by gMDSC. However, anti-DC-HIL Ab reversed the suppressor ability of MDSC at w8 more than those at w0 (~59% reversal to ~89%), showing that SAbR increased the criticality of DC-HIL pathway in their function. Five cases showed a high rise in DC-HIL expression at w8, with no significant fall in PSA levels at ~13 mons, and one with a noticeable fall in both levels. Conclusions: DC-HIL blockers may amplify the therapeutic effects of SAbR for PC treatment. DC-HIL expression may be a predictive marker for PC response to SAbR.