bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety of weight-based dosing of nivolumab with or without ipilimumab by body mass index (BMI) stratified by sex across 14 CheckMate clinical trials.
Authors: McQuade Jennifer Leigh , Hammers Hans J. , Furberg Helena , Engert Andreas , Andre Thierry , Blumenschein George , Tannir Nizar M. , Baron Ari David , Larkin James , El-Khoueiry Anthony B. , Carbone David Paul , Thomas John-Michael , Hennicken Delphine , Zoffoli Roberto , Reshef Daniel , Coffey Mary , Motzer Robert J.
Published: May 2020

e15114

Background: Associations between obesity and cancer risk, prognosis, and therapeutic outcomes have been extensively researched. However, the impact of BMI on safety in patients receiving immunotherapy has not been well described. Methods: A descriptive, retrospective analysis examined associations between BMI (kg/m2) (underweight/normal, BMI < 25; overweight, 25 ≤ BMI < 30; obese, BMI ≥ 30) and incidence of any-grade and grade 3/4 immune-mediated adverse events (imAEs) in patients receiving ≥ 1 dose of nivolumab 3 mg/kg as monotherapy (NIVO3; n = 2746). Data were pooled from CheckMate clinical trials across 8 tumor types. Data from nivolumab in combination with ipilimumab cohorts (n = 1026) and safety analyses by specific imAEs and tumor types will be presented. Results: Select NIVO3 monotherapy cohort patient demographics were: 68.5% male, median age of 61 years, median 10 doses received, and median BMI of 25.3 kg/m2. Results showed a trend towards higher incidence of any-grade, but not grade 3/4, imAEs in obese vs overweight and obese vs underweight/normal BMI patients (Table). BMI associations with imAE incidence were consistent with the overall trend across pre-defined subsets, including smoking status, age, and ECOG performance status. Both male and female patients had an increased incidence of any-grade imAEs with obesity; however, obese female patients had a higher incidence of grade 3/4 imAEs vs underweight/normal BMI (Table). Conclusions: This was a novel analysis of BMI and safety in 2746 patients across 8 tumor types in CheckMate clinical trials who were treated with nivolumab monotherapy. While obese patients showed a trend towards higher incidence of any-grade imAEs than those with overweight and underweight/normal BMI, incidence of grade 3/4 imAEs was consistent across BMI categories. Clinical trial information: CheckMate 017,026,057,025,039,205,040,066,067,141,275,142,016,214 (NCT numbers do not fit in field) . [Table: see text]
Immune checkpoint inhibitors combined with chemotherapy/radiotherapy, for EGFR wild-type lung cancer: Efficacy in real-world study.
Authors: Feng Jifeng , Shi Yue
Published: May 2020

e15117

Background: The role of immune checkpoint inhibitors (anti-PD-1 antibody, ICI) combined with chemotherapy/radiotherapy for EGFR wild-type lung cancer is controversial, especially in 2nd-line or later treatment. The purpose of this study was to investigate the possible beneficial factors for immunotherapy for EGFR wild-type lung cancer. Methods: A total of 279 patients with EGFR wild-type lung cancer who received ICI were retrospectively analyzed, including 138 adenocarcinoma, 76 squamous carcinoma and 31 SCLC patients. Beneficial factors were determined by multivariable Cox proportional hazards model for PFS. PFS and ORR were compared between different therapies. Results: The specific results are shown in table. In multivariable analysis, ICI combined radiotherapy (P = 0.018; HR, 0.152(95% CI: 0.032, 0.727)) was identified as an effective independent factor for EGFR wild-type lung adenocarcinoma. PFS in patients who received ICI combined radiotherapy was significantly longer than that in those who received ICI monotherapy ((p = 0.032; not reached vs. 9.6 m (95% CI: 5.627, 13.640))). Among lung adenocarcinoma patients who received ICI as 2nd-line treatment, patients treated by ICI combined chemotherapy showed more benefit than those treated by ICI monotherapy (P = 0.003; HR, 0.012(95% CI: 0.001, 0.213)).ICI combined chemotherapy can significantly prolong PFS compared with those treated by ICI monotherapy (p = 0.015; 14.3 m [95% CI: 8.711, 19.822] vs. 1.1 m (95% CI: 0.25, 1.883)) in the 2nd-line treatment. However, ORR showed no significant different between ICI monotherapy and ICI combined chemotherapy(P = 0.626). Conclusions: ICI combined with radiotherapy showed better result than those who didn’t receive radiotherapy for EGFR wild-type lung adenocarcinoma. The addition of chemotherapy to ICI for the 2nd-line treatment in EGFR wild-type lung adenocarcinoma patients seems get more clinical benefit than ICI monotherapy. [Table: see text]
Checkpoint inhibitor-associated immune-related adverse events as harbinger of favorable clinical outcome: Systematic review and meta-analysis.
Authors: Park Robin , Lopes da Silva Laércio , Saeed Anwaar
Published: May 2020

e15129

Background: Recent studies have observed an association between immune-related adverse events (irAE) and favorable clinical outcomes in the setting of cancer treatment with immune checkpoint inhibitors (ICI). However, results have been variable and inconclusive. Therefore, we have conducted a pan-cancer meta-analysis evaluating the relationship between irAEs and clinical outcomes. Methods: The search included PubMed, Embase, and Web of Science from conception to 12.28.2019 as well as abstracts published in the ASCO and ESMO meetings from 2015 to 2019. Studies were included if ICI was used in advanced or metastatic cancer settings and excluded if data contained only combination therapy regimens or contained anti-CTLA-4. Pooled sensitivity (SN), specificity (SP), positive (PPV) and negative predictive values (NPV), and odds ratios (ORs) were calculated using the 2 x 2 table and logit transformed proportions; and summary receiver operating curve (sROC) was generated using the bivariate approach for ORR. Pooled HRs were calculated using the means weighted by inverse of the variance for OS and PFS. Heterogeneity was assumed and random effects model was used throughout analyses. Results: Final analysis included 32 studies encompassing non-small cell lung cancer, melanoma, gastric cancer, renal cell carcinoma, urothelial carcinoma, and head and neck cancer. With respect to ORR, pooled SN, SP, PPV and NPV, and OR were 0.522 [0.423-0.619], 0.810 [0.771-0.844], 0.516 [0.413-0.618], 0.819 [0.764-0.864], and 4.59 [3.24-6.50] respectively. The area under the curve (AUC) derived from the sROC was 0.773. HR for OS and PFS were 0.47 [95% CI 0.37-0.60] and 0.46 [95% CI 0.37-0.56] respectively. Between-study publication bias was present for ORR, OS, and PFS but results remained significant after trim-fill analysis. Conclusions: irAEs predict OR, OS, and PFS across different types of cancer and may represent useful biomarkers in the clinical setting. [Table: see text]
Cardiotoxicity associated with immune checkpoint inibitors: A systemic review and meta-analysis.
Authors: Ba Aqeel Sheeba Habeeb , Lingamaneni Prasanth , Banskota Shristi Upadhyay , Farooq Muhammad Zain , Pichardo Rayli , Vohra Ishaan , Mangla Ankit
Published: May 2020

e15131

Background: Immune checkpoint inhibitors (ICI) are associated with multiple immune related adverse events (irAE). Cardiotoxicities are rare but fatal complications. Since PD-1 and PD-L1 are expressed on human cardiomyocyte, there is an increased risk of cardiotoxicity with use of ICI. We performed a systematic review and meta-analysis to assess cardiotoxicities associated with PDL1 and CTLA4 inhibitors. Methods: The Embase, Ovid, Pubmed and Scopus were searched from inception to 2019 by two independent reviewers. All Phase II and III clinical trials reporting cardiotoxicities with the combination of, or monotherapy with anti-PD-1/PD-L1 and/or anti-CTLA4 were included. Our primary outcome was assessment of cardiotoxicity of all grades that included, hypertension, arrythmias, pericardial effusion, myocardial infarction, myocarditis, cardiomyopathy and cardiac arrest. Statistical heterogeneity was quantified using I2 statistics. The publication bias was assessed with Eggers regression test. The estimates were reported as odds Ratio (OR) with 95% confidence intervals (CI) using random effect model. Results: A total of 2,876 trials retrieved in the initial database search were analyzed according to PRISMA guidelines. Twenty trials met the inclusion criteria and were included in the final analysis. A total of 8,905 patients were included in these trials. There was no statistically significant difference in reported overall cardiotoxicity with ICI compared to placebo or standard of care (OR 0.953 95% CI 0.542-1.675, I2 89.49 p < 0.001). Also, no statistical significance associated with myocardial infarction (OR 0.76, 95% CI 0.76-3.298 I2 0%, P = 0.83), pericardial effusion (OR 1.44, 95% CI 0.72-2.90. I2= 0%, P = 0.613) or hypertension (OR 0.543, 95% CI 0.219-1.346. I2 = 94.98, P < 0.001). Myocarditis was reported in 8 patients with a statistically non-significant increased risk compared to standard of care or placebo (OR 2.16, 95% CI 0.719-6.828 I2= 0%, P = 0.885). Other reported cardiac irAE included cardiac arrest in 4 patients, QT prolongation in 2 patients and cardiac tamponade in 1 patient. Conclusions: The overall risk of cardiac related irAE is not significantly higher with ICI when compared with placebo or standard of care. The reported events of severe cardiac irAE like myocarditis and cardiac arrest are very low in the reported trials.
The safety and efficacy of immune-checkpoint inhibitor therapy in HIV infected cancer patients.
Authors: Myint Phyo Thazin , Ali Faisal S. , Verghese Dhiran , Alrifai Taha , Thet Aye Mon , Kozma Kelley Elizabeth
Published: May 2020

e15141

Background: The clinical utility and safety of immune-checkpoint inhibitors (ICIs) in HIV infected cancer patients has not been well studied. Methods: We conducted a systematic search of Medline and Embase from inception to December 2019 to identify case reports and case series of ICI use in HIV infected cancer patients. Data were pooled utilizing a pre-specified protocol, and descriptive statistics were employed to report findings. Results: We identified 79 cases with a mean age of 52.5 (SD 11.65), 50 of whom were males. The most common cancers were NSCLC followed by Melanoma. Nivolumab was used in 54 patients whereas Pembrolizumab was used in 15 patients, with a mean of 25.7 months to ICI initiation from cancer diagnosis, and with a mean of 1.6 prior systemic lines of chemotherapy. 72 patients were on antiretroviral therapy. The mean baseline CD4 count was 385 (227.03), with a median baseline viral load of 40 (IQR 10.75-95.39). Mean CD4 count and median viral load during ICI therapy were 344.87 (SD 209.7) and 20 (0-400), respectively. 28 patients experienced and irAE; 63.2% and 63.6% of patients who experienced a decreased or increased CD4 count while on ICI therapy experienced an irAE, respectively. 27 patients experienced progressive disease (PD); 50% of patients who experienced a decrease in their CD4 count while on ICI therapy had PD. 13 patients experienced a complete response to ICI therapy; none of the patients who had a decreased CD4 count while on ICI therapy achieved complete response to ICI therapy, whereas 25% and 33% of patients who had an increased and stable CD4 count while ICI therapy experienced a complete response to therapy. The mortality rate was 24; 75% of patients who had a decreased CD4 count on ICI therapy suffered mortality, as opposed to 37.5% and 20% of patients with increased or stable CD4 count while on ICI therapy, respectively. Conclusions: Patients with a declining CD4 count while on ICI therapy may have poor outcomes with ICI therapy. The current body of evidence is weak, and further studies are needed to reach to a strong conclusion.
Inmunotherapy related hepatitis: A retrospective study of Chilean patients.
Authors: Salinas Carlos , Samtani Suraj Rajesh , Renner Alex , Aren Osvaldo Rudy , Rojas Carlos , Burotto Pichun Mauricio Emanuel
Published: May 2020

e15144

Background: Immune checkpoint inhibitors (ICI) have shown dramatic efficacy in many trials of advanced solid cancer. Data of toxicity for these agents setting in Chilean patients is lacking and is of importance to confirm the tolerance of immunotherapy in different population. Immunotherapy-related hepatitis (liver irAEs) represents a diagnostic and management challenge, and its frequency varies according to various factors. We aim to report the incidence, features and treatments used to manage liver irAEs in Chilean population. Methods: A retrospective review of 139 patients with diagnosis of NSCLC, Renal Cancer, Urothelial, Melanoma, treated with ICI from April 2013 until November 2019. Baseline clinical factors (age, ECOG score, cancer type, stage, Type and number of cycles of immunotherapy, comorbidities), biochemistries and treatment received were recorded for all patients with liver irAEs. Checkpoint-inhibitor-associated liver disease was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) V.4 Treatment outcomes were analyzed by measuring progression free (PFS) and overall survival (OS). Results: 32 (23%) patients developed liver irAEs. Median age at diagnosis was 62 years (range 37-86). 62% patients were male, 59% ECOG 1, 96% had de novo metastatic disease. The most frequent primary sites of cancer were Renal Cancer 71% and NSCLC 9%. 78% of patients received treatment with both anti-PD-1/PD-L1 and CTLA-4 drugs. Liver irAEs G2 and G3 were 43.7% and 56.2% respectively. 31,2% and 12,5% of patients treated with single agent immunotherapy developed G2 and G3 Liver irAEs respectively. The total averages of cycles administered were 12, 4 cycles. 28% of patients developed liver irAEs after the first cycle of treatment and 12.5% after the second cycle. 6.2% patients required hospitalization and 78.1% required treatment with steroids. Conclusions: Liver irAEs was more frequent in Chilean population than data reported on previous clinical trials with a high incidence caused by ICI monotherapy and further reinforced by combination therapy. Local registries play an important role in recognizing different patterns of toxicity according to different population. Early recognition and management of liver irAEs should be of vital importance in clinical practice and as prescribing physicians we must maintain strict vigilance of liver irAES in Chilean population.
Checkpoint inhibitors related renal vasculitis and use of rituximab.
Authors: Mamlouk Omar , Lin Jamie , Tchakarov Amanda , Glass William F , Abdelrahim Maen , Selamet Umut , Buni Maryam , Abdelwahab Noha , Abudayyeh Ala
Published: May 2020

e15145

Background: As the percentage of cancer patients eligible for checkpoint inhibitor therapy (CPI) is increasing rapidly over the past couple years and approaching 45%, more cases of CPI related nephrotoxicity, including a rare subset with vasculitis, are reported. To learn more about the clinical presentation of CPI associated renal vasculitis, its mechanism, treatment options, and prognosis, we describe cases from our institution and reviewed the literature for related cases. Methods: We retrospectively reviewed the charts of all cancer patients from 2014 to 2020 who were diagnosed with CPI related nephrotoxicity and underwent a kidney biopsy. Results: We identified 6 cases of renal vasculitis reach with different malignancy, 4 had pauci-immune GN and one of which had IgA vasculitis. 4 of the patients were on nivolumab and 4 of the patients had negative ANCA serology. All patients had microscopic hematuria and severe acute kidney injury (AKI) with Creatinine > 4.5 mg/dl upon diagnosis and 2 patients requiring renal replacement therapy (RRT). One patient had concurrent lung involvement. All patients were treated by discontinuing CPI and initiating corticosteroids and rituximab. 3 patients received plasmapheresis who required RRT or had lung involvement. 2 patients died within 8 months of diagnosis due to malignancy progression and none of the cases had a relapse of vasculitis. Conclusions: We demonstrated that CPI can be associated with different types of renal vasculitis that is predominantly ANCA negative and manifest as severe kidney. Despite the lack of strong evidence, treatment as primary ANCA vasculitis with corticosteroids and rituximab is well tolerated with favorable renal outcome.
Baseline blood parameters as predictive biomarkers of immunotherapy efficacy in solid tumors.
Authors: Marra Antonio , Criscitiello Carmen , Morganti Stefania , Viale Giulia , Zagami Paola , Nicolò Eleonora , Ferraro Emanuela , Repetto Matteo , Tarantino Paolo , D'amico Paolo , Trapani Dario , Locatelli Marzia Adelia , Esposito Angela , Curigliano Giuseppe
Published: May 2020

e15147

Background: Peripheral blood parameters, such as neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and LDH level, have been correlated to immunotherapy (IO) benefit in melanoma and lung cancer. We investigated if peripheral blood parameters could have the same predictive role in a variety of solid tumors treated with either single-agent IO or IO combinations. Methods: Baseline (0 to 14 days from treatment start) blood parameters, including NLR, dNLR, PLR, LMR and LDH, were collected in patients (pts) with metastatic solid tumors treated in phase I trials testing anti-PD-1/PD-L1 single agent (N = 59) and anti-PD-1/PD-L1-based combinations (N = 94), including combinations with immune checkpoint inhibitors/agonists or other agents. IO benefit was assessed for overall survival (OS), progression free survival (PFS), overall response rate (ORR), disease control rate (DCR), and 90-day mortality rate. Logistic regression, Kaplan-Meier method, and Cox regression were carried out to evaluate the impact of clinical and baseline blood parameters on IO efficacy. Results: From Aug2014 to May2019, 153 pts were included [median age 58 (32-80)]. Female/male ratio was 1.47:1 (91 females/62 males). The most common tumors were gastrointestinal, breast, and gynecological cancers (22.9%, 22.2%, and 15.0%, respectively). Sixty pts (39.2%) had received more than two lines of therapy. Overall, ORR, DCR, and 90-day mortality were 11.8%, 34.9%, and 15.7%, respectively. At multivariate analysis, LDH higher than upper limit of normal (ULN) was associated with reduced DCR (LDH ≤ULN vs > ULN: 50.8% vs 20.8%, OR 0.25, 95%CI 0.1-0.62, p = .003) and increased 90-day mortality (LDH ≤ULN vs > ULN: 7.9% vs 24.5%, OR 3.59, 95%CI 1.18-10.9, p = .025). At a median follow-up of 25.9 months (22.3-29.6), 138 pts (90.2%) experienced tumor progression and 117 (77.0%) had died. At multivariate Cox regression analysis, LDH > ULN and dNLR > 3 were independently associated with reduced PFS (LDH > ULN: HR 1.97, 95%CI 1.30-2.99, p < .001; dNLR > 3: HR 2.29, 95%CI 1.39-3.77, p < .001) and reduced OS (LDH > ULN: HR 2.04, 95%CI 1.26-3.28, p = .004; dNLR > 3: HR 2.06, 95%CI 1.12-3.79, p = .02). Conclusions: Our analysis confirms that baseline LDH > ULN and dNLR > 3 are predictive biomarkers for IO efficacy, regardless of tumor type and combinations with other drugs, representing an easy tool that deserves prospective validation in IO-based clinical trials.
Racial differences in development of immune-related adverse events.
Authors: Bhandari Shruti , Kumar Rohit , Nice Laura , Cheema Anmol , Kloecker Goetz H.
Published: May 2020

e15148

Background: Immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) are caused by non-specific immune system activation and develop in 30-70% of patients. The goal of this study is to examine the association of race with the development of irAEs secondary to ICIs as autoimmune diseases generally exhibit racial differences. Methods: A retrospective chart review was done using University of Louisville pharmacy database. Patients with solid cancers who received ICIs between Jan 2016 to June 2019 were included. IrAEs were identified through the review of electronic medical records. Descriptive analysis evaluated the incidence and severity of irAEs. Multivariable logistic regression was used to calculate standardized incidence of irAEs among Whites and African Americans. Results: A total of 476 patients were included in this study. The mean age was 61 years, 57% were males and 89.7% were whites. A majority of patients had melanoma (50%). The remainder of the dataset included lung (33.4%), gastrointestinal (7.4%), head & neck (4.8%), breast (2.5%) and genitourinary (1.9%) cancers. ICIs included single agent anti-PD-1 (74.8%), single agent anti-PD-L1 (9.4%), combination anti-CTLA-4 with anti-PD-1 (7.1%). Some patients were also treated with > 1 ICI as subsequent therapy (8.6%). Overall, the rate of irAEs was 44.3% with 33.8% grade 1-2 and 12.4% grade 3-4 irAEs. There was no difference in development of any grade irAEs in Whites as compared to African Americans after adjusting for age, sex, cancer type and ICIs (44.3% vs 44.2%; OR: 0.99, 95% CI: 0.50 – 1.97; p = 0.99). There was also no difference in development of grade 3-4 irAEs in whites as compared to African Americans (12.8% vs 14.5%; OR: 1.16, 95% CI: 0.43 – 3.12; p = 0.75). Conclusions: In this study, we found no racial difference in the development of irAEs between Whites and African Americans. This is in contrast to general autoimmune diseases which exhibit racial differences with higher prevalence among African Americans compared to Whites. We will continue to accrue patients to this study as larger sample size is needed to confirm these findings.
Personalized multimodality therapy (ICT) with immune checkpoint inhibitors (ICI), chemotherapy (CT), and targeted treatment (TT), in advanced/refractory cancer.
Authors: Salem Philip A. , Jabboury Khaled W. , Wheeler Thomas M. , Stenoien Randall
Published: May 2020

e15150

Background: Therapy for advanced/refractory malignancies is associated with poor prognosis. The combination of ICI and CT has been shown in lung and several other cancers to be superior to CT alone. Since ICI, CT, and TT have a convergent efficacy with divergent toxicity, the combination was evaluated in the treatment of these diseases. Initial evaluation was reported in JCO. 2019 37.15 suppl. e14254. Methods: Treatment was highly personalized and based on diagnosis, prior therapy, and eligibility for TT. Genomic profiling was done to determine TT. ICI included pembrolizumab in 14, nivolumab in 8, and atezolizumab in 2. Chemotherapy was given in 28-day cycles. 23 received multiple agents. 17 received platinum, 11 taxanes. TT included erlotinib in 6, bevacizumab in 6, cetuximab in 2, everolimus 2, and 8 received others. From 04/2016 to 12/2019, 24 patients, median (M) age 62 (27-78) received ICT; 15 females, 9 males. Tumor type: lung 9, pancreas 4, colon 2, glioblastoma multiforme 2, melanoma 2, stomach 1, cervix 1, cholangiocarcinoma 1, thymoma 1, Hodgkin's lymphoma 1. 18 patients had prior therapy, M2 (1-11), of them 6 had ICI and 5 TT. Response evaluation was based on PET scan. Tumor regression occurred after the first cycle. Results: All patients responded. 12 (50%) achieved CR, M14 months (3-32+); 11 (45.8%) had PR, M5+ months (1+ - 20+); and 1 minor response 1+ month. CR + PR was 95.8%. All 3 patients with lung cancer and metastases to brain, achieved CR in brain. Of 3 patients with advanced gastrointestinal cancer, 2 achieved CR and 1 achieved more than 95% reduction in disease. Tolerance was reasonable. No unexpected side effects were noted. Adverse events were primarily hematologic and febrile events/infection. Conclusions: Personalized ICT combination in advanced/refractory and diverse cancer diagnoses is associated with more than 95% response rate. In particular, it was effective in primary and metastatic CNS disease.
Characterizing toxicities, body composition, and health-related quality of life (HRQoL) among long-term survivors treated with anti-PD-1.
Authors: Patrinely James Randall , Young Arissa Caroline , Quach Henry , Williams Grant Richard , Ye Fei , Fan Run , Horn Leora , Beckermann Kathryn Eby , Gillaspie Erin Alexis , Sosman Jeffrey Alan , Friedman Debra L. , Moslehi Javid J , Johnson Douglas Buckner
Published: May 2020

e15158

Background: Anti-PD-1 agents produce durable responses in many cancers. However, the long-term impact of PD-1 blockade in terms of chronic toxicities, medical comorbidities, and HRQoL are not well-defined. Methods: We assessed 217 patients (pts) who received anti-PD-1 for melanoma, renal cell carcinoma or non-small cell lung carcinoma, with survival of > 2 years after treatment. Pt and tumor characteristics, immune related adverse events (irAEs), cardiometabolic parameters, body composition measurements (BCM), and HRQoL outcomes were tracked. Results: Median overall survival (OS) was not reached; 33 (15.2%) died during follow-up primarily from progressive cancer (n = 28). Acute irAEs developed during treatment in 65% of pts, 45.2% were grade 1/2, 35.5% required steroids, and most commonly presented with dermatitis (18.4%), thyroiditis (12.9%), or arthritis (9.7%). At last follow up, most pts were ECOG 0 (38%) or 1 (41%). There was no difference in blood pressure, glucose, or weight from baseline to 2 years after treatment initiation. BCM showed increased adiposity (140.1 vs. 144 cm2/m2, p = 0.05), skeletal muscle mass (47.05 vs. 47.72 cm2/m2, p = 0.03), and skeletal muscle gauge (1653.9 vs. 1671 AU, p = 0.04). The most common chronic irAEs at last follow-up included hypothyroidism (10.6%), arthritis (3.2%), adrenal insufficiency (3.2%), neuropathy (2.8%), pneumonitis (1.8%), and type 1 diabetes (0.8%). No pts died from chronic irAEs although one pt had fatal CNS radiation necrosis (with unknown contribution of ICI). Chronic irAEs were more common in pts treated with ipilimumab/nivolumab (49%) vs. those with monotherapy (26%). New comorbidities included type 2 diabetes (6.5%) and hypertension (6.0%). HRQoL at 2 years compared favorably to cancer and general populations, although younger age (p < 0.01) and need for subsequent therapy (p = 0.03) were associated with worse HRQoL using Functional Assessment of Cancer-General questionnaire (FACT-G). Acute irAEs were associated with worse National Comprehensive Cancer Network distress scores (p = 0.019). Conclusions: Durable responses to anti-PD-1 therapy and favorable HRQoL outcomes are encouraging in this long-term survivor population. Chronic irAEs may be more common than previously thought although no clear chronic adverse cardiometabolic effects were observed.
Predicting overall survival (OS) and overall response (OR) following durvalumab treatment in patients with multiple cancer types using a hybrid modeling strategy.
Authors: Chen Ting , Zheng Yanan , Roskos Lorin , Mager Donald E
Published: May 2020

e15161

Background: This study aimed to predict OS/OR and identify key predictors in patients with diverse cancer types treated with durvalumab, a PD-L1 targeting monoclonal antibody, using a hybrid modeling strategy that combines population pharmacodynamic (PD) modeling and machine learning (ML) algorithms. Methods: Individual longitudinal tumor size measurements and OS/OR data were available for 855 patients who received durvalumab therapy (10 mg/kg Q2W or 20 mg/kg Q4W; NCT01693562). Nine cancer types included non-small cell lung cancer (NSCLC), bladder cancer (BC), microsatellite instability-high (MSI-H) cancer, hepatocellular carcinoma (HCC), squamous cell carcinoma of the head and neck (SCCHN), gastroesophageal cancer (GEC), ovarian cancer (OC), pancreatic adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC). A tumor kinetic model was developed to characterize diverse temporal profiles using a population-based modeling approach. Individual estimated tumor kinetic model parameters and patient demographic/physiological factors were used as inputs for predicting OS/OR using several ML approaches. Results: The final tumor kinetic model with liver metastasis (LM), neutrophil/lymphocyte ratio (NLR), tumor size at baseline (TBSL) and cancer types as covariates characterized the temporal tumor size data well. HCC and MSI-H cancer have the slowest tumor growth rate constant (kg), while GEC, SCCHN and TNBC have the fastest kg. BC, NSCLC and OC have the highest tumor killing rate constant. The most important predictors of OS identified by ML approach were tumor kinetic parameters (kg, fraction of drug-sensitive cells, time-delay in immune response), along with baseline disease factors, including hemoglobin (HGBBL), albumin (ALB), and NLR. Decision tree-based algorithms showed the best performance in predicting OR with accuracy above 90%. In addition to tumor kinetic parameters, PD-L1 expression on tumor cells (TC) and ALB were the most important predictors of OR. Conclusions: A combined population PD/ML approach showed good predictions of OS/OR in patients with different cancer types treated with durvalumab. LM, NLR,TBSL and cancer types were found to be important factors for tumor kinetics. In addition to tumor kinetic parameters, HGBBL, ALB, and NLR were found to be important predictors of OS, and TC and ALB were found to be important predictors of OR. These findings could provide a guidance on patient selection in future clinical trials.
Nivolumab versus the standard of care for cancer therapy: A meta-analysis of 6 CHECKMATE trials comparing overall survival.
Authors: Al-Obaidi Ammar , Parker Nathaniel , Truong Quoc Van
Published: May 2020

e15165

Background: Nivolumab (N) is an antineoplastic agent approved for multiple different tumor origins as well as tumor agnostic based on MSI status. Thus, understanding the tumor characteristics most predictive of response is essential. Living meta-analysis provides a method to continuously assimilate emerging trials. In this study, we created a living meta-analysis to compare the effect of N on overall survival (OS). Methods: Meta-analysis was conducted according to the PRISMA guidelines. PubMed and Cochrane databases, and conference abstracts (e.g. ASCO, ESMO), were searched for phase III CHECKMATE RCT’s that reported OS among cancer patients receiving N. Results: Six phase III trials involving 3,342 patients (1,826 in N arms) treated for 4 different types of cancer were retrieved. Median follow up was 12.1 months [range: 5.1-25.2]. Improved efficacy and safety were observed in all N arms compared to control groups (22.8% ORR; 17.4% grade 3-5 AE vs 15.1% ORR; 51% grade 4-5 AE). Treatment was N alone, SOC chemo, and N + chemo in four (33%), six (50%), and two (16%) arms, respectively. Primary endpoints were OS in the first-line setting in 50% of all arms. Excluding one RCT due to insufficient survival data, the mean median OS was 11.1 [95% CI: 7.5-14.4] vs 8.7 [95% CI: 5.1-13.2] months in the total populations for all N and control arms, respectively. N improved OS when used in any cancer type, setting, or therapy for advanced refractory or chemo-naive cancer patients. Also, efficacy of N was improved with PD-L1% (Table). Conclusions: Among all trials, N was associated with improved OS. Additional meta-analysis is ongoing with R software (version 3.3.3; R Fdn.). Random-effects models will be used to compare OS. Heterogeneity will be assessed with Cochrane Q-statistic and quantified with I2test via subgroup analyses for cancer type, setting, therapy, and PD-L1%. [Table: see text]
Distribution of PD-L1 expression level across major tumor types.
Authors: Xu Shun , Tian Minqi , Zhang Xing , Qi Chuang , Song Chao
Published: May 2020

e15176

Background: Programmed death-ligand (PD-L1) expression is an efficacy predictive biomarker in cancer immunotherapy. PD-1/PD-L1 axis can restore the host immunity against malignancies causing durable tumor remissions, and thus the level of PD-L1 protein expression is of critical clinical significance. However, the knowledge of PD-L1 expression level of patients with different malignancies is still inadequate understanding. Methods: Based on the percentage of positive tumor cells (TC value) identified by immunohistochemistry (IHC) method, the protein expression of PD-L1 was divided into three groups as g1 (TC < 1%), g2 (1% ≤ TC < 50%) and g3 (TC ≥ 50%). The expressions of PD-L1 from 1772 patients with malignancies across eight types including 133 patients with liver cancer, 35 patients with bile duct cancer, 94 patients with gastric cancer, 146 patients with colorectal cancer, 48 patients with pancreatic cancer, 76 patients with melanoma cancer, 33 patients with glioma and 1207 patients with lung cancer cases were made. The relationships between cancer types and PD-L1 expression were calculated via χ2 test using SPSS v22.0. Results: The ratios of PD-L1 expression in three groups (g1, g2 and g3, respectively) across eight cancer types were 67.7, 30.8 and 1.5% in liver cancer, 65.7, 28.6 and 5.7% in bile duct cancer, 77.7, 20.2 and 2.1% in gastric cancer, 81.5, 18.5 and 0% in colorectal cancer, 64.6, 31.2 and 4.2% in pancreatic cancer, 50.5, 35.7 and 13.8% in melanoma, 30.3, 63.1 and 6.6% in glioma and 55.9, 34.0, 10.1% in lung cancer, respectively. Significant correlation between the PD-L1 expression and cancer types were found (χ2 = 140.543, Cramer’s V coefficient = 0.199, p = 5.53×10−23). The expression of PD-L1 in patients with lung cancer tended to be distributed in g3, in patients with melanoma tended to be distributed in g2, and in patients with gastric cancer, glioma, and colorectal cancer tended to be distributed in g1. Conclusions: Our study suggested the protein expression of PD-L1 was significantly heterogeneous among various cancer types and offered new references for cancer-specific characters of PD-L1 expression. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
The potential target of double negative T cells in cancer immunotherapy.
Authors: Okamura Kazumi , Nagayama Satoshi , Tate Tomohiro , Kiyotani Kazuma , Nakamura Yusuke
Published: May 2020

e15180

Background: Double negative T cell (DNT) is defined by the expression of CD3 (or TCRαβ) with the absence of CD4, CD8 and iNKT cell markers. DNTs account for 1-3% of the total peripheral lymphocytes. Although healthy donor cells derived allogeneic DNTs were reported to have anti-tumor effects in several cancer models, the function of DNTs in tumor microenvironment is not well understood. In this study, we aim to characterize DNTs in cancer tissues and lymph nodes of colorectal cancer patients including their immunological functions. Methods: A total of 14 colorectal cancer tissues and regional lymph nodes were collected and examined for the proportion and the immunological functions of DNTs by FACS analysis. Results: DNTs, which were defined in this study as TCRαβ positive with CD4-, CD8- and CD56- T cells, were detected in colorectal cancer tissues. DNT cells account for more than 5% of TCRαβ-positive populations in 12 cases and out of which 7 cases were more than 20% observed in this study. In all of these 7 cases, DNT cells were also found to be higher in the tumor tissues than in non-metastatic lymph nodes. In addition to colorectal cancer, DNTs were found to be more than 5% of TCRαβ-positive populations in cancer tissues in 3 out of the 6 cases of ovarian and uterine cancer cases.To further evaluate the potential immunological functions of DNTs, expression of cell membrane protein markers were evaluated. CD3ε expression was down regulated in almost all of the DNTs. The CD107a expression of DNTs were higher than that of CD8+ T cells in tumor tissues. When co-culturing DNTs with tumor cells, CD107a expression of DNTs was significantly upregulated. Notably, the intracellular production of perforin and granzyme B were lower than CD8+ T cells. Fas-L expression were found to be higher on DNT cells compared to other T cell populations, suggesting DNT might possess cytotoxic activity in the tumor microenvironment. It is known that upregulation of Fas expression is caused by T cell activation and subsequently induces T cell apoptosis. The upregulation of Fas expression was also observed in DNT cells from non-metastatic lymph nodes. In contrast, Fas expression of DNT cells in tumor tissues was observed to be lower than CD4+ or CD8+ T cells, suggesting that DNT could escape from apoptosis. This downregulation of Fas expression was speculated to be one of the reasons for the accumulation of DNTs in tumor tissues. Conclusions: Although the function of DNTs was still not well elucidated, the accumulation of DNT cells in tumor microenvironment suggests DNTs could be a potential target for cancer immunotherapy.
Effect of idronoxil combined with cisplatin on refractory immune responses in nasopharyngeal carcinoma.
Authors: Kam Ngar-Woon , Lee Victor Ho-Fun , Hung Tae Yang Desmond , Yim Man Kim , Tsao George , Laczka Olivier , Delebecque Frederic , Wilkinson John , Kwong Dora LW
Published: May 2020

e15186

Background: Nasopharyngeal carcinoma (NPC) is endemic in Southern China. Although it is both radio-and chemo-sensitive, resistance to these treatments remains a major problem for successful management of NPC. The main characteristic of a cancer cell is its resistance to undergo apoptosis; therefore, reversing this resistance may represent the best approach for the treatment of cancer. Additionally, NPC is well-known to be heavily infiltrated by lymphocytes and constitute a unique but poorly defined tumor microenvironment (TME). We aimed at delineating and defining the contribution of idronoxil (IDX) in restoring sensitivity to apoptosis and potentially modulating the immune microenvironment of NPC. Methods: The IC50 of cisplatin (Cis) and IDX from 2D and 3D spheroid cultures of four NPC cancer cell lines (C666, C17, and the paired NPC43 EBV-positive and EBV-negative cell lines) were evaluated. The migration and proliferation of cells treated with IDX and/or Cis were investigated by Transwell and XTT, respectively. Cell phenotype and migratory analyses were measured by flow cytometry on Cis/IDX-pretreated NPC cell lines cocultured with HLA-matched PBMC. Results: IDX and Cis inhibited NPC migration and cell proliferation (IC50 for IDX in 2D and 3D was 2µM; IC50 for Cis in 2D and 3D: was 0.6µM and 1.4µM, respectively). A dose-dependent induction of apoptosis in NPC cell lines by IDX was observed [early apoptotic cells (Annexin V+/PI- at 1µM); late apoptotic cells (Annexin V+/PI+ at 2µM), and necrotic cells (Annexin V-/PI+, at 4µM) were distinguished]. Intriguingly, IDX increased the migratory potential of PBMC towards tumor cells in both 2D and 3D spheroid cultures. Finally, IDX, but not Cis, facilitated the migration of CD8+ T cells toward tumor cells by 3.5-fold (p < 0.05) as well as promoted the expansion of proliferative CD8+ T cells (increased by ~2.8-fold) with degranulation activities (~1.3-fold and 3-fold increase in surface CD107a and intracellular granzyme B expression, respectively) in the cocultures. Conclusions: IDX was shown to induce apoptosis in NPC cells while inhibiting their migration and proliferation. Moreover, the ability of IDX to modulate T cell populations indicates the drug’s potential to enhance the efficacy of current chemotherapy treatments in NPC by upregulating cellular trafficking to the cancer cell.
Immunological functional study by use of the chemotherapy drug plus immunologic hapten like penicillin on the fibrosis of local tumor inflammatory reaction and the immunity of tumor-bearing mice.
Authors: Li Bian , Chen Dong , Han Yan , Zhang Jian , Zheng Guoqin , Wu Yanfei , Fu Qiang , Yu Baofa ,   Shandong Baofa Cancer Therapeutics, Inc.
Published: May 2020

e15196

Background: Observe the antitumor effect of intratumoral injection of chemotherapy drugs or combined with immune adjuvant on Balb/c and c57 tumor bearing mice and the local inflammatory response, fibrosis and immune effect of tumor. Methods: H22 ascites tumor was inoculated in the armpit of BABL / c mice left forelimb to establish subcutaneous solid tumor model of liver cancer, B16 melanoma tumor filtrate was inoculated in the armpit of C57 mice left forelimb to establish subcutaneous solid tumor model of melanoma. The mice were randomly divided into DNP control group, penicillin control group, I group, II group, III group, IV group, V group, VI group, DOX control group, PYM control group, BLM control group and control group when the longest tumor diameter was about 5-8mm. On the first day of the experiment, the mice in each group were injected with corresponding of different group drugs. Three mice in each group were killed on day 1, day 4 and day 7 respectively and then the tumors were taken The C57 mice were used for immunohistochemistry BABL/c mice to detect the content changes of various fibroproliferative, inflammatory and immune related factors. Results: I group: The expression of COL1A1, CD4, IL12A, TGFB1, elastin, NFkB, COX 2, CD11c, CD8 and TNFa in group I was higher than that in other factors at day 1. After 4 and 7 days of administration, all factors decreased significantly; The results of C57 Mouse immunohistochemistry showed that the expression of CD4, cd11bc, Foxp3 in tumor tissue of group V was significantly increased on the first day after administration, and the expression of CD4, CD8, CD86, CD11bc in tumor tissue of group V was significantly increased on the seventh day. Conclusions: The results of immunohistochemistry and PCR showed that the content of fibroproliferative, inflammatory and immune factors in tumor tissue changed significantly after administration og intratumoral injection of combination drugs and penicillin with H2O2. All the above results has showed that chemotherapy drug and hapten was released in the tumor through H2O2 and induced the inflammatory reaction inside tumor (including various fiber proliferation and tumor growth inhibition) as well as the systemic immune response, this also is called abscopal effect.
US oncologists' perception of the efficacy, safety, and willingness to prescribe biosimilar cancer therapies.
Authors: Galan Cesar , Johnson Kjel Andrew , Avalos-Reyes Elisea
Published: May 2020

e15213

Background: Biosimilars are the fastest-growing class of therapeutic products in the United States and can offer treatment options that can potentially lower healthcare-related costs in cancer care. It is essential to know if an oncologist will use such products. Therefore, we assessed the expected biosimilar prescribing behaviors of practicing oncologists for the originator products Avastin, Herceptin, Rituxan and Neulasta. Methods: We conducted an online cross-sectional survey of 75 hospital affiliated (46.7%) and community-based (53.3%) oncologists in July 2019 and used a Likert scale rating of “Never,” “Seldom,” “Sometimes,” “Often” and Always.” Descriptive statistics and percentages are reported; the Chi-square test was used for between-group comparisons. Results: The majority of oncologists (62.7%) worked in a for-profit practice, with 38.7% of primary practices offering exclusive in-office dispensing. Physicians currently reported prescribing branded drugs often or always 76% of the time. When asked to rate biosimilars by quality, safety and effectiveness, over 70% of providers perceived these four biosimilars to be the same or near equivalent to the branded drug. When asked to report their expected likelihood of prescribing a biosimilar in the future, 60% of providers believed they would often or always prescribe a biosimilar. There was no difference in the providers’ current biosimilar prescription pattern by type of insurance plan. Provided financial equivalence, oncologists reported being more likely to prescribe a biosimilar to new patients (85.3%) compared to existing patients (69.3%) (p = 0.019). The top 3 drivers of using biosimilar cancer therapies are the patient’s out of pocket cost, value of reimbursement and cost to the practice; 61%, 51% and 52%, respectively for fee-for-service reimbursement and 69%, 44% and 61%, respectively for value-based reimbursement. When asked why providers would not switch from buy-and bill to white-bagging, control of the drug (41.3%) and financial benefit to the providers’ practice (40%) were the top 2 reasons. Conclusions: Biosimilars are expected to reduce drug expenditures in cancer care. While providers in this study found biosimilars to be safe and effective, they reported being less likely to prescribe these drugs when there is a potential for their practice to lose money and control of the drug. Payment models for biosimilars in cancer care must support practice economics.
Immunomagnetic separation in LAK generation in patients with breast cancer.
Authors: Shamova Tatiana V. , Kit Oleg I. , Sitkovskaya Anastasia O. , Zlatnik Elena Yu. , Bondarenko Elena S. , Novikova Inna A. , Vashchenko Larisa N. , Kechedzhieva Emma E. , Dashkova Irina R. , Ausheva Tatiana V. , Andreiko Elena , Saforyan Natalya S. , Vladimirova Liubov Yu , Lisutin Aleksandr E.
Published: May 2020

e15220

Background: The purpose of the study was to evaluate the effect of IL-2 and INF-γ on the proliferation and phenotype of lymphocytes in patients with breast cancer (BC) after T-regs removal from the pool in vitro. Methods: Lymphocytes were isolated from the blood of 11 patients with stage II BC, T-regs were removed by immunomagnetic separation, and samples were cultured for 6 days with cytokines: IL-2 - 0.1/1 μg, INF-γ - 10 IU and their combinations. Results: The level of NK cells in the samples with IL-2 was maintained throughout the experiment, with IFN-γ - gradually decreased, and in the control (samples without stimulation) it decreased sharply. In experimental samples (IL-2, IL-2+IFN-γ), the amount of NKT remained at the initial level by day 6, and in the control it decreased by 2 times (p < 0.05). The number of CD335+ NK cells with high cytotoxicity against target cells increased after 3 days in the test samples with IL-2 by 5.2 times, and after 6 days - by 11.6 times in comparison with the control (p < 0.05). On day 6, the level of double-positive T cells increased by 1.8 times in co-culturing with IL-2+INF-γ (1 μg/10 IU), (p < 0.05). The percentage of double-negative T cells increased in the dynamics of cultivation from days 1 to 6, in some cases statistically significantly (IL-2 - 1 μg: by 2 times; IL-2+INF-γ - 0.1 μg/10 IU: by 1.8 times; p < 0.05). The percentage of CD4+CD38+ cells on day 6 of incubation with IL-2 at both doses increased by 1.8-2 times compared with the control, and CD8+CD38+ by 4-6 times. The percentage of CD4+HLA-DR+ cells after 6 days of cultivation with IL-2 increased by 6 times, and CD8+HLA-DR+ by 8-9 times. Cultivation with INF-γ reduced the stimulating effect, and in some cases it did not appear. The combined effect of IL-2 and INF-γ on day 6 led to an increase in the proportion of CD4+CD25+CD127dim cells by 1.8 times in comparison with the control (p < 0.05), and when exposed to INF-γ only, the number of these cells remained at the control levels. Conclusions: INF-γ is not an effective inducer of activation of immune effector cells, while the effect of IL-2, both alone and in combination with INF-γ, leads to a significant increase in the proportion of cytotoxic cells, as well as to activation of the T cell unit, including CD4 + CD25 + CD127dim.