bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive value of baseline clinicopathological factors in non-small cell lung cancer (NSCLC) patients on checkpoint inhibitors (CPI).
Authors: Newman James , Preeshagul Isabel Ruth , Sullivan Kevin M. , Kohn Nina , Seetharamu Nagashree 
Published: May 2019

e14119 Background: Tumor PD-L1 expression and tumor mutational burden currently serve as primary predictive markers for CPI efficacy in NSCLC. However, these markers are imperfect due to tumor heterogeneity, changes over time, and lab variations. These challenges highlight importance of developing dynamic, readily available predictive biomarkers. We evaluated predictive value of pre-treatment Neutrophil-to-Lymphocyte Ratio (NLR), smoking history (SH), body mass index (BMI) and smoking intensity (SI) in NSCLC patients (pts) on CPIs. Methods: Retrospective analysis of NSCLC pts treated with CPIs July 2015 to November 2017. Pt demographics, tumor PD-L1 status positive (pos) or negative (neg) (PD-L1 > 0% or 0% respectively), SH, SI (heavy smokers (HS) or non-heavy smokers (NHS) [ = / > 20 pack-year (PY) and < 20 PY respectively], NLR and BMI high or low based on cutoffs of 5 and 25, respectively were captured. Disease Control Rate (DCR) was defined as objective response or stable disease per RECIST 1.1 at 3 months (m). Median overall survival (OS) and time to progression (TTP) were calculated. Fisher’s exact test and chi-square test were used to compare DCR for each group. Kaplan-Meier curves were used to estimate OS and TTP for each factor. Results: 140 pts were included. NLR was associated with DCR, OS, and TTP. 62/90 (68.9%) pts in the low NLR group and 18/47 (38.3%) in the high NLR group had DCR (p < 0.0006). Median OS for low NLR was 15 m (95% CI: 11.75, 22.25) vs. 5.25 m for high NLR (95% CI: 2.75, 9.75) (p < 0.0005). Median TTP for low NLR was 8 m (95% CI: 6.00, 11.25) vs 3 m for the high (95% CI, 2.00, 4.00) (p < 0.0001). SH was not associated with DCR or survival, but was predictive of TTP. SI was predictive of DCR, but not OS or TTP. 65/100 (65.0%) HS and 15/34 (44.1%) NHS had DCR (p < 0.0320). BMI and PD-L1 (n = 55) were not associated with any outcome. There was association between high BMI and low NLR (P < 0.0381). There were no other associations between factors. Conclusions: NLR < 5 was associated with improvement in all measures of outcome while smoking was associated with some. Neither BMI nor PD-L1 were predictive of any outcome. A score incorporating NLR and smoking status may be beneficial in choosing patients for CPIs.
Immune checkpoint inhibitor toxicity in the clinical practice setting.
Authors: Schmidt Laura , McGuire Brian , Hui Wendy , Carro George W. , Hensing Thomas A. , Shevrin Daniel H. , Campbell Nicholas Paul , Hanson Britt Erika , Brockstein Bruce 
Published: May 2019

e14128 Background: Immune checkpoint inhibitors (ICIs) are changing the landscape of treatment in oncology. The use of ICIs is growing rapidly as the indications for these medications broaden and new ICIs become approved. Given the rapid growth and relative infancy of the use of ICIs, much information stands to be gained on their use in the clinical practice setting, especially regarding toxicity. Methods: The primary objective of this project was to examine the incidence and severity of immune-related adverse events (irAEs), after treatment with single-agent or combination ICIs at a multi-site community cancer center. A retrospective chart review was conducted on all patients who had received ipilimumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab plus nivolumab from May 1, 2011 to June 30, 2017. Data collected included patient demographics, disease state, treatment information, preexisting autoimmune disease, previous immunotherapy, and adverse event details. The results were analyzed using descriptive statistics. Results: Data was collected on 383 patients. Dermatologic irAEs were common across single agent ICIs (overall incidence 23%). Diarrhea and/or colitis incidence was highest with CTLA-4 inhibitor ipilimumab (26% at 3 mg/kg and 22% at 10 mg/kg) versus the other monotherapy PD-1/PDL-1 inhibitors. Endocrinopathies were most common with ipilimumab 10 mg/kg (55%) and pneumonitis incidence was highest with nivolumab (6%). ICI toxicity occurred in 63% of patients with preexisting autoimmune disease versus 54% of those without a baseline autoimmune disease. Incidence of hospitalization and treatment holds due to irAEs was higher with combination therapy (57% and 66%, respectively) than with monotherapy (10% and 24%, respectively). Conclusions: Overall, there was increased incidence in ICI toxicity in patients at this oncology institution versus what has been reported in clinical trials. Patients with preexisting autoimmune diseases appeared to have mainly low-grade toxicities with slightly increased incidence of irAE compared with those without pre-existing autoimmune disease. Treatment holds and hospitalizations were higher in patients treated with combination therapy ICIs compared to monotherapy ICIs.
Predictors and outcomes of thyroid dysfunction with immunotherapy: A single institution observational experience.
Authors: Mangla Ankit , Paydary Koosha , Yadav Udit , Liu Jiaxiang , Lad Thomas E. 
Published: May 2019

e14134 Background: Immune-related endocrine dysfunction is unique to immunotherapy (IT). We aimed to explore the clinical parameters associated with development of thyroid disorder (TD) in patients receiving IT and their outcome. Methods: We designed a retrospective study of patients treated with anti-CTLA4 and/or anti-PD1/PDL1 IT at Cook County Hospital, Chicago between January 2015 to January 2018. Patients with incomplete charts and those who received less than two cycles of IT were excluded. Demographics, clinical and pathologic data were recorded at the time of diagnosis and prior to start of IT. Pearson Chi-square, independent sample t-test and logistic regression were used for data analysis. Results: We included 104 patients in the study, out of whom 66 were male and 38 were female. Most common diagnosis was non-small cell lung cancer (42.4%) followed by squamous cell cancer of head and neck (21.2%), renal cell cancer (12.5%), small cell lung cancer (12.5%) and melanoma (8.7%). Majority of patients (91.4%) had metastasized and were treated with either Nivolumab (71.1%) or Pembrolizumab (21.2%) in the 2nd (50%) or 3rd line (29.8%) setting. Twenty-eight patients developed TD while on IT, out of whom, 13 developed hypothyroidism, 12 developed hyperthyroidism followed by hypothyroidism and 3 developed hyperthyroidism. TD developed between 1st to 6th cycle of IT in 96.5% patients. Older age (p-0.009), history of radiation (RT) to neck (p-0.007), history of RT to chest (p-0.015), history of venous thrombosis (p-0.007) and higher thyroid stimulating hormone (TSH) level (17.76±35.67) prior to starting IT (p-0.029) were significantly associated with TD. Multivariate logistic regression showed that history of RT to neck was a significant predictor of developing TD after adjustment for age, race and sex (adjusted OR 9.64, 95% CI 1.88-49.36, p-0.007). No patient reported thyroid related symptom and IT was continued uninterrupted in all patients. Levothyroxine was the drug of choice for treating hypothyroidism. No patient received steroids or antithyroid medications. Conclusions: History of radiation therapy to neck is significantly associated with development of thyroid dysfunction in patients receiving immunotherapy. Thyroid replacement therapy is sufficient to bring down the levels of TSH and immunotherapy need not be interrupted.
Effect of antibiotic exposure in patients with metastatic melanoma treated with PD-1 inhibitor or CTLA-4 inhibitor or a combination of both.
Authors: Kapoor Vidit , Runnels Juliana , Boyce Tawny , Pankratz V. Shane , Rixe Olivier 
Published: May 2019

e14141 Background: Pre clinical studies have demonstrated the effect of gut microbiome in the efficacy of immune check point inhibitors. The effect of antibiotic exposure to patients receiving PD-1/CTLA-4 inhibitor therapy has not been extensively studied, especially in metastatic melanoma. In this study, we demonstrate the effect of antibiotic exposure to metastatic melanoma patients receiving PD-1/CTLA-4 inhibitor therapy. Methods: We performed a retrospective analysis of 108 patients with stage 4 metastatic melanoma who received immunotherapy with PD-1 inhibitors or CTLA-4 inhibitors or combination of both between Nov 2010 and Oct 2017. Patients were divided into Abx(+) and Abx(-) groups that were defined as patients exposed or not exposed to antibiotics respectively. The time frame for antibiotic exposure was taken from 6 months prior to 1 month after initiation of immunotherapy. We compared progression free survival (PFS), overall survival (OS) and response rate (RR) between the two groups. RR was calculated based on the entire length of follow-up. PFS and OS were assessed using Kaplan-Meier estimates. Cox proportional hazards were used to calculate hazard ratios. Results: Out of 108 patients, 66 (61.1%) were men, with a mean age 64.6 ± 15.1 years. 46 (42.6%) patients were exposed to antibiotics of varied classes. Median PFS in abx(+) group [88 days (95%CI: 70, 104)] was shorter as compared to abx(-) group [322 days (95%CI: 191, 410), p < 0.0001)]. Patients in abx(-) group had a 68% (95%CI: 45, 82) reduced risk of progression within 200 days of immunotherapy initiation adjusting for sex, age and number of immunotherapy cycles (p < 0.0001) . Median OS in ab(+) group [294 days (95%CI: 198, 345)] was shorter as compared to abx(-) group [573 days (95%CI: 453, 677)], p < 0.0001. Response rate defined as percentage of patients whose cancer was stable or entered remission was 12.9% (95%CI: 5.7, 23.9) in abx(-) group as compared to 8.7% (95%CI: 2.4, 20.8) ab(+) group. Patients in abx(-) group had a 52% (95% CI: 24, 69) reduced risk of death adjusting for sex, age and number of immunotherapy cycles (p = 0.002). Conclusions: Antibiotic exposure is associated with poorer outcomes in patients with advanced metastatic melanoma being treated with PD-1/CTLA-4 inhibitors which is likely related to alteration of gut microbiome. Antibiotics should be prescribed with caution in patients undergoing treatment with immune check point inhibitors. These data should be validated in a larger patient population.
Results of an Italian CORE-IMMUNO study: Safety and clinical-related biomarkers as predictors of immunotherapy (IT) benefit in real-world treatment of various advanced tumors (ATs).
Authors: Masini Cristina , Berselli Annalisa , Romagnani Alessandra , Bonelli Candida , Fantinel Emanuela , Pagano Maria , Banzi Maria , Prati Giuseppe , Gasparini Elisa , Moretti Gabriella , Gervasi Erika , Gnoni Roberta , Stridi Giovanna , Pinto Carmine 
Published: May 2019

e14156 Background: Checkpoint inhibitors in cancer therapy have shown survival benefits in the treatment of several ATs. However, the risk of serious side effects seems greater in certain types of tumors presenting reduced compliance with therapy. The aim of this study is to evaluate the safety profile and clinical benefits of IT, as appraised using clinically related biomarkers of pts outside clinical trials. Methods: In this retrospective study, data were evaluated on pts in the Reggio Emilia Provincial Oncology Network who were treated for ATs using Nivolumab, Pembrolizumab and Ipilimumab monotherapy in clinical practice. The pts included in the study had received at least 1 dose of IT by June 2018. LDH and neutrophil–lymphocyte ratio (NLR) were collected at baseline, antibiotic therapy (ATB) was considered during IT, and immunorelated adverse events (irAEs) were assessed with CTCAE v.4.1. Results: A total of 169 pts were examined: 78 with NSCLC, 57 with melanoma, 29 with kidney cancer, 3 with head-neck cancer and 2 with colorectal cancer. 123 pts (73%) were treated with Nivolumab, 36 (21%) with Pembrolizumab and 10 (6%) with Ipilimumab. Overall, 62 pts (37%) experienced irAES of any degree: 17/29 (59%) pts with kidney cancer presented irAES, while only 35% (20/57) and 31% (24/78) of pts with melanoma and lung cancer did, respectively. A total of 27/62 (43%) pts delayed IT due to toxicity, but only 7/62 (11%) pts discontinued treatment due to irAEs. Statistically significant increases in PFS (11 vs. 5 months, p = 0.002) and OS (19.9 vs. 8.7 months, p = 0.002) were found between pts who experienced irAEs and those who did not. As previously demonstrated in other groups of pts, in the Cox regression performed for OS, a baseline value of LDH≥1.5xULN and median NLR ≥2.93 correlates with poor prognosis. Unlike what is already known, the use of ATB during IT (35% of pts) correlates with increased survival (HR 0.59; IC95% 0.37-0.94, p = 0.028). Conclusions: These data confirm the tolerability of IT in an unselected real-world population. In particular, the development of irAEs could be considered a positive predictor of outcome, but with a different incidence among MTS.
Outcomes and toxicities in sarcopenic patients with metastatic solid tumors treated with check point inhibitors.
Authors: Haik Laura , Gonthier Aurore , Frison Eric , Gross-Goupil Marine , Domblides Charlotte , Veillon Remi , Quivy Amandine , Ravaud Alain , Daste Amaury 
Published: May 2019

e14166 Background: Evidence suggests that sarcopenia is a significant predictor of worst outcomes and treatment toxicities in metastatic solid tumors patients (pts). We investigated whether sarcopenia was associated with outcomes and severe toxicities (ST) in patients treated with check point inhibitors (CPI). Methods: All consecutive metastatic solid tumors patients treated with CPI from January 2013 to December 2017 in Bordeaux University Hospital (France) were retrospectively reviewed. Sarcopenia was evaluated using computed tomography (CT) obtained within 1 month before treatment initiation. Skeletal muscle mass index (SMI) were measured from axial L3 CT section. Sarcopenia was defined as SMI ≤ 52.4 cm2/m2 for males and SMI ≤ 38.5 cm2/m2 for women. Clinical characteristics included Performance Status (PS) and anthropometric parameters. ST included grade III-IV according to NCI-CTC v4.0 and any grade of toxicity leading to treatment interruption. Results: Among 261 pts included, 179 (69%) had metastatic lung cancer and 151 (58%) had previously received one line of treatment. Median age was 61 years old and there were 198 males (76%). PS status was 1 in 55% of pts. CPI treatment was: anti PD1, anti PD-L1, anti CTLA-4 and CPI combination in 192, 43, 3 and 20 pts, respectively. The prevalence of sarcopenia was 64%. At inclusion, sarcopenia was associated with poor PS (p = 0.002), anorexia (p < 0.001), lower albumin (p = 0.002) and hemoglobin (p < 0.001). Objective Response Rate (ORR) was 28% in sarcopenic pts and 26% in non-sarcopenic pts. Median progression free survival (PFS) was 6.9 and 7.6 months in sarcopenic pts and non-sarcopenic pts respectively (p = 0.5). In multivariate analysis, sarcopenia was not associated with PFS or ORR. Median overall survival (mOS) was 10.2 months in lung cancer, without significant difference between sarcopenic and non-sarcopenic patients (mOS: 9 months and 17 months respectively, p = 0.06). In general population, ST occurred in 36 (14%) pts; among which 23 (64%) presented sarcopenia. In multivariate analysis, sarcopenia was not associated with ST (OR = 1.16, p = 0.71). Conclusions: Sarcopenia was not associated with outcomes or toxicities in metastatic solid tumors patients treated with CPI in this study.
Immunotherapy efficacy and patients' age: A systematic review and meta-analysis.
Authors: Duan Jianchun , Cui Longgang , Zhao Zhengyi , Wang Guoqiang , Chen Shiqing , Bai Yuezong , Cai Shangli , Xiong Lei , Zhao Xiaochen , Wang Zhijie , Wang Jie 
Published: May 2019

e14168 Background: Immunotherapy has revolutionized the treatment of cancer, however, little is known about the effect of patients’ age on the efficacy of immune checkpoint inhibitors. We did a systematic review and meta-analysis to assess the heterogeneity of immune checkpoint inhibitor efficacy between young and elder patients in pan cancer. Methods: We systematically searched PubMed, Cochrane library, and Embase from January 2000 to November 2018 for randomized controlled trials that had available hazard ratios (HRs) for death according to patients’ age. 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). We calculated the pooled overall survival HR and 95% CI in young and elder patients using a random-effects model. Results: A total of 3365 publications were retrieved through initial literature search, 19 randomized controlled trials involving 12276 patients with solid tumors were included for this meta-analysis. PD-1 inhibitors exhibited significantly improved OS over PD-L1 inhibitors in younger patient population (HR 0.67, 95% CI 0.53-0.85), while no differences have been observed in elder population (HR 0.89, 95% CI 0.70-1.13). Subgroup analysis showed that PD-L1 inhibitors plus chemotherapies led to significantly improved overall survival (OS) in elder population (> = 65 years old) over that in younger population (< 65 years old) (HR 1.29, 95% CI 1.01-1.64). However, the opposite tendency was observed with PD-1 inhibitors plus chemotherapies, showing that the younger population obtained better OS benefit compared to the elder population (HR 0.69, 95% CI 0.47-1.01). Conclusions: In general, PD-1 inhibitors exhibited better clinical performance for survival outcome over PD-L1 inhibitors in younger patients. When combined with chemotherapies, PD-1 inhibitors and PD-L1 inhibitors showed distinct efficacy tendency across different age groups, indicating that age should be taken into account when making decisions about treatment strategies. Future studies and explorations of the underlying mechanisms are needed for the further optimization of treatment strategies in clinical practice.
Defining real-world criteria for immune-related adverse events (irAEs).
Authors: SINGH PRABHSIMRANJOT , Brito Amanda , Abdulnour Raja-Elie E , Grover Shilpa , Yenulevich Eric , Stuver Sherri Oliver , Kehl Kenneth L. , LeBoeuf Nicole R. , Jacobson Joseph O. , Rahma Osama E. 
Published: May 2019

e14172 Background: Management of Immune checkpoint inhibitors (ICIs) associated irAEs requires accurate diagnosis and severity measurement. However, outside of clinical trials, there is no clear definition of irAEs to guide treatment. Methods: We established a dedicated immune toxicity inpatient service (ITox) for patients admitted with irAEs using institution-developed guidelines adapted from NCCN and ASCO. We developed definitions for ICI associated hepatitis, colitis and pneumonitis and created algorithms for defining an irAEs as definite, likely, possible, or unlikely. Algorithm fields were completed twice, by two independent reviewers including medical oncology specialists and toxicity specialists (a pulmonologist or gastroenterologist) to evaluate the accuracy of the algorithm in defining irAEs. Results: From June to November 2018, 65 patients were admitted to iTox with suspected irAEs. Various cancers patients treated with ICI were included; with lung and head and neck cancers the most common (36.9%). Pembrolizumab was the most common ICI (47.7%). ICI in combination with non-checkpoint inhibitor treatment was used in 23 (37.7%) and concurrent radiation therapy in 5 patients (7.7%). Forty (71.4%) patients discontinued ICI due to toxicity. Fifty-one patients were evaluable with irAEs: colitis (19); pneumonitis (24) and hepatitis (8). Multiple irAEs were reported in 17 patients. When applied to clinical cases, our algorithms generated a toxicity definition in 63% of cases, with which reviewers agreed most of the time (84-100%) (Kappa 0.7-1.0). Concordance between the two reviewers was 75-87% (Kappa 0.55-0.82) (Table). Conclusions: Our algorithms generated irAEs definitions with fair inter-rater reliability. These findings have real-world implications; accurate diagnosis of irAEs is essential for proper management. Defining irAEs outside the clinical trial context remains an important challenge. [Table: see text]
Toxicities of single agent and combination immune checkpoint inhibitors in patients with autoimmune diseases.
Authors: Cytryn Samuel , Efuni Elizaveta , Sandigursky Sabina 
Published: May 2019

e14176 Background: Autoimmunity is associated with increased risk of malignancy. However, patients with pre-existing autoimmune diseases (AIDs) have been excluded from trials of immune checkpoint inhibitors (ICIs) known to cause immune activation and lead to immune related adverse events (irAEs). Data is limited on the safety and efficacy of these agents when used in AID patients and physicians are therefore wary to use them in this at-risk population. Methods: We conducted a single institution retrospective study to evaluate the safety and efficacy of ICI therapy in patients with pre-existing AIDs from 2011 to 2018. Primary endpoints were irAEs and AID flares. The secondary endpoint was overall survival (OS). Results: Of 84 total patients, 70 (83%) received ICI monotherapy and 14 (17%) received combination therapy. AIDs included: rheumatic 40 (48%), dermatologic 25 (30%), endocrine 16 (19%) and gastrointestinal 14 (17%) diseases of which 18 (21%) were on immune suppression. Combination therapy was associated with higher rates of severe grade 3-4 irAEs in 5/14 (36%) patients versus 8/70 (11%) with monotherapy (p = 0.022). ICIs were discontinued due to irAEs in 10/84 (12%) of all patients; 4/14 (29%) in the combination group and 6/70 (9%) in the monotherapy group (p = 0.057). While 32 patients (38%) had at least one AID flare, ICI was only permanently discontinued in 2 patients. Flare rates were higher for combination use: 8/14 (57%) compared to 23/70 (33%) for monotherapy (p = 0.086). Combination therapy was associated with higher median OS 27.8 months [95% CI 11.4-44.3] compared to monotherapy 12.3 months [95% CI 9.7-14.8] (p = 0.0007). OS had a positive correlation with flare (p = 0.007) and severe irAEs (p = 0.037). Conclusions: Our data suggest that rates of irAEs in patients with pre-existing AIDs are similar to those reported in the literature with single agent ICIs. While risk of severe irAEs and flares is increased with combination therapy, they are associated with overall survival. In our cohort, irAEs and flares were manageable and in most patients did not require permanent discontinuation for monotherapy or combination therapy suggesting that ICIs should be offered to this population, albeit with caution.