bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of systemic corticosteroids on survival outcomes in patients with immune-checkpoint inhibitor enterocolitis.
Authors: Thompson Leah L. , Katznelson Ethan , Leet Donna E. , Durbin Sienna , Yoon Jaewon , Park Jin K. , Dougan Michael L. , Chen Steven T. 
Published: May 2020

e15065 Background: Current guidelines for immune-checkpoint inhibitor enterocolitis (ICI-EC) recommend systemic corticosteroids (SCS) for moderate to severe cases, but whether these therapies have an impact on survival outcomes remains unclear. Prior work has been limited, considering only select cancer types, ICI regimens, and indications for immunosuppression. We therefore sought to examine the relationship between SCS for ICI-EC and survival outcomes, accounting for all other steroid exposures. Methods: We retrospectively reviewed the medical records of patients with biopsy-confirmed ICI-EC seen at our institution between August 2011 and April 2019, collecting patient demographics, cancer features, anti-neoplastic therapies, other immune-related adverse events (irAEs), SCS exposures, progression-free survival (PFS), and overall survival (OS). We further categorized SCS exposures by indication (ICI-EC, other irAE, other medical reason) and previously established dose thresholds (“high” ≥1mg/kg for ≥1 week; “moderate” ≥7.5mg for ≥2 months, or “none”). We assessed the relationship between SCS use for ICI-EC and PFS/OS using Cox proportional hazards models adjusted for age, sex, cancer type and stage, baseline brain metastases, functional status (Eastern Cooperative Oncology Group score), anti-neoplastic therapies, and other SCS exposures. Results: 90 patients (mean age 62.5 years, 37.8% female) had biopsy-confirmed ICI-EC, most commonly precipitated by CTLA-4 monotherapy (43.3%). Nearly all (80.0%) required SCS for their first episode of ICI-EC, with half (46.7%) requiring doses exceeding the highest threshold. Patients who received high-dose SCS for first ICI-EC episode had reduced PFS (HR = 2.50, p = 0.028) compared to those who did not receive SCS for this indication. OS was not affected by SCS therapy for ICI-EC at any dose. Conclusions: In cancer patients with biopsy-proven ICI-EC, receipt of high-dose SCS for first ICI-EC episode was associated with decreased PFS, but not OS. These findings suggest a nuanced and potentially dose-dependent relationship between SCS and survival outcomes meriting further investigation for a larger array of immunotoxicities.
Predicting cardiac adverse events in patients receiving immune checkpoint inhibitors: A machine learning approach.
Authors: Dreyfus Brian , Heilbroner Samuel P , Few Reed , Kratt Christine , Gomez Andres 
Published: May 2020

e15075 Background: Many oncology treatments have been associated with cardiovascular (CV) adverse events. Cases of CV events, including myocarditis have been reported for PD-1 and PD-L1 therapies. We created a machine learning model to predict potential CV events in PD-(L)1 patients using the CancerLinQ database. Methods: A XGBoosted decision tree model was trained to predict a patient’s risk of serious CV adverse events. The model was trained on 80% of all advanced non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) patients from our database including those who received PD-(L)1 therapy. Index date was defined as date of first PD-(L)1 administration or date of advanced diagnosis if no PD-(L)1 drug was given. The model contained approximately 400 potential risk factors for cardiac disease including elements of past medical history, social history, vitals, common labs, cancer history (e.g. stage, cancer type), medication history, and PD-(L)1 specific factors including PD-(L)1 expression status and PD-(L)1 therapy administered. The model was tested on two separate validation sets (patients not used in training): one using advanced NSCLC, melanoma, and RCC patients and another with PD-(L)1 patients only. Each factor’s importance to the model’s predictions was calculated using SHAP summary plots, a qualitative technique for interpreting machine learning models. Results: A total of 27,172 advanced cancer patients were included in our study. 4,966 received PD-(L)1 therapy. The model was trained on 21,758 patients and 5,414 patients were set aside for testing. The model predicted serious cardiac events within 100 days of index with an AUC-ROC of 0.75 in all patients and 0.79 in PD-(L)1 patients. The top predictors of cardiac risk in PD-(L)1 patients included a history of heart disease, weight loss, the % lymphocyte count, and median LDH. The % lymphocyte count and weight loss were noticeably more predictive in PD-(L)1 patients than in non-PD-(L)1 patients. However, in general SHAP summary plots of all and PD-(L)1 patients were nearly identical, suggesting that both cohorts’ cardiac risk is determined in a similar way. PD-(L)1 and autoimmune disease associated factors did not appear in the top 40 most predictive risk factors. Conclusions: Using traditional cardiac risk factors, our model was able to predict potential cardiac events in PD-(L)1 patients. Our model found that high lymphocyte count may be protective while weight loss and a history of cardiac disease (e.g. heart failure) could indicate a poor prognosis.
Multidisciplinary team management for high grade immune-related adverse events (irAEs): A single center experience.
Authors: SINGH PRABHSIMRANJOT , Abu-Shawer Osama , Brito Amanda , Yenulevich Eric , Grover Shilpa , Abdulnour Raja-Elie E , LeBoeuf Nicole R. , Ott Patrick Alexander , Hodi F. Stephen , Jacobson Joseph O. , Rahma Osama E. 
Published: May 2020

e15076 Background: Immune checkpoint inhibitors (ICIs) are increasingly used in the management of cancer. High grade irAEs are uncommon but can be severe and require hospital admission. There is an urgent need for early identification and triage of patients with irAEs in order to improve their management and outcomes. Methods: We established Immunotherapy toxicity (ITOX) team as the first in nation inpatient service at DFCI and Brigham and Women's Hospital (BWH) along with our partners at Massachusetts General Hospital (MGH) that is specifically devoted to mitigating irAEs. The ITOX service is consistent of 2 PAs and a medical oncology attending with an expertise in immunotherapy. The service utilizes algorithms that are modified from the ASCO and NCCN guidelines by our medical subspecialty experts at BWH. The service uses a multi-disciplinary approach with around the hour consulting service from experts in the field including GI, pulmonary, endocrinology and others. We leveraged EPIC to triage patients who are admitted to BWH and have ever received or currently on immune checkpoint inhibitors (ICIs). The daily list generated by EPIC is then curated manually by a PA to identify patients with potential irAEs. Results: A total of 138 patients with high grade irAEs were admitted to BWH between June 2018 and June 2019. Seventy percent of the 201 irAEs- related admissions were to ITOX service (70% accuracy in triaging). Most common irAEs was colitis (31%), pneumonitis (28%) and hepatitis (13%) which is consistent with the most common reported irAEs due to ICIs. Eighty five percent of the patients had grade 3 irAEs and 15% were admitted with life threatening grade 4 adverse events. About half of the patient had received ICI monotherapy; 33% received combination of ICI and non-ICI (chemotherapy or targeted therapy) and 17% received combination of ICIs. Most patients responded to steroids and only 9% had steroid-refractory irAEs requiring other immunosuppressive agents. The average length of stay for irAEs-related admission was 11 days with readmission rate of 26% within a year. Over 50 patients consented for tissue and blood biospecimen collection at the time of toxicity. Conclusions: We demonstrated the feasibility of empowering EMR to accurately triage patients with suspected irAEs to the ITOX service that is supported by institution developed guidelines and specialists. Our model is adaptable in major academic centers and can have major impact on quality improvement and future research studies that can be conducted in this unique setting.
Nephrotoxicity due to immune checkpoint inhibitors in rural oncology.
Authors: Leon Chady Abboud 
Published: May 2020

e15084 Background: Case studies and retrospective chart reviews of health system data have demonstrated an increased risk of nephrotoxicity in patients receiving immune checkpoint inhibitors (CPIs) compared to the incidence of nephrotoxicity reported in clinical trials. The primary objective of this study is to determine the extent to which CPIs may induce nephrotoxicity in a real-world, rural population. The secondary objectives are to identify risk factors for renal dysfunction and describe real-world use of this relatively new class of medications. Methods: This represents a retrospective review of patients receiving at least one dose of a CPI at Marshfield Clinic Health System (MCHS) in Central Wisconsin from May 2013 to November 2019. Baseline serum creatinine, defined as the average of all serum creatinine values obtained within 6 months of the CPI start date, was compared to all serum creatinine measurements during CPI therapy and through 60 days after the last CPI dose. Acute kidney injury (AKI) was defined using the Kidney Disease Improving Global Outcomes definition. Patients developing an AKI of at least three day duration were further assessed to determine the likely cause of AKI. The incidence of potentially CPI-induced AKI was our primary outcome. Chi-square test will be used to compare incidence of AKI among different CPIs. A subdistribution hazard regression will be used to assess the association between the incidence of potentially CPI-induced AKI and patient characteristics (including comorbidities, type of cancer diagnosis, demographics, baseline ECOG score, CPI line in therapy, time lapse between diagnosis and CPI start, and concomitant nephrotoxic medications) while accounting for the competing risk of death. Results: A total of 922 patients received at least one dose of a CPI at MCHS during the study period. After applying exclusion criteria, a total of 920 patients were included in the analysis. The incidence of AKI of any duration and due to any cause was 29.5% (272 of 920 patients). Conclusions: The raw incidence of AKI in our patient population receiving CPIs is higher than previously published studies. However, our data are still being refined and research is in progress.
Immunohistochemistry analyses of LAG-3 expression across different tumor types and co-expression with PD-1.
Authors: Chen Francine , Sherwood Thomas , De Costa Anushka , Yee-Toy Nicholas , Lung Peter , Easton Ann , Sumrow Brad , Bonvini Ezio , Moore Paul A. 
Published: May 2020

e15086 Background: Concomitant blockade of LAG-3 and PD-1 has been shown to restore T-cell activation and enhance anti-tumor immunity in preclinical models. Clinical trials evaluating anti-LAG-3/anti-PD-1 mAb combinations or bispecific molecules are ongoing. Establishing the tumor expression profile of LAG-3 and its relationship to PD-1 will aid in patient selection and interpretation of clinical responses to combined inhibition. Methods: LAG-3 Ab clone EPR4392(2) (Abcam) and PD-1 Ab clone NAT105 (Ventana) were developed as individual or combined dual IHC assays on the Ventana Discovery Ultra platform. LAG-3 IHC was performed on panels of commercially available tissues: 33 normal human tissues (2 each) and various tumor types including anal (n = 39), cervical cancer (40), cholangiocarcinoma (11), DLBCL (40), gastric cancer (34), HCC (18), SCCHN (39), HER2-positive breast cancer (48), mesothelioma (40), NSCLC (39), ovarian cancer (47), SCLC (48), and TNBC (40). LAG-3 IHC expression was confirmed by in situ hybridization (ACD RNAScope). Positivity was defined as at least one LAG-3+ve or PD-1+ve tumor-infiltrating lymphocyte (TIL) per 40x magnification hot spot field (HSF); high LAG-3 expression was defined as > 15 LAG-3+ve TILs per HSF. Results: LAG-3-specific staining in normal tissues was limited to mononuclear cells in lymphoid organs and GALT, with no staining observed in normal parenchyma. Across various tumor types, the frequency of LAG-3+ve tumor samples and high expression, respectively (%, %), were as follows: cervical (100; 57.5), anal (97.4; 30.8), DLBCL (95; 75), NSCLC (92.3; 25.6), TNBC (90; 22.5), gastric (88.2; 44.1), SCCHN (87.2; 56.4), HER2-positive breast (85.4; 39.6), HCC (83.3; 22.2), cholangiocarcinoma (81.8; 9.1), ovarian (70.2; 21.3), SCLC (50; 14.6) and mesothelioma (25; 10). In addition to TILs, LAG-3 expression was observed on tumor cells in DLBCL and a fraction of anal, breast, cervical, gastric, hepatocellular, SCCHN, NSCLC and ovarian cancers. LAG-3/PD-1 double IHC staining revealed dual positivity across 92.3% of NSCLC samples, with approximately 60% demonstrating TIL co-expression of PD-1 and LAG-3. Conclusions: LAG-3 expression was detected on TILs across a broad range of solid tumors and DLBCL, with varying level of intensity or association with PD-1 expression. Correlative assessments of LAG-3/PD-1 expression with clinical responses to MGD013, an investigational bispecific DART(R) molecule targeting LAG-3/PD-1 (NCT03219268), will be undertaken.
Incidence and risk factors for pneumonitis associated with immune checkpoint inhibitors in advanced-stage non-small cell lung cancer: A single center experience.
Authors: Soto Felipe , Zhong Linda , Shannon Vickie R , Wilson Nathaniel , Zarifa Abdulrazzak , Akhmedzhanov Fechukwu , Heymach John , Arain Muhammad H , Lewis Jeff , Rinsurongkawong Waree , Lee J. Jack , Zhang Jianjun , Swisher Stephen , Mendoza Tito R. , Naing Aung , Sheshadri Ajay , Altan Mehmet 
Published: May 2020

e15089 Background: Conventional treatments for advanced-stage non-small cell lung cancer (NSCLC) confer a progression-free survival of only about 6 months. Immune checkpoint inhibitors (ICIs) have become standard therapies in the management of advanced NSCLC, but are associated with a variety of immune-related adverse events that may be dose-limiting (irAEs). Risk factors for ICI-related pneumonitis, a potentially fatal irAE, have not been well established. We sought to determine the incidence and risk factors for ICI-related pneumonitis in NSCLC in a cohort of patients treated with ICIs as standard of care or as part of a clinical trial. Methods: We performed a retrospective review of 525 patients with advanced NSCLC who received ICI therapy with PD-1 inhibitors, with or without CTLA-4 inhibitors, at MD Anderson Cancer Center between 2015 and 2018. Patients with incomplete data were excluded from the study. Clinical data was collected at the time of ICI therapy and at the time of irAE. The diagnosis of pneumonitis was based on clinical presentation, imaging findings, and microbiological results. We constructed a Fine-Gray competing risks regression model with pneumonitis as the outcome of interest and all-cause mortality as the competing risk. Results: In our initial data analysis based on available data shows a 9.7% raw incidence of pneumonitis (17/177). We found no association between age, race, gender, type of anti-PD-1 therapy, concurrent use of CTLA-4 inhibitors, tumor histology, cumulative radiation dose, or smoking pack-years with the risk for pneumonitis. Patients who were therapy-naïve at the initiation of ICI therapy (hazard ratio [HR] 3.3, 95% confidence interval [CI] 1.0-10.6, p = 0.04), and patients with prior lung disease (HR 2.7, 95% CI 0.8-8.5, p = 0.1) had around a three-fold increase in the risk for pneumonitis after accounting for the competing risk of mortality. Conclusions: NSCLC patients who are therapy-naïve or have prior lung disease on initiation of ICI therapy have a higher risk for pneumonitis. Other studies have shown an increase in pneumonitis in therapy-naïve patients, but the association with prior lung disease is novel. Further analysis on this cohort is ongoing.
Smoking status and immunotherapy outcomes in smoking-associated cancers.
Authors: Jun Tomi , Ganta Teja , Qin Qian , Patel Vaibhav G. , Wang Bo , Mellgard George , Gogerly-Moragoda Mahalya , Leiter Amanda , Gallagher Emily J. , Oh William K. , Galsky Matt D. , Tsao Che-Kai 
Published: May 2020

e15097 Background: Improved immunotherapy (IO) outcomes have been observed among non-small cell lung cancer patients with a current or former smoking history. This is thought to be a consequence of increased immunogenic mutation burden among smoking-related cancers. We set out to explore the association between smoking status and immunotherapy outcomes in lung and other smoking-associated cancers. Methods: This was a retrospective analysis of 200 consecutive patients with advanced, smoking-associated solid tumor types, treated with single-agent anti-PD1/PDL1 therapy at a single center between July 2014 and February 2018. The primary outcome was overall survival from date of IO initiation. The secondary outcome was overall response, defined as radiographic complete response or partial response, by RECIST 1.1 criteria. The primary predictor was smoking status (former/current smoker vs. never smoker). The primary and secondary outcomes were analyzed using multivariable Cox proportional hazards models and multivariable logistic regression models, respectively. Models were adjusted for age and sex, and stratified by cancer type. Results: The majority of patients were male (64%) with a history of smoking (72%); the average age was 67.1 ± 11.4 years. Cancer types represented were: non-small cell lung cancer (NSCLC, N = 81), hepatocellular carcinoma (HCC, N = 41), urothelial carcinoma (BLCA, N = 39), head and neck squamous cell carcinoma (HNSC, N = 21), and renal cell carcinoma (RCC, N = 18). Over a median follow-up of 11.3 months (range 0.5-53.2), there were 96 deaths and 27% of evaluable patients achieved radiographic response. Response was not evaluable in 27 patients. In multivariable regression analysis, smoking status was not significantly associated with overall survival nor overall response in any cancer type examined (Table). Conclusions: Smoking status was not associated with outcomes in our cohort of IO-treated patients with smoking-associated cancers, though sample size was limited. [Table: see text]
Pharmacokinetic (PK)-pharamcodynamic (PD) analysis and receptor occupancy data to support every other week maintenance dosing of magrolimab in combination with azacitidine in MDS/AML patients.
Authors: Agoram Balaji , Jin ChaoYu , Maute Roy , Takimoto Chris H.M. , Chao Mark , Sallman David Andrew 
Published: May 2020

e15098 Background: Magrolimab (Hu5F9-G4) is a monoclonal IgG4 antibody that binds to CD47 receptor and blocks its interaction with SIRPA, thereby enabling tumor cell phagocytosis and activation of an anti-tumor T-cell response. Magrolimab has shown encouraging efficacy and tolerable safety profiles in treatment-naïve myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) patients on an every week (QW) maintenance dosing schedule. Reduced dosing frequency (e.g. every other week – Q2W) is desired to enhance patient convenience and quality of life. Methods: Interim pharmacokinetic (PK) and CD47 receptor occupancy (RO) data from study 5F9005 (Clinical Trial: NCT03248479) were used for this analysis. A previously developed population PK (PopPK) model of magrolimab was verified with observed PK data from study 5F9005. The PK model was linked to peripheral blood and bone marrow blast CD47 RO. The model-predicted RO was validated with observed RO data. Simulations of PK and RO were conducted to justify the proposed reduced dosing frequency of Q2W starting in Cycle 3 onward. Simulations were compared with preliminary observed RO data from the ongoing 5F9005 study after switching to Q2W dosing. Results: The results showed that observed magrolimab PK in study 5F9005 was consistent with model predictions. Model predicted RO was aligned with observed RO data. PK and RO simulations based on the model indicated > 99% RO in peripheral blood and ~90% RO in bone marrow are expected after switching to Q2W dosing regimen from Cycle 3 onward. Preliminary observed RO data confirmed these predictions. Conclusions: Magrolimab PK in AML/MDS is consistent with other patient populations including solid tumors and lymphomas. Model-based simulations and preliminary RO data support Q2W dosing of magrolimab from Cycle 3 onward as optimal RO is expected with the proposed dosing regimen. Clinical trial information: NCT03248479 .
Oral adverse events in cancer patients treated with immune checkpoint inhibitors.
Authors: Xu Yuanming , Sonis Stephen T. , Wen Natalie , Salous Moaiad , Villa Alessandro 
Published: May 2020

e15106 Background: Immune-checkpoint inhibitors (ICIs) are increasingly used to treat a variety of cancers. Immune-related adverse events (irAEs) have been reported. Oral manifestations of irAEs include stomatitis, oral ulcers, and xerostomia. However, the trajectory and frequency of oral irAEs remain unclear. This study aims to evaluate the prevalence, trajectory and nature of oral irAEs and their association with primary cancer diagnosis and other irAEs. Methods: A retrospective electronic chart review using the Partners Research Patient Data was performed for all patients treated with ICIs at Partners Healthcare hospitals and the Dana-Farber Cancer Institute between 12/2011 and 9/2019. Keywords specific to oral irAE such as oral mucositis, stomatitis or mouth sore were used. We collected data on demographics, cancer features, treatments, and characteristics of oral irAEs. Results: 822 of 4683 patients who received ICIs therapy were identified by keyword filtering. Lung cancer, gastrointestinal cancer, and skin cancer (including melanoma) were the most common types of primary malignancies with a frequency of 35.5%, 12.4 % and 11.7%, respectively. Oral irAEs were identified in 106 patients with the median age of 69 (range: 29-92) years and the female to male ratio of 1:1. 57.5% (n = 61) presented with symptomatic oral mucosal lesions. 47.2% (n = 50) had xerostomia and 17.0% (n = 18) had dysgeusia. The median time from the date of ICIs initiation to the date of oral irAE onset was 105 days (range: 2-631 days) in patients presented with oral mucosal lesions, 103 days (2-860 days) in xerostomia patients, and 156 days (range: 5-836 days) in dysgeusia patients. Melanoma was the most common cancer seen in oral irAE patients (30.2%), followed by lung cancer (26.4%) and oral/oropharyngeal cancer (12.3%). 60, 42, and 12 patients received pembrolizumab, nivolumab, and ipilimumab, respectively. 86.8% of oral irAE patients received only one type of ICIs therapy. Concomitant cutaneous, intestinal, and rheumatological irAEs were commonly reported with a frequency of 19.4%, 15.3%, and 12.2%, respectively in those patients. Conclusions: Oral irAEs can present with both acute and chronic onset in patients with ICIs therapy but are not as common as oral AEs associated with conventional cytotoxic regimens. While data relative to capturing oral irAEs is still preliminary, the current provides insight into their nature and course. Prospective studies focused on assessing the impact of ICI on oral irAEs are likely to provide additional insight into the character, course and impact of these conditions.