bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of soluble DC-HIL/gpnmb receptor in the blood of metastatic non-small cell lung carcinoma treated with anti-PD1/PDL1 monoclonal antibodies.
Authors: Chung Jin-Sung , Ramani Vijay , Kobayashi Masato , Popat Vinita , Cruz Ponciano D , Gerber David E. , Ariizumi Kiyoshi
Published: May 2019

e14038

Background: Anti-PD1/PDL1 therapy benefits only a minority (10-20%) of treated NSCLC. Identifying markers distinguishing responders vs. non-responders will improve management of NSCLC. DC-HIL receptor is a new checkpoint whose inhibitory mechanisms are divergent from the PD1 pathway. Tumor cells express DC-HIL receptor and its soluble form (sDC-HIL). We tested whether sDC-HIL expression regulates NSCLC response to anti-PD1/PDL1 Ab using animal models and human clinical samples. Methods: Tet-Off controlled sDC-HIL-transfected LL2 lung cancer cells were i.v. injected into mice (lung mets) and treated with doxycycline (Dox). Day 6, mice were sorted into 2 groups with/without Dox and treated with i.p. 200 μg Ab, every 2 d /6 shots. Day 18, # of lung-LL2 cells were counted by FACS and IFN-γ+ T cells in tumors analyzed. Advanced NSCLC patients (n = 51) treated with immune checkpoint inhibitors were every 6 weeks evaluated for partial response (PR), stable (SD) and progressive disease (PD) by RECIST. Serum were collected on weeks 0, 2, and 6 and assayed for sDC-HIL amounts by ELISA. Results: In mice treated with Dox (halt sDC-HIL expression), anti-PDL1 Ab treatment markedly reduced lung mets and increased IFN-γ+ T cells (p < 0.001), whereas this excellent outcome was not noted in Dox-untreated mice (induce sDC-HIL). For NSCLC, PD1/PDL1 therapy produced PR (n = 3), SD (n = 25) and PD (n = 23) at week 6. sDC-HIL blood levels at week 0 did not correlate with tumor size, but the levels at week 6 of PD patients were significantly higher than PR/SD patients (8.4 ± 5.6 vs. 4.0 ± 1.6 ng/ml, p = 0.001, Mann-Whitney test) and healthy donors (2.6 ± 0.9 ng/ml). Most patients (26 out of 30 cases) showed fluctuation in sDC-HIL levels during treatment. PD-patients (14/15 cases) showed increasing or persistently elevated levels ( > 4 ng/ml), with one case at low levels ( < 4 ng/ml). SD/PR-patients (13/15) had decreasing or persistently low levels, with 2 exceptions with high levels in all time points. Conclusions: sDC-HIL blood level may serve as a biomarker to indicate tumor-resistance of advanced NSCLC patients to PD1/PDL1 therapy. The degree and direction of sDC-HIL fluctuation may be useful to predict prognosis for NSCLC.
Correlation of response to stereotactic radiotherapy and immunotherapy with toxicity and predictions by differences in Treg population.
Authors: Reinwald Simone , Ratnayake Gishan , Yu Di , Ward Rachel , Smith Robin , Haydon Andrew , Van Zelm Menno , Senthi Sashendra
Published: May 2019

e14039

Background: Combining stereotactic ablative radiotherapy (SABR) and anti-PD1 therapy may result in synergism but the response and toxicity rates has not been established. Biomarkers to predict clinical outcomes in this setting could improve patient selection, informed consent and cost-effectiveness. Here, we report exploratory analyses from Phase I clinical trial. Methods: Metastatic melanoma patients with at least two metastases received SABR to a single metastatic site and standard dose immunotherapy with anti-PD1 and/or anti-CTLA4 therapy. Peripheral blood mononuclear cells (PBMC) were collected prior to each immunotherapy cycle and analysed with 17-color flow cytometry to quantify CD4+ and CD8+ T cell subsets as potential biomarkers for response and toxicity. RECIST v1.1 at six months dichotomized responders (stable disease or any response) from non-responders (progressive disease). The presence of CTCAE v4 defined grade 3 or higher toxicity within six months dichotomized those with and without significant toxicity. Mann-Whitney tests were used to assess differences in biomarkers between response and toxicity groups. The Phi Coefficient (pr) was used to correlate these groups. Results: Sixteen of 25 patients had bloods available for testing. There were 11 responders (5 non-responders) and three with significant toxicity (13 without). At 12 months all responders were still alive, while all non-responders had died. Response significantly correlated with developing toxicity (pr = 0.869, p = 0.027). Prior to treatment, responders had a significantly higher percentage of total regulatory T cells (Tregs; CD4+CD25+CD127-) compared to non-responders (p = 0.011). After SABR and four cycles of immunotherapy, Treg frequencies had significantly changed (p = 0.046), with decreases in most responders and increase in all non-responders. Other CD4+ and CD8+ did not correlate with response or toxicity. Conclusions: Patients developing significant toxicities appear more likely to respond, reinforcing the importance of aggressively managing toxicities rather than ceasing treatment. Patients with higher pre-treatment Treg population and decreasing levels with treatment were significantly more likely to respond to SABR and immunotherapy. Clinical trial information: ACTRN12616001064493.
TCR repertoire analysis from peripheral blood for prognostic assessment of patients during treatment.
Authors: Vodala Sadanand , Nguyen Andrew , Rodriguez Noe , Sieling Peter , Vaske Charles Joseph , Lew Jon Van , Niazi Kayvan , Lee John H. , Soon-Shiong Patrick , Rabizadeh Shahrooz
Published: May 2019

e14040

Background: Immune checkpoint inhibitors offer substantial clinical advantage to a subset of patients but predictive/novel prognostic indicators are still scarce. T cell receptors (TCRs) play a crucial role in adaptive immunity and anti-tumor immune responses. Net diversity of TCR repertoires are altered in patients receiving immune checkpoint inhibitors. To study the prognostic significance of T cell repertoires as a biomarker of immune responses in cancer patients, we characterized TCR repertoires from peripheral blood using high throughput sequencing. Methods: Total RNA from peripheral blood mononuclear cells (PBMCs) was extracted and used to generate sequencing libraries from five pancreatic cancer patients, four triple negative breast cancer (TNBC) patients and two squamous cell carcinoma (SCC+) patients. Blood draws were collected pre- and post-treatment and target lesion analysis was performed using immune-related response criteria (irRC) and Recist1.1. TCR alpha and beta CDR3s were clonotyped for each sample, and profiles of clonotype proportions were tracked through time/serial biopsies. Additionally the Shannon-Wiener diversity metric was calculated for each time point. Results: Patient samples showing consistent positive responses as measured by irRC and Recist1.1 showed TCR clones persisting throughout all time points. A TNBC super responder showed dramatic increases in mean Shannon-Wiener index from 74 prior treatment to 1177 at first biopsy post treatment (34% decrease by irRC and 26% by Recist1.1 analysis) and achieved an index as high as 3516 in a subsequent biopsy (83% and 64% decrease by irRC and Recist 1.1 respectively). Patients that showed poor response by irRC and Recist1.1 showed TCR clones that were in constant flux. Loss of clonality and/or decrease in absolute numbers was observed in previous and later time points. Conclusions: Patients that show positive response had TCR clones that were stable, which may indicate an existing immune related response towards their tumor. Therapy would allow these existing T-cells to overcome blockade by tumor cells. Patients showing poor response show a TCR repertoire that is constantly changing potentially indicating that the tumor cells are not eliciting a strong T cell specific response. Further functional studies of T cell populations would expand our understanding of T cell based immune therapies.
Plasma biomarkers to predict pembrolizumab response in HCC patients.
Authors: Feun Lynn G. , Li Ying-Ying , Wu Chunjing , Wangpaichitr Medhi , Jones Patricia Denise , Kwon Deukwoo , Hosein Peter Joel , Savaraj Niramol
Published: May 2019

e14043

Background: Pembrolizumab (PEM) has been approved as second line therapy for the treatment of hepatocellular carcinoma (HCC). We conducted a single institution investigator-initiated clinical/biomarkers trial to assess potential biomarkers to predict response in unresectable HCC patients (pts) receiving PEM. Methods: PEM was administered at 200mg iv. every 3 weeks for advanced HCC pts who progressed on, were intolerant of, or refused sorafenib. The circulating levels of cytokines/chemokines included IL-1β, IL-6, IL-8, IL-12, IL-18, IFN-γ, TGF-β, IL-10, CXCL9, CCL4, CCL5, as well as PD-1, PD-L1, PD-L2 were measured by ELISA at baselines and at day 60-90. PD-L1 expression in tumor was also assessed by histopathological staining. Results: 29 pts have been treated and 28 were evaluated for response. One pt had complete response, 8 had partial response and 4 had stable disease. Among all the biomarkers tested, only TGF-β at baseline predict response. The mean of plasma TGF-β in responders were 141.9pg/ml vs. 1071.8pg/ml in nonresponders. The cut-off values was determined based on the near medians. The plasma concentration of TGF-β of ≥200pg/ml was an index for nonresponder (P = 0.003). Kaplan-Meier analysis showed that the median overall survival (OS) and progression-free survival (PFS) in pts with TGF-β ≥200pg/ml were 7 months and 2 months, respectively, while in pts with TGF-β < 200 pg/ml, the OS and PFS were over 25 months(P = 0.005 and P = 0.008, respectively). Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1/PD-L-1 (P < 0.05). Since tumor PD-L1 expression is upregulated by IFN-γ, and IL-10, and interacts with PD-1 to suppress T cell, to confirm these relationships, the linear regression was used to analyze the data. Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1 and PD-L1 levels ( P < 0.05). Nine of these 24 patients had tumor available for PD-L1 scoring (PD-L1-positive:3 pts and PD-L1-negative:6pts). Similar to plasma PD-L1 concentration, pts with positive tumor PD-L1 had high levels of plasma IFN-γ or IL-10 ( P < 0.05). Conclusions: Our study confirmed that PEM is active in HCC and TGF-β is a predictive markers for tumor response, PFS, and OS. Support by grant from Merck
Real-time monitoring of circulating stromal cells in the blood to predict responsiveness of new-line therapies in metastatic breast cancer.
Authors: Adams Daniel , Alpaugh R Katherine , Martin Stuart S , Lapidus Rena G. , Chumsri Saranya , Tang Cha-Mei , Williams William , Lacher Markus , Cristofanilli Massimo
Published: May 2019

e14048

Background: Cancer associated macrophage like cells (CAMLs), a circulating stromal cell subtype, has been shown as an independent prognostic indicator of survival in late stage metastatic breast cancer when cells enlarge to ≥50µm. However, no study has evaluated the clinical relationship between changes in CAML size and their ability to predict treatment response. While CAMLs are prognostic for progression, we hypothesized that monitoring changes in CAMLs after initiation of therapy may be predictive for responsiveness of new treatment regimens. Methods: A prospective 12 months blind multi-institutional pilot study was undertaken to evaluate CAMLs before, and after, induction of a new line of investigational therapy based on CT scans. Patients with progressive metastatic breast cancer (n = 29) who had failed at least 2 prior therapies were recruited. A baseline (BL) blood sample was taken prior to induction of a new therapy and a 2nd sample (T1) taken after initiation (~30 days). Blood was filtered by CellSieve filtration.The quantities and sizes of CAMLs were analyzed based on PFS hazard ratios (HRs) by censored univariate analysis. Results: CAMLs were found in 97% of BL samples and 93% of T1 samples. At first CT scan, after the assigned dose of investigational treatment, 17 of 29 patients had clinical progression with 14/17 (82%) patients having an increased CAML size and 3/17 (18%) having a decreased CAML size. The remaining 12 of 29 patients saw clinically stable, or regression, of disease with 10/12 (83%) having decreased CAML size and 2/12 (17%) having increased CAML size. Overall CAML size change after therapy induction was 83% accurate at predicting response or progression based on CT scans. Further, patients with increasing CAML size at T1 had a 4 month mPFS vs 10 month mPFS for decreasing CAMLs, with a lower 12 month PFS HR = 3.7 (95%CI = 1.5-10.1, p = 0.020). Conclusions: Our data suggests that in metastatic breast cancer, monitoring CAMLs changes over the first 30 days of treatment accurately predicts responsiveness of disease to new treatments. Further, we suggests using blood sampling may increase the clinical value of blood based diagnostics by rapidly predicting the benefit of subsequent therapies.
Assessment of extracellular matrix and tissue derived metabolites in a liquid biopsy for identifying endotypes of metastatic melanoma patients with differential response to immune checkpoint inhibitor treatment.
Authors: Willumsen Nicholas , Bager Cecilie Liv , Jensen Christina , Karsdal Morten Asser , Madsen Daniel Hargbøl , Hansen Morten , Schmidt Henrik , Svane Inge Marie
Published: May 2019

e14050

Background: The extracellular matrix (ECM) is a major component of tumors. Several recent findings link ECM composition with outcome in cancer patients treated with immune checkpoint inhibitors (ICIs). The aim here was to explore circulating ECM- and tissue-derived metabolites to enable clustering of patients with metastatic melanoma (MM) into putative endotypes and evaluate patient characteristics and outcome when treated with Ipilimumab accordingly. Methods: Serum was collected from MM patients prior to treatment with Ipilimumab (n = 64). Wards hierarchical clustering of patients was based on 15 ECM- and tissue-derived metabolites measured in serum by ELISA. Identified clusters (endotypes) were compared to clinical characteristics and evaluated for associations with disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: Three putative endotypes (cluster A, B, C) were identified including 14, 30 and 20 patients, respectively. Overall a stepwise increase in ECM metabolite median levels were detected from C-B-A with the largest absolute change seen from B-A. There was no difference between A, B, and C according to age, gender, lactate dehydrogenase levels, number of metastasized organs and whether patients were treated previously. At follow-up, the DCR was 0%, 60% and 45% in A, B, and C, respectively. Likewise, patients with endotype A had a median PFS/OS time of 69/85 days versus 174/520 and 165/589 days for endotype B and C. In support, endotype A predicted for poor survival outcomes (PFSAvsB+C:HR = 3.9, 95%CI:2.0-7.6, p = 0.0001; OSAvsB+C:HR:2.5, 95%CI:1.2-4.9, p = 0.0108). Conclusions: Hierarchical clustering of MM patients based on 15 ECM- and tissue-derived metabolites measured in a liquid biopsy identifies 3 putative endotypes. One endotype (A) seems to reflect patients with an overall high and differentiated ECM turnover profile. These patients experience poor outcome when treated with Ipilimumab. If validated, this supports a link between ECM remodeling and outcome in cancer patients treated with ICIs.
GLS-010, a novel anti-PD-1 mAb in Chinese patients with relapsed or refractory classical Hodgkin’s lymphoma: Preliminary result of a phase II clinical trial.
Authors: Song Yuqin , Zhu Jun , Lin Ningjing , Zhang Chen , Zhang Mingzhi , Bai Hai , Cui Jie , Liu Hui , Ke Xiaoyan , Jiang Yongsheng , Zhang Zhihui , Zhang Ying , Liu Lihong , Zang Aimin , Chen Chris , Li Jing , Du Hong , Meng Baotong , Xu Kehui , Meng Haijin
Published: May 2019

e14072

Background: GLS-010 is a novel fully human anti-PD-1 mAb. Previous Phase 1 study exhibited favorable result of tolerance, preliminary efficacy and 240mg fixed dose q2w was selected as Recommended Phase 2 Dose (RP2D). This Phase 2 clinical trial is aimed to further evaluate the safety and efficacy profile of GLS-010 in Chinese patients(pts) with relapsed or refractory classical Hodgkin’s Lymphoma( r/r cHL). Here we reported the preliminary result. Methods: All pts enrolled received GLS-010 240mg every 2 weeks. Tumor response was assessed by Lugona 2014 every 8 weeks. Adverse events (AEs) were graded by NCI CTCAE v4.03. Results: Until Jan 30th 2019, 39 pts were enrolled in this ongoing study. The median dosing number was 4 (range: 1~12). 17 pts received response evaluation. Of 17 evaluable subjects, an objective response was reported in 15 patients (88.3%), including 4(23.5%) pts with a complete response(CR) and 11 pts(64.7% )with a partial response(PR), 1 patient(5.9%) with stable disease(SD)and 1 remaining patient(5.9%) with unconfirmed progressive disease(PD)(observed stable disease(SD) in the first assessment).The most common treatment related AEs included Neutrophil count decreased (10/32), White blood cell count decreased (7/32), Fever (6/32), Alanine aminotransferase increased (4/32), etc. Treatment–related grade 3-5 AEs include Neutrophil count decreased (2/6), Interstitial lung disease (1/6), Influenza like illness (1/6). Conclusions: GLS-010 showed impressive therapeutic activity and an acceptable safety profile in Chinese r/r cHL patients. Current evidence support further development of GLS-010 in this and more indications. Clinical trial information: NCT03655483.
Efficacy and safety of nivolumab monotherapy as the late line for patients with advanced gastric cancer in the real-world.
Authors: Kusumoto Tetsuya , Hashimoto Kenkichi , Yoshinaga Keiji , Kusumoto Eiji , Sakaguchi Yoshihisa , Ikejiri Koji , Oki Eiji
Published: May 2019

e14074

Background: The ATTRACTION-2 study found that nivolumab showed a significant survival benefit for the patients with unresectable metastatic or locally advanced gastric cancer (AGC) following more than 2 regimens. Based on this trial, nivolumab was currently proved to be one of the most effective regimens for the patients with AGC as the 3rd-line treatment in Japan. We herein examined the clinical significance and validation of nivolumab as late line chemotherapy in patients with AGC. Methods: In October 2017 to December 2018, 26 patients received nivolumab monotherapy in our institute. We conducted a retrospective review of the data of 23 patients with AGC who received more than 2 cycles of nivolumab following the standard chemotherapy regimens including fluoropyrimidines, platinum derivatives and taxanes. Adverse events, tumor responses, and survival data were analyzed. Results: Only 2 patients enrolled here showed ECOG performance status (PS) 2 in the study. The time to treatment failure of them were shorter than those of the other patients with PS 0/1. Four patients quitted the continuation of nivolumab except for the progressive disease, due to non-hematological toxicities higher than grade 3 including myositis, hypothyroidism, dermatitis and liver dysfunction. The rate of hematological toxicities, which showed severe anemia of higher than grade 3 was 21.7%. The ORR and the DCR were 4.3% and 52.3% for the patients in this study. The survival data showed that the median PFS and the OS after nivolumab administration were 75 days and 274 days, respectively. Conclusions: Nivolumab monotherapy might be one of the best regimens for Japanese patients with AGC as the late line treatment following the standard chemotherapy.
Prognostic score for second or further line immunotherapy in advanced non-small cell lung cancer (aNSCLC): An external validation.
Authors: Prelaj Arsela , Lo Russo Giuseppe , Proto Claudia , Signorelli Diego , Ferrara Roberto , Galli Giulia , De Toma Alessandro , Randon Giovanni , Zilembo Nicoletta , Trevisan Benedetta , Montrone Michele , Longo Vito , Pesola Francesco , Varesano Niccolò , Del Bene Gabriella , Pizzutilo Pamela , Galetta Domenico , Garassino Marina Chiara , Di Maio Massimo , Catino Annamaria
Published: May 2019

e14077

Background: Beyond PD-L1, nowadays oncologists can only use clinical characteristics to candidate patients for immunotherapy (IO). Previously, a clinical prognostic score composed by ECOG performance status (PS), sex, histology, stage, uses of platin-based therapy at first-line (1L) and response to 1L categorized 3 different prognostic groups for patients treated with second-line (2L) chemotherapy (CHT) (Di Maio, EJC. 2010 Mar;46(4):735-43.). The aim of this study is to assess if the same score is able to discriminate the outcome of aNSCLC pts treated in 2L or further-line IO, potentially helping decision making. Methods: We recorded data of patients collected from two institutional databases: Istituto Nazionale Tumori of Milan and IRCCS Oncologico Giovanni Paolo II of Bari, Italy. Overall survival (OS) was the primary endpoint and also progression-free survival (PFS) was assessed. Prognostic score was generated, and pts were divided into 3 prognostic groups: best (B: < 5), intermediate (I:5-9), worst (W: > 9). Results: Overall, 347 pts were included in the analysis (193 from Milan and 154 from Bari). Median age was 66 years (y) (30 – 88y), most were < 70 y (67.5%), male (70.7%), smokers (79.5%) and adenocarcinoma (74.6%). ECOG PS was: 0 (23%), 1 (54.5%) and 2 (22.5%). Pts distribution was: 28%, 51% and 21% in the B, I and W groups, respectively. Median OS was 18.0 months for B group, 8.5 months for I group (HR vs B 1.83, 95%CI 1.35 – 2.47, p < 0.001) and 2.6 months for W group (HR vs B 5.77, 95%CI 3.99 – 8.33, p < 0.001). Median PFS was 3.4 months for B group, 3.7 months for I group (HR vs B 1.35, 95% CI 1.03 – 1.77, p = 0.032) and 1.9 months for W group (HR vs B 2.51. 95% CI 1.80- 3.50, p < 0.001). Similar results were obtained stratifying the model by Institution. Conclusions: This clinical prognostic score, that was generated in patients treated with second-line chemotherapy, is able to highly predict outcomes of patients treated with IO. These results demonstrated that in pre-treated aNSCLC pts, the worst category has a dismal absolute life expectancy, and probably would not benefit from any active systemic therapy (independently if CHT or IO). Perhaps for these pts best supportive care could be the best choice.
A comprehensive meta-analysis of endocrine immune-related adverse events of immune checkpoint inhibitors and outcomes in head and neck cancer and lung cancer.
Authors: Gomes-Lima Cristiane Jeyce , Kwagyan John , King Fred , Fernandez Stephen J , Burman Kenneth D , Veytsman Irina
Published: May 2019

e14096

Background: Immune checkpoint inhibitors (ICPi) have emerged as an effective treatment for a variety of cancers. However, important immune-related adverse events (irAEs) can occur. The aim of this study was to determine the prevalence of endocrine irAEs in patients with head and neck cancer and lung cancer that have used a ICPi and outcomes. Methods: A systematic literature review was performed within PubMed and EMBASE databases. Search terms included “durvalumab”, “atezolizumab”, “nivolumab”, “pembrolizumab”, “ipilimumab”, “head & neck cancer”, “lung cancer”. Studies published before September 2018 were included. The search was limited to randomized controlled trials (RCTs) phase III written in English. Data were extracted about patient characteristics, interventions, overall survival (OS), progression free survival (PFS), and endocrine irAEs. A summary hazard ratio (HR) and 95% confidence interval were calculated using the software Comprehensive Meta-Analysis and a scatter plot was generated. Results: Twelve RCTs comprising 7060 patients were reviewed; 3815 used an ICPi (treatment arm). The mean follow-up time of 12.2 months ± 7.1 SD. The survival rate of the treatment arm was enhanced (HR, 0.75; 95% CI, 0.70-0.80), compared to the alternate arm. Similarly, the PFS of the treatment arm was improved (HR, 0.77; 95% CI, 0.72-0.81) but with a higher incidence of endocrine irAEs. The most common endocrine irAE reported was hypothyroidism;193 patients in the treatment arm vs. 29 in the alternate arm (p < 0.001); grade 3/4 AE was observed in 10 patients vs. 1 patient, respectively. Other endocrine irAEs were reported in 168 patients in the treatment arm vs. 26 patients in the alternate arm (p < 0.001); grade 3/4 AE was observed in 28 patients vs. 3 patients, respectively. A significant positive correlation between endocrine irAEs and OS was observed (p = 0.019). Conclusions: ICPi are a powerful tool in the treatment of cancer. The prevalence of endocrine irAEs in this meta-analysis was 9%. There is evidence of improved overall survival in patients who developed endocrine irAEs. Further studies are needed to correlate the development of irAEs and OS advantage.
Real-world Merkel cell carcinoma outcomes from a tertiary care center.
Authors: Canavan Theresa N , Doudican Nicole Adell , Stevenson Mary , Pavlick Anna C. , Carucci John
Published: May 2019

e14098

Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin that is highly immunogenic. Checkpoint inhibitors (CPI) have recently revolutionized the treatment of advanced MCC. In this study we sought to better understand how CPI are used in an outpatient setting and to better define MCC outcomes associated with their use. Methods: We conducted a retrospective chart review of MCC patients seen in the New York University Hematology and Oncology Department from 2012-2018. Patient characteristics and treatment regimens were compared between those with and without disease progression at any point during follow-up. Results: Fifteen patients were identified, 46.7% of whom presented with nodal or distant disease (Table). Nine patients experienced relapse during follow-up. There were no MCC-specific deaths, and 92.3% of patients were without evidence of MCC at the end of follow-up. Ten patients were treated with one or more CPI (pembrolizumab, nivolumab, ipilimumab) either in the setting of first line systemic therapy (71.4%) or after experiencing disease progression (28.6%). There was a trend toward improved relapse free survival with CPI use (P = 0.054). Conclusions: Although recurrences were common, overall outcomes at the end of follow-up were very good. CPI were well tolerated and were associated with a trend toward improved relapse free survival. Patients with advanced stage MCC would benefit from consideration of CPI as part of their treatment options. [Table: see text]
Bone metastases treated with immune checkpoint inhibitors: A single center experience.
Authors: Grover Punita , Karivedu Vidhya , Zhu Zheng , Jandarov Roman , Wise-Draper Trisha Michel
Published: May 2019

e14105

Background: We conducted a retrospective study to analyze the overall survival (OS) and progression free survival (PFS) among patients with bone metastases (BMs) from Non Small Cell Lung Carcinoma (NSCLC), Melanoma, Head and Neck Squamous Cell Carcinoma (HNSCC) and others (including genitourinary carcinoma) treated with immunotherapy (Nivolumab, Pembrolizumab, Ipilimumab or a combination). Methods: We retrospectively evaluated patients with BMs treated at our institute from 2012-2017 who received either immunotherapy alone or in combination with other therapies for BMs including: medical therapy (zoledronic acid or denosumab), radiation or surgery. Univariate analysis was utilized to analyze OS and PFS. Results: A total of 58 patients were identified, median age at diagnosis of BMs was 61 years (range 29 – 94). 39 patients were male (67.2%) and 47(81%) patients had good performance status (KPS 70-100) at the time of immunotherapy initiation. The median time to diagnosis of BMs was 11.4 months. 20 patients had a single BM, 16 had 2-4 BMs and 22 had ≥5 BMs. Axial-only BMs were seen in 27 patients, appendicular-only in 8 and both in 23 patients. 40 patients were symptomatic and 28 patients had skeletal events (pathological fractures, spinal cord compression or hypercalcemia). 51 patients had other metastatic sites at the time of initiation of immunotherapy. 25 patients received nivolumab, 20 patients received pembrolizumab and 4 patients received combination immunotherapy. 41 patients received additional treatments for BMs. The median OS from the start of immunotherapy was 5.15 months and median PFS was 3 months. On univariate analysis male sex (p = 0.03) and combination immunotherapy (p = 0.06) were associated with better OS. Patients who received additional treatments for BMs (p = 0.04) and combination immunotherapy (p = 0.02) had better PFS. Conclusions: Combination immunotherapy and use of additional treatment modalities for BMs is associated with better survival. Further analysis is required to validate these results. [Table: see text]
Major lab abnormalities as biomarkers in patients treated with immune checkpoint inhibitors: A single institution study of 1044 patients.
Authors: Laukamp Kai , Liput Joseph , Smith Daniel Arnold , Nelson Ariel Ann , Ramaiya Nikhil H. , Hoimes Christopher J.
Published: May 2019

e14108

Background: Over the past decade, immune checkpoint inhibitors (ICI) have gained increased importance in modern cancer treatment. In this study we investigate the relationship between major lab abnormalities and ICI treatment duration. Methods: 1044 patients receiving ICIs between 2010-2018 were included in this retrospective study. The following parameters were analyzed: gender, age, race, cancer type, lab abnormalities for kidneys, pancreas, liver and thyroid, and treatment duration. Lab abnormalities were grouped and used in a scoring-system (0: no lab abnormalities, 1: one abnormal parameter, and 2: two or more abnormal parameters). For statistical analysis, Likelihood Ratio Chi-Square and Mann-Whitney U tests were applied. Results: The patient cohort included 386 female and 473 male patients with a mean age of 67.8±12.5 years. Primary cancer distribution included lung cancer (n = 439), melanoma (n = 253), head and neck cancer (n = 72), renal cancer (n = 53), lymphoma (n = 33), bladder cancer (n = 42), breast cancer (n = 28), and other malignancies (n = 124). Patients received one (n = 875) or a combination (n = 169) of ICIs for a mean of 152.2±215.8 days, with highest counts for nivolumab (n = 465), pembrolizumab (n = 275), ipilimumab (n = 95), and nivolumab & ipilimumab (n = 130) and others (n = 79). Patients with higher values in the scoring-system or more lab abnormalities had significantly longer treatment duration (Score 0: 107±170, 1: 159±199, 2: 244±282 days, p < 0.001). Furthermore, patients treated with ICI combination therapy demonstrated higher scores (1.1±0.8 vs. 0.5±0.7, p < 0.001) and longer treatment durations (236±304 vs. 127±175 days, p < 0.001). Patients with scores of ≥1 in the scoring system had improved overall survival (451±475 vs. 369±526 days, p < 0.001), and patients treated with two or more ICIs lived longer (563±524 vs. 377±496 days, p = 0.003). Therapy duration was also positively correlated with survival (Spearman’s rho correlation r = 0.64, p < 0.001). Conclusions: Our current exploratory study demonstrates associations between major lab abnormalities and both treatment duration and overall survival in patients treated with immune checkpoint inhibitors.
Effect of smoking on the efficacy of immune checkpoint inhibitors in advanced cancers: A systematic review and meta-analysis.
Authors: Lee Chia Ching , Tham Ivan Weng Keong , Soon Yu Yang , Tey Jeremy Chee Seong
Published: May 2019

e14109

Background: The association between smoking history and benefit from treatment with immune checkpoint inhibitors (ICIs) was unclear. We performed a meta-analysis to assess the efficacy of ICIs in advanced cancers according to smoking status (never-smokers vs ever-smokers). Methods: We searched MEDLINE and EMBASE for randomized controlled trials (RCTs) comparing immunotherapy with standard-of-care in the treatment of advanced cancers which reported overall survival (OS) as the outcome, stratified by smoking status. We calculated pooled hazard ratios (HRs) and 95% confidence interval (CIs) for OS using random-effect models and assessed the differences in OS between the two estimates (never smoker (vs) ever smoker). using a test of heterogeneity. We also performed prespecified subgroup analyses based on disease site, line of therapy, proportion of never-smokers in the trials and trial conclusion to assess the potential association of oncologic and methodologic factors in effect modification of smoking status with the efficacy of ICIs. Results: We identified ten RCTs on non-small cell lung cancer, head and neck, and urothelial cancers, including 4,245 ever-smokers and 972 never-smokers. The difference in the effects of ICIs on OS between ever-smokers (HR, 0.74; 95% CI, 0.66-0.84) and never-smokers (HR, 0.79; 95% CI, 0.61-1.02) was not statistically significant (interaction P-value = 0.69). There were no significant differences in the effects of ICIs on OS between ever-smokers and never smokers in the pre-specified subgroups. Conclusions: There was no significant association between smoking status and improved survival outcome with ICIs in the treatment of advanced cancers. Smoking status should not be used as a biomarker for guiding treatment with immunotherapy.
Expression of PD-L1 and IDO in hormone receptor negative DCIS.
Authors: Phadke Sneha Deepak , Clamon Gerald H. , Bashir Amani , Keeney Matthew , Ginader Timothy
Published: May 2019

e14116

Background: Although outcomes from ductal carcinoma in situ (DCIS) are generally excellent, hormone receptor (HR) negative DCIS is associated with a higher rate of recurrence. There is no chemopreventative agent that has been effective in this subgroup. The aim of our study was to evaluate expression of PD-L1 and IDO (Indoleamine 2,3-Dioxygenase) in HR negative DCIS, in an effort to identify a possible target for prevention using immunotherapy. Methods: Using pathology databases at the University of Iowa, we identified 60 cases of HR negative DCIS from 1995-2017, and 41 of these cases had adequate DCIS tissue for immunostaining. Immunohistochemical staining with antibodies against PD-L1 and IDO was performed on slides prepared from formalin-fixed paraffin-embedded tissue blocks retrieved from pathology archives. IDO was assessed by IHC using the mouse monoclonal antibody clone 10.1 (Millipore Sigma). An initial assessment for PD-L1 (M3653 mouse monoclonal antibody clone 22C3, DAKO) was negative. A repeat assessment for PD-L1 on a smaller sample in a different laboratory was also negative. Clinical data was abstracted from the medical record of each patient. Results: Of the 41 subjects with enough tissue for staining, the median age at diagnosis was 56.76 years, and median BMI was 26.59 kg/m2. Most common method of DCIS detection was screening mammogram (80.5%) versus a patient detected breast finding (19.5%). Most subjects had high grade DCIS (92.7%) and none had low grade DCIS. Six subjects (16.7%) had an ipsilateral in situ recurrence while another 6 subjects developed ipsilateral invasive cancer. Most of the subjects had HER2+ DCIS (63.9%). None of the 41 cases stained positive for IDO or PD-L1, thus no statistical analysis was done to analyze associations with clinicopathologic characteristics. Conclusions: Our sample of HR negative DCIS tumors did not express PD-L1 or IDO, making these receptors unlikely targets for immunopreventative efforts. It is still possible that tumor mutation burden, expression of PD-L2, PD-L1 or IDO expression on TILs, or expression of CTLA-4 may be future considerations for work in the DCIS microenvironment.
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.