bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of a dedicated multidisciplinary tumor board on care for patients with brain metastases.
Authors: Wang Nancy , Cohen Justine Vanessa , Goss Nathaniel C. , Bertalan Mia , Keeley Maura C. , Cahill Daniel P. , Oh Kevin S. , Brastianos Priscilla Kaliopi
Published: May 2019

e13585

Background: Brain metastases are the most common tumors to affect the central nervous system. Treatment options have recently evolved with the use of targeted therapies, immunotherapy, and increased clinical trials availability. We describe our institutional experience with a novel, weekly tumor board dedicated to brain metastases and its impact on treatment decisions and survival. Methods: We conducted a single institution cohort study at a large academic hospital with a dedicated center for CNS metastases. Attendance at tumor board included representatives from neuro-oncology, medical oncology, radiation oncology, neurosurgery, and neuroradiology. We prospectively gathered data on patient demographics, clinical history, and tumor board recommendations. Patients were followed to assess treatment course and survival. The Kaplan Meier method was used to calculate time to progression. Results: A total of 49 patients were presented over 2 months, with 4 patients presented twice. The median age at presentation was 63 yrs with a median ECOG of 1. The primary malignancy was 35% melanoma, 49% lung, 22% breast, the remainder other. Most patients had advanced, heavily pretreated disease: 69% had Stage IV disease at time of tumor board presentation with a median of 2 prior lines of systemic therapy, 73% had multiple brain metastases, 39% had prior surgical resection of brain metastases, and 57% had prior CNS radiation. The tumor board recommended a change in management in 26/53 case presentations: 5 surgery, 8 radiation, 9 medical therapy, 3 clinical trial, and 1 surveillance. Recommendations were followed in all except 4 cases due to patient preference and loss to follow-up. When active therapy was recommended, the median time to start was 7 days. Only 3 patients have died at a median follow-up of 62 days. 9 patients have progressed, with a median time to progression of 57 days. Conclusions: A multidisciplinary brain metastasis tumor board provides unique opportunities in the management of complex brain metastasis patients in an era of rapidly evolving therapeutic options. Additional follow-up is needed to assess long-term outcomes, and comparison to non-tumor board presented patients will be necessary.
A phase I dose escalation and dose expansion study of the anti-programmed cell death-1 (PD-1) antibody AK105.
Authors: Kotasek Dusan , Coward Jermaine , de Souza Paul L. , Underhill Craig , Jin Xiaoping , Li Baiyong , Xia Yu , Prawira Amy
Published: May 2019

e14006

Background: AK105 is a humanized IgG1 mAb that blocks PD-1 binding to PD-L1 allowing T-cells to recognize and kill tumor cells. Key attributes of AK105 include antibody engineering to eliminate Fc mediated effector function, and a slower off-rate on antigen binding resulting in improved receptor occupancy (RO). These features offer more robust biological effect and enhance anti-tumor activity of AK105. Methods: A multicenter, Phase I, open-label dose escalation and expansion study in solid tumors (NCT03352531) began in Dec 2017, evaluating the safety and efficacy of AK105 administered IV q2w till confirmed progression (RECIST v1.1). For dose escalation, pts were enrolled at dose cohorts of 1, 3, and 10 mg/kg. Expansion of AK105 at the RP2D of 200 mg q2w is ongoing in pts with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma; esophageal squamous-cell carcinoma; hepatocellular carcinoma (HCC); microsatellite instability-high (MSI-H) colorectal cancer. Results: As of 1 Feb, 2019, 34 pts (median age 66.5 years [30–79], female 44%, ECOG 0/1 ([68%/32%]) in cohorts of 1 mg/kg (n = 3), 3 mg/kg (n = 6), 10 mg/kg (n = 7), and 200 mg q2w (n = 18), received a median of 5 (1–29) doses of AK105. No DLTs were reported. Treatment-related adverse events (TRAEs) occurred in 41% of pts (G3 in 12% [4/34], no G4, treatment interruption in 9% [3/34]). Most frequent TRAEs ( > 5%) were hyperthyroidism (9%), hypothyroidism (6%), fatigue (6%), and rash (6%). PD-1 RO analysis showed that pts maintained full occupancy ( > 80%) for all dose levels. Of 25 evaluable heavily pretreated pts, ORR was 24% (6/25; 29% [4/14] in dose escalation and 18% [2/11] in expansion phase) and disease control rate (DCR) was 56% (14/25). Five responses are confirmed and ongoing (HCC, pancreatic carcinoma, cholangiocarcinoma, GBM, gastric adenocarcinoma), one is pending confirmatory scan (GEJ). Conclusions: The RP2D obtained from the dose escalation phase, reported safety profile and encouraging antitumor activity of AK105 supports continued clinical development, which include: pivotal studies in classic Hodgkin lymphoma and nasopharyngeal carcinoma, phase 2/3 combination studies with chemotherapy in NSCLC and combination study with anlotinib, a multi-targeting tyrosine kinase inhibitor in HCC. PD analysis is ongoing and expansion is ongoing at the RP2D. Clinical trial information: NCT03352531.
PD-L1 expression on circulating tumor cells and prognosis of breast cancer patients.
Authors: Wang Xuefei , Zhang Guochao , Sun Qiang
Published: May 2019

e14028

Background: Nowadays programmed cell death (ligand) 1 (PD1/PD-L1) inhibitors in the clinic show benefit for appropriate patient. There are clinical trials for specific breast cancer patients. We all know that the prognosis of breast cancer is associated with CTC. However, PD-L1 expression on circulating tumor cells (CTC) is lack of research. It is crucial for the prediction and supervision of molecular-targeted therapy, while the predictive biomarker response to PD(-L)1 checkpoint inhibitors is lacking. So we tried to explore the relationship between overexpression of PD-L1 on CTCs and prognosis and clinicopathological features of breast cancer patients. Methods: We analyzed CTC and PD-L1 mRNA expression on CTC in 20 primary breast cancer patients, through mRNA probe hybridization. The relationship between clinicopathological features and PD-L1 expression on CTC was analyzed by chi square test. Kaplan-Meier and univariate Cox proportional hazards model analyses were used to compare the survival of patients with high PD-L1 expression and patients with low PD-L1 expression. Results: The median follow-up time was 40 months (range, 36-43 months). Of the 20 patients, 15 had more than 1 CTC in 7.5ml peripheral blood. Among the 15 patients, each one has at least 1 CTC showing PD-L1. The expression of PD-L1 on CTC was divided into low expression, medium expression and high expression, then we gave 1 score for low expression, 2 score for medium expression and 3 score for high expression. PD-L1 high expression was total score≥3, while PD-L1 low expression was total score ＜ 3. We found PD-L1 expression on CTC is related to the tumor size(P = 0.012) lymph node status (P = 0.001) and PR status (P = 0.037). There was significant difference between T2 and T3 in large tumor group(P = 0.003), while in node status group statistical difference can be found in N1 vs N3(P = 0.000) and N2 vs N3(P = 0.015). Our data indicated that patients with high PD-L1 expression on CTC had poor overall survival(P = 0.004) compared to low PD-L1 expression on CTC (Table). Univariate Cox proportional hazards model analysis showed that high PD-L1 expression on CTC was an independent prognostic factor. Conclusions: PD-L1 on CTC is indeed associated with some poor clinicopathological features. High expression of PD-L1 on CTC is an independent prognostic factor for shorter survival. [Table: see text]
Quantification of activated and exhausted immune cell populations and simultaneous characterization of circulating tumor cells (CTCs) in peripheral blood of cancer patients receiving checkpoint inhibitor therapy.
Authors: Vansant Gordon , Krupa Rachel , Richardson Robin , Ontiveros Priscilla , Byun Jiyun , Landers Mark , Dittamore Ryan
Published: May 2019

e14033

Background: Immune checkpoint inhibitors (ICIs) are becoming standard treatment options in many indications. However, a substantial portion of patients will not respond. Single biomarkers such as PD-L1 are insufficiently accurate to predict patient benefit. We sought to expand the Epic Sciences non-invasive liquid biopsy platform to identify predictive, peripheral blood biomarkers for ICIs using both molecular analyses of CTCs and immune cell changes. Methods: Blood samples from prostate, kidney, and bladder cancer patients treated with ICIs were collected at baseline and on-therapy and sent to Epic Sciences. Nucleated cells were plated on glass slides and stained with CTC (pan-CK, CD45, PD-L1 and DAPI) and immune panels for activation (CD4, CD8, Ki-67, and DAPI) and exhaustion (CD8, Ki-67, PD-1, Lag-3, Tim-3, and DAPI). Changes in populations of immune cells and circulating tumor cells were assessed using high throughput digital pathology. Results: CTCs were detected in 73% (24/33) patients, of which 12% (4/33) had PD-L1+ CTCs detected. No PD-L1+ CTCs were detected in the nine on-therapy samples tested. Of 14 patients with matched samples, 57% (8/14) patients had an increase in activated CD4+ leukocytes and 36% (5/14) patients had an increase in activated CD8+ leukocytes in on-therapy samples compared to baseline. The exhaustion assay was performed on a subset (6 of 14) of matched samples. In baseline and on-therapy samples, one patient had higher levels of exhausted CD8+ leukocytes compared to healthy donor controls, and two patients had lower levels versus controls. No change in exhausted CD8+ leukocytes was observed from baseline to on-therapy. Conclusions: We developed a liquid biopsy-based platform that can simultaneously measure biomarkers in CTCs and leukocytes from a single peripheral blood sample. Changes in activated and exhausted immune cell populations with ICI treatment were detected and PD-L1 expression on CTCs was evaluated. Efforts to further stratify immune and rare cell populations are ongoing.
Revisiting the ethics of phase 1 oncology trials in the era of precision medicine: A systematic review.
Authors: Mackley Michael Patrick , Fernandez Nicholas R , Fletcher Benjamin , Woolcott Christy , Fernandez Conrad Vincent
Published: May 2019

e14060

Background: Phase 1 clinical trials are a crucial step in the evaluation of new cancer therapies. However, critics cite a low rate of response to therapy (5%), together with a not insignificant risk of death from associated toxicities (0.5%), suggesting a risk-benefit ratio that may limit the ethics of inviting patients to participate in Phase 1 trials. With the introduction of novel targeted therapies, a contemporary estimate of the risks and benefits is needed. Methods: A systematic review was conducted. Eligible for inclusion were phase 1 trials in both adult and pediatric populations published between Jan 2015 to July 2018 of targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents for solid and hematological malignancies. We systematically searched PubMed and Embase. Rates of objective response (complete and partial), stable disease, and Grades 3, 4 and 5 treatment-related adverse events were extracted and pooled. The protocol was prospectively registered in PROSPERO (CRD42018100386). Results: 116 trials (109 adult, 6 pediatric, 1 mixed) met inclusion criteria. The studies reported on nearly 4300 patients (52% male, 48% female), ages ranging from 1 to 90. Most trials reported on molecularly targeted therapies (58%), followed by immunomodulators (33%). The combined overall objective response rate was 6% (95% CI 4% to 8%), with a complete response rate of 0.3% (0.1% to 0.7%) and a partial response rate of 5% (3% to 7%). The rate of stable disease was 34% (30% to 38%). Of the three types of therapies, the objective response rate appeared highest in the molecularly targeted therapies, at 8% (5% to 11%). Overall, the rate of treatment-related deaths was 0.02% (0% to 0.2%). Conclusions: Our results suggest that response rates for single agent, targeted phase I anti-cancer therapies are not materially different from estimates derived in the conventional chemotherapy setting. In an era where providers tout the benefits of precision medicine, this is an important consideration when counselling patients considering participation in phase I trials. Treatment-related death rates were very low, weakening criticism that participation puts patients at great risk. Reporting was highly inconsistent across included studies, highlighting a need to improve the quality of reporting in phase I trials.
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.
The safety and tolerability of PD-1/PDL-1 inhibitors in hematologic malignancies: A meta-analysis.
Authors: Myint Phyo Thazin , Ali Faisal , Alrifai Taha , Gong Zimu , Nandar Phoo Pwint , Kozma Kelley Elizabeth
Published: May 2019

e14131

Background: The safety of programmed death receptor and ligand-1 (PD-1/PDL-1) inhibitors in hematologic cancers is not well-defined. We conducted a meta-analysis to investigate their safety. Methods: Pubmed & Cochrane databases were searched from 1968-2018. Full-text articles of clinical trials reporting treatment-related adverse events (AE) of PD-1/PDL-1 inhibitors in hematologic cancers were included. Incidences of all-grade and high-grade (≥grade 3) AEs were pooled and generated with a 95% confidence interval (CI) using a random effect model on STATA. Results: Eight studies (5 nivolumab & 3 pembrolizumab) were identified, with 703 patients and the median age of 34. Six studies were done in patients with relapsed/refractory (R/R) classical Hodgkin Lymphoma, one in R/R diffuse large B-cell lymphoma and one in combined hematologic cancers. There were 1092 total AEs, with a pooled high grade AEs rate of 13% (95% CI 9-17%). High-grade AEs (HAE) are summarized in the Table. Lipase elevation was the most common HAE for nivolumab (pooled incidence of 13%; 95% CI 6-23%), whereas leukopenia was the most common HAE reported with pembrolizumab use (pooled incidence of 36%; 95% CI 10-65%) There were 47 treatment discontinuation due to treatment-related AE. For Nivolumab, there was one treatment-related death (of a heavily pretreated patient) due to fatal pneumonitis. Conclusions: PD-1/PDL-1 inhibitors are well-tolerated in hematologic malignancies with a favorable risk of adverse events and very low treatment-related mortality. The HAE profile of Nivolumab differs from Pembrolizumab, and future studies should assess this heterogeneity further. [Table: see text]
Blocking LILRB and KIR receptors by B57 open conformers induces potent antitumor activity and acts synergistically with checkpoint blockade inhibition.
Authors: Renner Christoph , Curran Michael A. , Kolibaba Julia , Liu Yang , Petrausch Ulf , Zippelius Alfred , Stenner Frank , Rafiei Anahita , Marroquin Belaunzaran Osiris
Published: May 2019

e14137

Background: HLA open conformers (OC) are defined as HLA class I molecules lacking beta-2-microglobulin (β2m) and peptide. OC can be derived from different HLA I molecules such as HLA-B27, -B57, and –Cw08. OC have a different three dimensional structure when compared to their respective HLA/β2m/peptide counterpart and induce distinct immunological processes by binding to LILRB and KIR molecules, both key receptors of the innate immune system. B57 OC expression is associated with enhanced immunity against viruses and can cause autoimmunity. Its potential anti-tumor activity has not been exploited so far. Methods: B57 OC and control molecules were expressed as IgG4 fusion proteins in CHO cells. The affinity for protein-ligand interaction was measured by surface plasmon resonance (SPR). Human macrophages M1/M2, phagocytosis and NK cytotoxicity were assessed by flow cytometry and cellular assays. Syngeneic pancreatic cancer (Pan02) or colon cancer (MC38) mouse models were used. Mice with tumors of 80mm3were treated twice weekly at 5 mg/kg. Tumor and blood samples were analysed. FDA cancer panels were assessed by IHC for LILRB1-5 expression. Results: B57 OC displays distinct protein-ligand interactions with high affinity binding to LILRB2 & 4, KIR2L1-3, and KIR3DL1. Therapeutic efficacy in pancreatic and colon cancer models was observed with monotherapy (p < 0.01), and combo therapy using PD1 and/or 41BB antibodies (p < 0.0001). Ex vivotumor sample analysis revealed a significant reduction of MDSC & Tregs, and an increase of M1 type macrophages. In addition, loss of MDSC functionality and enhanced CD8+ T cell expansion was noticed. IHC of human tissue demonstrated enhanced LILRB2 expression, notably in colon and lung cancer. Conclusions: B57 OC has a unique binding profile to LILRB and KIR receptors. B57 OC induces anti-tumor activity in diverse syngeneic mouse models and acts synergistically with PD1 or 41BB antibodies. Pre-clinical and human in vitroexperiments demonstrate that B57 OC mode of action is established with inhibition of MDSCs, macrophage polarization to M1 phenotype, activation of NK cells and LILRB blockade on tumor cells, which in turn support the adaptive immune system by increasing CD8+ effector T cells and reducing Treg numbers. B57 OC is a first-in-class therapeutic with robust anti-tumor activity.
Toxicity of PD-1/CTLA-4 inhibitor immunotherapy among elderly patients.
Authors: Kapoor Vidit , Rixe Olivier
Published: May 2019

e14139

Background: The use of Immune check point inhibitors in advanced metastatic melanoma is becoming increasingly common especially in the elderly population. With metastatic melanoma being mostly a disease of the elderly, the safety and toxicity profile of immune check point inhibitors in this population group continues to remain controversial. Prior studies have hypothesized that due to reduced immune responses in the elderly, toxicity to immune check point inhibitors is expected to be low. In this study we aim to analyze the association of check point inhibitor induced immuno-toxicity with age. Methods: We analyzed 108 patients with stage 4 metastatic melanoma who were treated with anti-PD1 and/or anti-CTLA-4 immunotherapy. Out of these patients, 58 (53.7%) were 65 or more years old and 50 (46.3%) were < 65 years old. Overall, 64 (59.3%) patients had autoimmune side effects; 35 (60.3%) were 65 years or older and 29 (48%) were < 65 years old. The most common side effects were dermatitis (n = 22, 20.4%) and colitis (n = 21, 19.4%). Incidences of various autoimmune side effects were calculated in both groups (65 years or older and < 65 years old). Fisher exact test was used to calculate p values Results: There was a significant difference between the incidence of dermatitis between the two groups. (51.4% in 65 years or older and 24.1% in < 65 years old group, p = 0.04). The incidence of colitis was more in the 65 years or older group (37.1%) as compared to < 65 years group (31.1%) however results were not statistically significant (p = 0.79). Similarly, there was no significant difference in other autoimmune side effects including hepatitis, arthritis, pneumonitis, thyroiditis, hypophysitis, adrenalitis, anemia and thrombocytopenia between the two groups. Also, there was no significant difference in the incidence of different grades of side effects (1 to 4) between the two groups. Conclusions: Patients who are 65 years or older can safely tolerate immunotherapy as compared to patients < 65 years old but with an increased risk of dermatitis. These data should be validated by a larger study population.
Experience with CXCL12 inhibitor NOX-A12 plus pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer.
Authors: Halama Niels , Pruefer Ulrike , Frömming Anna , Beyer Diana , Eulberg Dirk , Jungnelius Jarl Ulf B. , Mangasarian Aram
Published: May 2019

e14143

Background: NOX-A12 is an inhibitor of the chemokine CXCL12 which prevents receptor engagement and blocks the formation of chemotactic CXCL12 concentration gradients. The OPERA study (NCT03168139) is a Phase 1/2 study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 as well as safety and efficacy of a combination with pembrolizumab in metastatic microsatellite-stable (MSS) colorectal (CRC) and pancreatic (PaC) cancer where PD-1 inhibition alone has not shown clinical benefit. Methods: Patients received 300 mg NOX-A12 twice weekly during a 2-week monotherapy phase. Biopsies were taken from liver metastases before and after NOX-A12 monotherapy for analysis of immune cell infiltration and cytokine signature. In a combination phase, patients received repeated 21-day cycles of 300 mg NOX-A12 and 200 mg pembrolizumab until progression or intolerable toxicity. Results: 11 of the patients had CRC and 9 PaC. All patients were heavily pretreated with 5 (CRC) and 3 median lines (PaC) of prior treatment. Best responses to last prior treatment was progressive disease for 95% of patients. The AE profile was comparable with the pembrolizumab profile or typical for the underlying diseases. At baseline, mean T cell density at the invasive margin was 327 cells/mm², clearly below the 600 cells/mm² that are predictive for a good prognosis. 2 weeks of NOX-A12 monotherapy induced Th1 cytokines (IFNγ, IL-2, IL-16) in approx. half of the patients. Although there were no objective responses, 25% of patients achieved stable disease; 7 patients showed prolonged time on treatment vs. the prior line of therapy. Updated figures for progression-free survival and overall survival for the whole patient cohort will be presented. Conclusions: In patients with MSS metastatic PaC and CRC cancer with impaired immune systems and a high tumor load that have failed multiple prior lines of therapy, NOX-A12 plus pembrolizumab shows induction of immune response, stable disease in 25% of patients, and prolonged time on treatment vs. prior therapy for 35% of patients. The safety profile of the combination therapy was consistent with that of pembrolizumab in advanced cancer patients. Clinical trial information: NCT03168139.
A phase II, open label, randomized, noncomparative study of eFT508 (tomivosertib) alone or in combination with avelumab in subjects with relapsed/refractory microsatellite stable colorectal cancer (MSS CRC).
Authors: Hubbard Joleen Marie , Patel Manish R. , Bekaii-Saab Tanios S. , Falchook Gerald Steven , Freilich Bradley L. , Dasari Arvind , Knisely Benjamin T , Anderson Marlisa , Chiang Gary Gene , Webster Kevin R , Sperry Sam , Barton Jeremy , Bendell Johanna C.
Published: May 2019

e14145

Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.