bluuebunny/crossref_metadata_2025 huggingface dataset:
A RNA signature predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.
Authors: Lu Zhihao , Chen Huan , Li Shuang , Jiao Xi , Wu Lihong , Yu Jianing , Shen Lin , Zhang Henghui
Published: May 2019

e14071

Background: Cancer therapy has been greatly revolutionized in recent years by the conceptual developments in the field of cancer immunology. Growing evidence support the utility of immune checkpoint inhibition (ICB) in gastrointestinal (GI) cancer. However, a central question lies in understanding how therapeutic responsiveness is predicted. Methods: To address this, we evaluated tumor FFPE specimens from 97 patients who received ICB treatment. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Tumor RNA before ICB treatment was analyzed on a multiplex RNA immune oncology (RNA IO) profiling sequencing panel. Results: We show that four immune-related gene expression signatures were upregulated in responders versus non-responders in the discovery cohort. Three of the four signatures showed significant correlation with clinic response and disease control rates. However, two previously reported RNA signatures, PD-L1 expression and MMR status revealed less predictive values in GI cancers. More importantly, we identified that higher levels of a 19-gene signature were remarkably associated with favorable overall survival (OS) and progression-free survival (PFS) when compared to patients with lower levels of signature in both the discovery and validation cohorts. Of note, a joint biomarker of tumor mutation burden (TMB) and the 19-gene signature may better stratify responders from non-responders in GI cancer patients. Conclusions: Our data provide evidence that a responsive feature, defined by a multi-gene expression pattern across different GI cancer types, can be obtained via a RNA quantitative strategy and may be explored as a future pan-cancer biomarker.
Efficacy and safety of PD-1 inhibitors in combination with chemotherapy versus chemotherapy as first and second line treatment in advanced gastric and gastroesophageal junction cancer: Preliminary data from a real-world setting.
Authors: Hu Yi , Li Tao , Zhang Fan , Zhao Lei , Zhao Xiaochen , Cai Shangli , Zhao Jing , Jiao Shun Chang
Published: May 2019

e14079

Background: Unresectable locally advanced or metastatic gastric and gastroesophageal junction (G/GEJ) cancer is an aggressive disease with poor outcomes. Although pembrolizumab monotherapy has been approved as third-line therapy for selected G/GEJ tumors expressing programmed death ligand 1 (PD-L1), the combination regimens of PD-1 inhibitor with chemotherapy are rarely studied. Our study explored the efficacy and safety of PD-1 inhibitors combined with conventional therapy as first and second line treatment in advanced G/GEJ cancer. Methods: Patients with stage IV G/GEJ cancer treated with PD-1 combination therapy or chemotherapy alone in the Cancer Center of the Chinese People’s Liberation Army from January 2016 to January 2019 were screened for eligibility. Patients with third-line treatment and beyond were excluded. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety profile. Kaplan-Meier estimates and Cox regression were performed in the analysis of PFS and OS. Results: 60 patients were included in our analysis, including 20 patients with PD-1 inhibitors plus chemotherapy and 40 patients with chemotherapy alone. ORR was achieved in 7 of 20 (35%) patients in combination group versus 7 of 40 (17.5%) in chemotherapy group. In the first-line setting, ORR was 70% in combination group versus 16.1% in the chemotherapy group. Combination group showed significant favorable PFS compared with chemotherapy alone (median PFS, not reached versus 4.95 months; HR, 0.41; 95% CI, 0.48 to 0.93; P = 0.03). Preliminary data of OS showed a trend of superiority of combination group but did not present statistically significance (HR 0.33, 95% CI 0.08-1.33, P = 0.10). Incidence of grade 3 or worse treatment-related adverse event was similar between groups (3 of 20 [15%] in combination group, 7 of 40 [17.5%] in chemotherapy group). Conclusions: Addition of PD-1 inhibitor into chemotherapy could be effective and tolerable as first and second line treatment in advanced G/GEJ cancer. These findings need further evaluation by randomized controlled studies. Survival follow-up of present cohort is ongoing.
A clinical prognosis model for Asian advanced melanoma patients receiving immunotherapy.
Authors: Wang Xuan , Yan Xieqiao , Chi Zhihong , Si Lu , Sheng Xinan , Kong Yan , Mao Lili , LIAN BIN , Tang Bixia , Zhou Li , Cui Chuanliang , Guo Jun
Published: May 2019

e14081

Background: Immunotherapy PD-1 inhibitor therapy shows relative lower efficacy in Asia especially in acral and mucosal subtypes. The identification of predictive factors of immunotherapy remains a crucial but unmet clinical need. The objective of this study was to evaluate advanced melanoma patients treated with anti-PD-1 in order to identify risk factors for PFS, OS and develop a prognostic scoring system for immunotherapy. Methods: Patients with unresectable melanoma treated with PD-1 inhibitor enrolled on trials between 2015 and 2017 at Peking University Cancer Center were included. A nomogram to predict survival was developed based on a multivariable Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan–Meier curve and calibration plots. Results: The discovery cohort comprised 133 patients with unresectable melanoma. 38.3% acral and 21.8% mucosal melanomas were included, 26.3% with liver metastases, 31.6% with an elevated serum LDH, 20.3% harbored BRAF mutations. The median PFS was 4.8 months, based on the Cox model, four factors were selected for the nomogram and assigned specific scores: tumor metastases number≥3, 1; tumor size≥80 mm,1; LDH level, 1 (higher limit of normal range); liver metastases,1. The model achieved relatively good discrimination and calibration, with a C-statistic of 0⋅804 (Table). BRAF mutations were associated with shorter PFS in univariate analysis but not in multivariate analysis. Subtypes were also not related to PFS in this cohort. The median OS was 22.8 months. Univariate analysis identified eight factors were associated with significantly worse OS among 21 factors ( BRAF and subtype included, which not found as risk factors). Based on the Cox model, five factors were selected for the nomogram and assigned specific scores: ECOG > 1, 0.6; Hemoglobin < 120g/ml,0.6; tumor size≥80 mm,1.4; LDH level, 0.5; liver metastases, 1. C-statistic was 0⋅85, with extremely strong predictability (Table). The overall survival rate for patients with a higher score was significantly worse than lower cohort (Score: < 0.6 vs. 1-2 vs. 2-4.1; OS: not reached vs. not reached vs. 8.3m; P < 0⋅001). Conclusions: The nomogram facilitates personalized assessment of prognosis for Asian patients with advanced melanoma with PD-1 inhibitor. [Table: see text]
Safety and tolerability of immune checkpoint therapies and related adverse effects at a tertiary care hospital in Saudi Arabia.
Authors: Al Nuhait Mohammed , Al Awlah Yousef , Bajnaid Eshtyag
Published: May 2019

e14082

Background: Immunotherapies associated with many toxicities with a potential immune-mediated cause and has been associated with many adverse events in the literature. As the incidence of emergency room (ER) visits in adult patients receiving immune checkpoint therapies and most frequent immune-related adverse events are not yet established well for our population since this class of medications is newly introduced in the oncology field. This research is aimed to shed the light on this new class of medications. Methods: This is a single-center retrospective cohort study to determine incidence of ER visits in adult patients receiving immune checkpoint therapies and to explore most frequent related adverse events. The study involved adult patients who were treated at King Abdulaziz Medical City. Study participants were identified by identified using our electronic health care system to identify patients who were treated with immunotherapies during the study period (January 2016 to December 2018). Inclusion criteria was patients aged more than 18 years who had received immunotherapies. Results: A total of 53 patients met the specified inclusion criteria for our study. The number of patients in each treatment group were as follows: Nivolumab 37, Atezolizumab 10 and Pembrolizumab 6. Average age was 59 years. The percentages of cancer patients presenting to the ER with various related adverse effects after beginning immune checkpoint therapy were (65%) Nivolumab, (80%) Atezolizumab and (83%) Pembrolizumab. The average number of ER visits after beginning immune checkpoint therapy was 3 visits (SD = 2.8). Renal adverse events were occurred following the immunotherapy use, 9 patients (17%) and none of cases experienced a grade≧3 event. 13 patients (24.5%) experienced hepatic adverse event. Only one patient experienced a grade≧3 event that lead to discontinuation of treatment. For diarrhea, among all patients received the immunotherapies, 14 (26%) experience diarrhea and five of them experience grade≧3 event. Thyroxine abnormalities occurred in 7 patients (13%) after use of immunotherapies. (7.5 %) of patients had pneumonitis with immunotherapy. Other adverse events were noted with immune therapies (skin reaction, nausea, vomiting, thrombocytopenia, neutropenia and neurological adverse events). All others adverse events that is reported had a grade 1-2 adverse events. Conclusions: Patients treated with immunotherapies may have a spectrum of adverse drug events that might lead to discontinue the treatment and increase ER visits.
Differences in prescribing and patient demographics of cki agents among United States patients < 65 and 65+ years old.
Authors: Angel William H , Franceschetti Alessandra
Published: May 2019

e14097

Background: Since FDA approval, immune checkpoint inhibitors (CKIs) have become increasingly important in treating NSCLC, particularly among mutation-negative patients who did not benefit from biomarker testing. Because clinical trials typically recruit healthy patients, little information is available to understand the role of CKIs in treating older patients, who also face immunosenescence. This study explores differences in prescribing behavior of CKIs for mutation-negative NSCLC patients < 65 y/o and 65+ y/o in the US and satisfaction with results. Methods: The Ipsos Global Oncology Monitor: an online multi-center medical chart review study of stage IIIb-IV NSCLC patients currently receiving drug treatments seen in consultation from June – November 2018. 170 US physicians provided de-identified data on 1484 patients negative or untested for EGFR, ALK, ROS1 and BRAF. Results: Compared to patients < 65 y/o (n = 539), those 65+ y/o (n = 945) were prescribed a CKI significantly more often, 63% vs 70% (p < 0.01), driven by CKI monotherapy (CKIm) use, 47% vs 55% (p < 0.01). This trend was seen among patients on 1L therapy (n = 1015), with 42% of patients < 65 y/o and 50% of patients 65+ y/o on CKIm (p < 0.05), and on 2L therapy (n = 337), with 62% of patients < 65 y/o and 76% of patients 65+ y/o on CKIm (p < 0.01). In both lines, this was due to more use of nivolumab among 65+ y/o patients (p < 0.01), while among 2L patients < 65 y/o there was also greater use of pembrolizumab (p < 0.05). Physicians’ stated satisfaction with 1L CKI results was similar in both cohorts but, at 2L, greater among patients 65+ y/o (μ = 8.45; σx̅= 1.26) vs patients < 65 y/o (μ = 8.01; σx̅= 1.38) (p < 0.05). Older 2L CKIm patients were more likely to be ECOG 2+ (18% vs 5%; p < 0.01) and to have 2+ concomitant conditions (60% vs 36%p < 0.01). Conclusions: Satisfaction with 2L CKIs is higher in older vs younger patients, despite the former’s association with poorer outcomes. Potentially, lower expectations at treatment initiation caused higher satisfaction for similar treatment success, but this may also be due to immunosenescence, one study suggesting CKIs are more effective in older melanoma patients ( https://dx.doi.org/10.2147%2FOTT.S165368 ). The role of age in CKIs’ efficacy in NSCLC merits further investigation.
Anti-PD-1 therapy combined with chemotherapy in patients with advanced pancreas cancer in a real-world clinical setting.
Authors: Sun Danyang , Ma Junxun , Wang Jinliang , Han Chun , Qian Yuanyu , Chen Guangying , Li Xiaoyan , Zhang Juan , Cui Pengfei , Du Wushuang , Wu Zhaozhen , Chen Shixue , Zheng Xuan , Yue Zhichao , Song Jia , Cai Shangli , HU YI
Published: May 2019

e14103

Background: Pancreatic cancer (PC) is a highly lethal disease and characterized by a strong resistance to current radiotherapy and chemotherapy. As PC has the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma which involved in immune system control, the immune system has been hypothesized to play an important role in PC. However, there was no response in patients who received immune checkpoint inhibitors (ICIs) monotherapy. Though small sample studies revealed that ICIs combined with chemotherapy is effective, a head-to-head comparison of ICIs plus chemotherapy and chemotherapy is limited. Methods: Advanced PC patients treated with chemotherapy alone or plus ICIs were retrospectively screened for eligibility. Patients previously treated with any agent targeting T-cell co-stimulation or checkpoint pathways was excluded. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. Results: In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). Combination group presented significantly longer OS than chemotherapy group (median, 18.1 vs 6.1 months, HR 0.46 [0.23-0.90], P = 0.021). Median PFS was 3.2 months in the combination group and 2.0 months in the chemotherapy group (HR 0.57 [0.32-0.99], P = 0.041). The ORR was similar between the combination group and the chemotherapy group with no significant difference (18.2% vs 19.4%, P = 0.906). And all the patients, who reached partial response, accepted a two-chemotherapic-drugs regimen regardless of combinating with ICIs. Adverse events of grade 3 or higher occurred in 31.8% of the patients in the combination group and in 16.9% of those in the chemotherapy group. Though the incidence rate of serious treatment-related adverse events (TRAEs) was higher in the combination group than the chemotherapy group, no statistical significance existed (P = 0.183). Conclusions: Combination of ICIs plus chemotherapy is effective and tolerable for advanced PC. Accepting ICIs combined with a two-drug chemotherapy regimen might be the better choice.
Gene expression profiles of peripheral blood mononuclear cells from patients with advanced non-small cell lung cancer treated with anti-PD-1 monoclonal antibodies.
Authors: Wu Jie , Cheung Yee Him , Huang Weihua , Yin Changhong , Fallon John T , Dimitrova Nevenka , Fanucchi Michael Paul
Published: May 2019

e14107

Background: Anti-PD-1 monoclonal antibodies have improved the outcome for patients with advanced non-small cell lung cancer (NSCLC). The goal of this study is to characterize the longitudinal gene expression profiles of peripheral blood mononuclear cells (PBMCs) in patients with advanced NSCLC treated with anti-PD-1 monoclonal antibodies and to evaluate the potential of this technology to predict response to therapy. Methods: PBMCs were collected using density centrifugation from patients with stage III/IV NSCLC before the first (T0) and second (T1) treatments, and, for responding patients, before the third (T2), fourth (T3), fifth (T4) and sixth (T5) treatments. Total RNA was extracted, and libraries were prepared using TruSeq Stranded mRNA LT Sample Prep Kit and sequenced by Illumina NextSeq. The paired-end reads were mapped to human reference hg38 using STAR and gene expressions were calculated using RSEM. Longitudinal differential gene expression with pathway analysis and principal component analysis (PCA) was performed across all time points. Genes with Bonferroni-adjusted p values < 0.05 were selected for pathway enrichment analysis with DAVID. Results: Nine of 15 patients have been enrolled. Six patients had a PR by RECIST 1.1, 2 patients have had stable/PD, 1 patient too early. Differential gene expression (DE) is available for the 8 patients with response assessment. There was differential expression of certain genes between T0 and T1 in the following pathways in responders but not in stable/PD: T cell receptor complex (p = 3.1E-6), regulation of immune response (p = 2.5E-5), T cell costimulation (p = 3.9E-3) were upregulated. CD24 is downregulated, while C4B is upregulated. Using PCA analysis we detected strong signal from the beta-hemoglobin HBB transcript. We observed HBG1 and HBM consistently upregulated at T1 (adjusted p = 7.9E-19 and p = 2.3E-10 respectively) through to T4 (adjusted p = 8.8E-27 and p = 3.8E-18 respectively). Conclusions: Anti-PD-1 monoclonal antibodies induce DE of genes in PBMCs from patients with advanced NSCLC. This technology may provide a predictive test for response to anti-PD-1 monoclonal antibodies.
Eosinophilia during treatment of immune checkpoint inhibitors (ICIs) to predict succeeding onset of immune-related adverse events (irAEs).
Authors: Kizawa Rika , Miura Yuji , Oda Yasuhiro , Nagaoka Yukiko , Ozaki Yukinori , Kondoh Chihiro , Moriguchi Shuhei , Takahashi Yui , Ogawa Kazumasa , Tanabe-Hashimoto Yuko , Taniguchi Shuichi , Okaneya Toshikazu , Kishi Akiko , Hayashi Nobukazu , Kishi Kazuma , Takano Toshimi , Masuda Jun
Published: May 2019

e14110

Background: ICIs such as anti-PD-1/-L1 Inhibitor and anti-CTLA-4 Inhibitor have been used in many types of cancer, and irAEs occur in a considerable proportion of patients. Predictive biomarkers could help us to manage irAEs promptly. Methods: We retrospectively analyzed the consecutive patients treated with nivolumab, pembrolizumab, atezolizumab or ipilimumab, not used as investigational drugs, between March 2015 and December 2018 based on the electric medical records in our institution. We evaluated the relationship between clinical and laboratory factors (gender, age, body mass index, lymphocyte-to-monocyte ratio and eosinophilia) and the occurrence of irAEs using univariate and multivariate analyses. Eosinophilia was defined as absolute eosinophil count over 500/mm3 at least once between initiation of treatment and the occurrence of irAEs. We graded irAEs according to CTCAE v. 5.0. Results: Among 139 patients analyzed in this study, 136, 13 and 6 patients were treated with PD-1, PD-L1 and CTLA-4 inhibitors, respectively (cumulative total of 155 patients). This study included non-small cell lung cancer (n = 78; 56.1%), renal cell carcinoma (n = 17; 12.2%), melanoma (n = 16; 11.5%), gastric cancer (n = 15; 10.8%), Hodgkin lymphoma (n = 7; 5.0%), urothelial carcinoma (n = 3; 2.2%), head and neck carcinoma (n = 3; 2.2%) and mesothelioma (n = 1; 0.7%). Any grade and grade 3-5 irAEs occurred in 60 (38.7%) and 23 (14.8%) cumulative patients, respectively. The most common irAEs in any grade were endocrine disorders including thyroid dysfunction and adrenal insufficiency (n = 21) and skin disorders (n = 20). Eosinophilia occurred in 43 cumulative patients (27.7%). Eighteen patients out of them had eosinophilia from baseline. Among the clinical and laboratory factors, only eosinophilia was significantly associated with the occurrence of any grade of irAEs in both univariate (p = 0.0193) and multivariate (p = 0.0464) analysis. Notably, endocrine irAEs were significantly related to eosinophilia (p = 0.0287). Conclusions: Eosinophilia after the initiation of treatment with ICIs predicts succeeding onset of irAEs.
Real-world use and survival outcomes of immune checkpoint inhibitors in patients with non-small cell lung cancer.
Authors: Youn Bora , Trikalinos Nikolaos , Mor Vincent , Wilson Ira , Dahabreh Issa
Published: May 2019

e14111

Background: Little is known about the real-world use and survival outcomes of immune checkpoint inhibitors among elderly patients with non-small cell lung cancer (NSCLC). Methods: Using the SEER-Medicare data, we identified 1,338 patients who were diagnosed with pathologically confirmed stage 1-4 NSCLC between 2002 and 2015 and initiated nivolumab or pembrolizumab in 2016. We examined the association of patient and disease characteristics, and treatment history with overall survival, from initiation through December 31, 2017. We estimated survival curves using the Kaplan-Meier method and identified predictors of survival using multivariable Cox proportional hazards regression. Results: The median age at immune checkpoint inhibitor initiation was 74.8 years. The majority of patients were initially diagnosed with stage 4 disease (42.7%). Median time from diagnosis to initiation were 13.9 and 19.0 months for those initially diagnosed with stage 4 and 1-3 disease, respectively. Median overall survival was 9.5 months. In multivariable analyses, multiple comorbid conditions, squamous histology, history of non-platinum doublet systemic therapy, recent radiation therapy, and shorter time from initial diagnosis to initiation were statistically significantly associated with increased hazard of death (Table). Demographics, stage at initial diagnosis, and prior oral targeted therapy were not significantly associated with the hazard of death. Conclusions: Real-world data show that factors that are generally related to poor prognosis remain predictors of survival in elderly patients treated with immune checkpoint inhibitors.[Table: see text]
A retrospective review of nutritional status and immunotherapy in lung cancer.
Authors: Lee Chung-Shien , Sin Rebecca , Fishbein Joanna Stein , Devoe Craig E. , Zhu Xinhua , Lee Mee-Young , Seetharamu Nagashree
Published: May 2019

e14112

Background: Immunotherapy has transformed cancer treatment, including lung cancer. Approximately 20-25% of patients respond, therefore making it pivotal in understanding what factors may effect outcomes. There have been previous reports of obesity associated with an increased efficacy of PD-1/PD-L1 blockade and cachectic patients not responding as well. In this study, we aim to assess the association of body mass index (BMI) with outcomes of lung cancer patients being treated with immunotherapy. Methods: An IRB approved retrospective review of lung cancer patients receiving immunotherapy between 2014 and 2017 at the Monter Cancer Center, Northwell Health was conducted. Patients were categorized in underweight (BMI < 18.5), normal weight (BMI of 18.5 to < 25), overweight (BMI 25 to 30) or obese (BMI > 30) arms. The groups were compared using the log-rank test. Kaplan-Meier was used for overall survival (OS) and progression free survival (PFS) and Cox regression models were used to adjust for potential confounders. Results: A total of 116 were included in the analysis, with a median age of 70 (95% CI, 62.5 to 75.5). Ten (8.6%) were underweight, 44 (37.9%) were normal weight, 32 (27.6%) were overweight, and 30 (25.9%) were obese. BMI classification were not found to be a significant predictor of survival, after adjusting for therapy duration (p = 0.44). PFS was 6.6, 6.0, and 6.9 months for patients in the underweight, normal weight, and overweight/obese groups, respectively. Of 116 subjects, 46 (40%) died within the follow up period: 3 (30%), 17 (39%), 11 (34%), and 15 (50%) respectively. Additional post hoc analysis showed that patients with low nutritional status as defined by either a BMI < 18.5 and/or baseline albumin < 3.5 mg/dL had a median PFS of 2.2 months compared to those who did not of 5.2 months (p < 0.00032). Conclusions: In this single institution retrospective review, BMI or albumin as solitary factors did not have a significant effect on outcomes receiving immunotherapy in lung cancer patients. However, a more comprehensive nutritional assessment using a composite endpoint of BMI and serum albumin predicted response to checkpoint inhibitors. Additional studies are needed to validate these findings.
Dual blockade of PD-1 and PD-L1 is effective but causes severe pneumonitis in lung metastasis: Syngeneic mice study for validation of clinical observation.
Authors: Chen Yu-Jen , Liu Shin-Yi , Shieh Hui-Ru , Ko Chun-Chuan , Liu Hung-Chang
Published: May 2019

e14115

Background: In clinical practice, the shifting use of PD-1 inhibitors and its ligand PD-L1 inhibitors due to ineffectiveness or toxicity is becoming more common and has distinct responses. To validate clinical observation, we examined the anti-cancer effect, tumor microenvironment (TME) modulation and toxicity of dual blockade of PD-1 and PD-L1 in mice. Case Presentation: Three patients with metastatic lung adenocarcinoma received nivolumab (5, 5 and 11 doses); after the initial response and subsequent progression, they were shifted to receive atezolimumab (1, 1 and 4 doses) at intervals of 70, 38 and 43 days, respectively. All 3 patients obtained partial response according to iRECIST. Two of the 3 patients developed pneumonitis at days 3 and 15 after the first dose of atezolimumab and pneumonitis subsided by methylprednisolone injection for 7 and 4 days. Methods: The Balb/c mice bearing lung metastasis of CT26 colon cancer cells were treated. Assessments included optical imaging for tumor burden, multi-parameter flow cytometry for TME, pathology and immuohistochemistry. Results: The pathology of lung showed that all the mice (100%, n = 3 for each group) treated with a combination of anti-PD-1 and anti-PD-L1, either sequential or simultaneous, developed severe clustered inflammatory infiltrates, mucus filling in bronchus and thrombi in small vessels. Among infiltrating leukocytes, combinatorial blockade increased LyC6+ inflammatory monocytes and NKG2D+ T cells and reduced tumor-associated macrophages in lung. Peripheral leukocytes in spleen had no such alteration. In lung metastatic foci, the expression of PD-1 was noted mainly within tumors, and this expression was reduced by combinatorial blockade. PD-L1 expression had no change. For control of lung metastasis, the combinatorial treatments exhibited better control, and anti-PD-L1 followed by anti-PD-1 was the most effective. No significant pneumonitis was noted in single blockade groups. Conclusions: The combination of PD-1 and PD-L1 blockade, either sequential or concurrent, may have better tumor control but cause severe pneumonitis. Dual blockade of PD-1 and PD-L1 should be used with caution.
Immune-related adverse events (irAEs) and survival in solid tumors treated with immune checkpoint inhibitors (ICIs): A systematic review and meta-analysis.
Authors: Grizzi Giulia , Petrelli Fausto , Ghidini Michele , Ghidini Antonio , Ratti Margherita , Panni Stefano , Cabiddu Mary , Ghilardi Mara , Borgonovo Karen , Parati Maria Chiara , Barni Sandro , Tomasello Gianluca , Passalacqua Rodolfo , Berruti Alfredo , Brighenti Matteo
Published: May 2019

e14130

Background: irAEs are autoimmune-toxic effects associated with ICIs used for treatment of advanced solid tumors. The correlation of these irAEs with survival is presently unknown. The objective of this meta-analysis is to assess the outcome of cancer patients treated with ICIs who develop irAEs. Methods: Two independent reviewers selected prospective or retrospective studies from PubMed, EMBASE, and the Cochrane library database from their inception to November 2018. Studies were selected if: 1) they reported correlation of irAEs (any) with outcome, 2) they included patients with solid tumors; 3) they included treatment with anti-PD-(L)1 or anti-CTLA-4 agents, 4) patients had no previous history of autoimmune disorders, 5) they were published in English language, and 6) they provided availability of adequate data to calculate hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs). Data were pooled using HRs for overall survival (OS) or progression-free survival (PFS) or ORs for overall response rate (ORR) of irAEs vs no irAEs according to fixed or random effect model. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. Hazard ratio for PFS and ORs for ORR were secondary endpoints. Results: A total of 29 studies for a total of 4242 patients treated with ICIs were selected. Patients who developed irAEs presented a reduced risk of death (HR = 0.52, p < .001). Similarly, the occurrence of irAEs was associated with a reduced risk of progression (HR = 0.51, p < .001). The combined odds of response was 4.87 (p < .001). Conclusions: In patients treated with ICIs, irAEs predict survival and response. Although this correlation cannot be fully explained, it may be related to the strongest T cell activation. Patients showing any form of irAEs can be informed about the positive prognostic effect, and physicians can detect patients with favorable outcome to ICIs.
Prognostic value of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in patients with advanced solid tumors treated with PD-1 inhibitors.
Authors: Gonzalez Velez Miguel , Suero-Abreu Giselle Alexandra , McKenna Marshall , Johnson Camille Michelle , Gutierrez Martin
Published: May 2019

e14132

Background: The use of PD-1 inhibitors (PD1) has been limited due to the lack of prognostic markers of response. Previous studies have suggested that indirect inflammatory markers such as neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) may correlate with response to treatment and improved survival. We sought to evaluate the impact NLR and PLR in a real world cohort of patients (pts) with advanced solid tumors treated with PD1. Methods: Records of all pts treated with PD1 between 2011-2017 at the John Theurer Cancer Center were reviewed. NLR and PLR were registered at baseline and longitudinally. We dichotomized as low (lNLR/lPLR), and high (hNLR ≥5/hPLR ≥160). Univariate logistic regression and Cox proportional hazards were used for progression free survival (PFS), and overall survival (OS). Landmark analyses were performed at cycles 2 (C2), and 5 (C5). Results: 178 pts received 1131 cycles of PD1. Median age was 65 (range 24-93); 43% were female. ECOG was ≥1 for 85%. 142 pts (80%), and 89 (50%) received ≥2C and ≥5C respectively. In univariate analyses, baseline hNLR and hPLR were independently associated with inferior OS (median 7.8 vs 18.3 months; HR 1.77, 95% CI 1.21-2.43; p = 0.004), ) and (median 6.4 vs 15.6 months; HR 1.42, 95% CI 1.09-2; p = 0.04) respectively. On landmark analyses, lNLR and lPLR were associated with longer PFS and OS at 2C, and 5C. Longitudinally, lNLR and lPLR correlated with response rate; NLR decreased by 0.08 (95% CI: -0.19 to -0.04; p = 0.03) and PLR by 17 (95% CI: -29 to -14; p = 0.07) per month in responders compared with non-responders. hNLR or hPLR did not correlate with increase in autoimmune toxicities. Conclusions: hNLR, hPLR are adversely prognostic markers in pts receiving PD1 inhibitors in a “real world cohort”. These markers correlate with a longitudinal response and may help predict response. Further prospective studies are needed to determine their utility in decision making during treatment.
Immune-related toxicities in non-small cell lung cancer: Real-life predictors of outcome to checkpoint inhibitors?
Authors: Romano Emanuela , Poli Roberta , Dumont Clement , Pietrogiovanna Lisa , Vigan Marie , Servois Vincent , Bidard Francois-Clement , Beaucaire-Danel Sophie , Daniel Catherine , Girard Nicolas , Hescot Segolene , Savignoni Alexia
Published: May 2019

e14135

Background: Immune checkpoint inhibitors (ICIs) are approved for the treatment of non-small cell lung cancer (NSCLC) and are associated with immune-related adverse events (irAEs). However, real-life data on type, occurrence and kinetics of irAEs, and their predictive value on treatment outcome are lacking. Here, we report on the relation between irAEs, including endocrine irAEs, and outcome to anti-PD-/L-1 (programmed cell death protein-/ligand-1) ICIs. Methods: A total of 147 patients (pts), with locally advanced/metastatic NSCLC, treated with anti-PD-1 (N 140; 95%) or anti-PD-L1 agents (N 7; 5%) as ≥ 2 line treatment were included in two independent, prospective, cohorts at the Institut Curie (ALCINA-NCT02866149) and at Biella Hospital (Italy). PD-L1 status was assessed by immunohistochemistry (clone 22C3, Dako). Progression-free survival (PFS) and overall survival (OS) were estimated with Kaplan-Meier curves. Results: Median follow-up of 147 pts was 10.2 (range: 0.7-42.8) months; median age, 66 (35-85) years; 100 men (68%). After treatment initiation, irAEs were observed in 72 pts (49%). Thirty one (43%) pts had only endocrine irAEs, mostly thyroid dysfunctions (N 44, 61%). Pre-existing thyroid disease was present in only 6 pts (4%). Dermatologic toxicity in 21 (29%) pts was the next most frequent irAE, 22 (30%) pts had other types of irAEs. Among patients with irAEs, 61 (85%) had ≤ 2 coexisting irAEs, and 13 (18%) pts had > 2 irAEs. Most irAEs were G1 (63%) and G2 (18%). Onset and kinetics differed according to irAE type. There was no association between PD-L1 status and irAE occurrence. Median PFS was 7.2 and 4.2 months in irAEs vs no-irAEs group, respectively [HR 0.70 (95% CI 0.46;1.08), p 0.11]. Median OS in the irAEs group was 18.1 months vs 13.6 months no-irAEs group [HR 0.64 (95% CI 0.37;0.98), p 0.039]. Median OS in the endocrine-irAEs group was 23.5 vs 13.6 months in the no-irAEs group [HR 0.58 (0.74;3.92), p 0.2]. Conclusions: In this study, we show that irAEs – including endocrine type – are frequent in NSCLC pts treated with ICIs and that their occurrence is associated with a survival benefit.
Is a clinical biomarker predictive of outcomes with immune checkpoint inhibitor (ICI) therapy in a phase I patient population.
Authors: Vaishampayan Ulka N. , Kim Seongho , Karwa Jaswinder , Mamdani Hirva , Lange Lisa , Harfoot Danielle , Jamison Andrea , Williams Lindsay , Wilson Kelley , Weise Amy M.
Published: May 2019

e14136

Background: NLR is reported to be a prognostic marker in multiple malignancies and has reported potential predictive value with ICI. We evaluated NLR as a predictor of response and time to treatment failure (TTF) in a phase I patient population treated with ICI. Methods: Regulatory approval was obtained. A retrospective chart review of patients treated on phase I trials with ICI based therapy at Karmanos Cancer Institute, was conducted. Data were collected on demographics, performance status, tumor type, response rate, TTF and NLR pre and post therapy. Associations with clinical benefit (response rate and stable disease) and TTF were conducted by univariable logistic and Cox regression analyses. Results: 100 pts; 52 female and 48 male were evaluated. Median age was 62 years (range 22-84 years). 11 were African American (AA) and all patients were pretreated with standard therapy and had progressed prior to enrollment. Median pretherapy NLR was 3.31 (range 0.91-25.5). 26 patients showed clinical benefit with ICI based therapy; 6 partial responses and 20 with stable disease. Univariable Cox analysis for baseline continuous NLR associated with TTF showed a significant relation between NLR and TTF (p = 0.023). Univariable logistic and Cox analyses for dichotomized baseline NLR with optimal cut-off values, resulted in low NLR favoring higher chance of clinical benefit (Odds ratio = 0.169 95% CI 0.028,1.013, p = 0.043) and longer TTF (Hazard ratio = 1.841, 95% CI 1.188,2.854 p = 0.006). Conclusions: Pretherapy NLR was a statistically significant predictor of clinical benefit with ICI therapy in a phase I patient population. NLR is an easily applicable clinical predictive biomarker that may help guide clinical trial choice, especially in a patient population with limited life expectancy.
A machine learning based prediction model of anti-PD-1 therapy response using noninvasive clinical information and blood markers of lung cancer patients.
Authors: AHN Beung-Chul , Pyo Kyoung Ho , Jung Dongmin , Xin Chun-Feng , Kim Chang Gon , Hong Min Hee , Cho Byoung Chul , Kim HyeRyun
Published: May 2019

e14138

Background: Immune checkpoint inhibitors have become breakthrough therapy for various types of cancers. However, regarding their total response rate around 20% based on clinical trials, predicting accurate aPD-1 response for individual patient is unestablished. The presence of PD-L1 expression or tumor infiltrating lymphocyte may be used as indicators of response but are limited. We developed models using machine learning methods to predict the aPD-1 response. Methods: A total of 126 advanced NSCLC patients treated with the aPD-1 were enrolled. Their clinical characteristics, treatment outcomes, and adverse events were collected. Total clinical data (n = 126) consist of 15 variables were divided into two subsets, discovery set (n = 63) and test set (n = 63). Thirteen supervised learning algorithms including support vector machine and regularized regression (lasso, ridge, elastic net) were applied on discovery set for model development and on test set for validation. Each model were evaluated according to the ROC curve and cross-validation method. Same methods were used to the subset which had additional flow cytometry data (n = 40). Results: The median age was 64 and 69.8% were male. Adenocarcinoma was predominant (69.8%) and twenty patients (15.1%) were driver mutation positive. Clinical data set (n = 126) demonstrated that the Ridge regression (AUC: 0.79) was the best model for prediction. Of 15 clinical variables, tumor burden, age, ECOG PS and PD-L1, were most important based on the random forest algorithm. When we merged the clinical and flow cytometry data, the Ridge regression model (AUC:0.82) showed better performance compared to using clinical data only. Among 52 variables of merged set, the top most important immune markers were as follows: CD3+CD8+CD25+/Teff-CD28, CD3+CD8+CD25-/Teff-Ki-67, and CD3+CD8+CD25+/Teff-NY-ESO/Teff-PD-1, which indicate activated tumor specific T cell subset. Conclusions: Our machine learning based model has benefit for predicting aPD-1 responses. After further validation in independent patient cohort, the supervised learning based non-invasive predictive score can be established to predict aPD-1 response.
Rates of immunosuppressive treatment and hospitalization after checkpoint inhibitor therapy in melanoma and lung cancer patients with autoimmune diseases.
Authors: Bender David Andrew , Spina Catherine , Heilbroner Samuel P. , Xanthopoulos Eric , Wang Tony J. C. , Reuscher Paul , Hyde Brigham , Cheng Simon
Published: May 2019

e14140

Background: Immune checkpoint inhibitors (ICIs) are known to cause immune-related adverse events. Patients with autoimmune diseases (AID) were excluded from most ICI clinical trials due to the potentially high risk of adverse effects. Data on the safety of ICIs in patients with a diagnosis of AID is therefore limited. Methods: A retrospective cohort study was conducted using a de-identified large oncology health care and pharmacy claims database with data from March 2010 until April 2017. Patients analyzed had a diagnosis of either melanoma or lung cancer and were treated with either of the anti-PD-1 inhibitors nivolumab or pembrolizumab. We assessed whether patients with AID compared with no AID were more likely to require medical interventions within 180 days of ICI therapy. We determined the percentage of patients receiving oral prednisone, IV methylprednisolone, or were hospitalized, which may represent responses to ICI toxicity. Results: 16.7% (16/96) of patients with either melanoma or lung cancer and AID received oral prednisone treatment within 180 days of ICI treatment, while 8.3% (131/1573) of patients without AID received oral prednisone during the same period. 8.4% (16/190) of patients with AID received IV methylprednisolone compared to 3.6% (79/2190) of patients without AID. Among melanoma patients, 24.1% (13/54) of patients with AID were hospitalized following ICI treatment, compared to 5.8% (28/480) of patients without ICI. Among lung cancer patients, 38.2% (52/136) of patients with AID were hospitalized compared to 31.6% (541/1711) of patients without AID. All comparisons are significant at p < 0.05 except hospitalizations in lung cancer patients. Conclusions: Patients with AID were more likely to receive interventions after ICI treatment that may represent responses to immune-related adverse events, suggesting that patients with AID are at increased risk for toxicity when being treated with ICIs.
IRX-2 therapy with PD-L1 blockade in immunocompetent animal model.
Authors: Wen Lu , Wolf Gregory T. , Shah Monil , Page David B. , Sadowski-Mason Lynn , Prince Mark , Moyer Jeffrey , Chang Alfred E. , Li Qiao
Published: May 2019

e14149

Background: Multiple therapeutic components in IRX-2 including IL-2, IL-1, IFN-γ, TNFα, IL-6, GM-CSF, and IL-8 work synergistically to activate various immune cells including T cells, dendritic cells, and natural killer cells to recognize and kill tumors. Previous Phase 1 and Phase 2a clinical trials in head and neck cancer with IRX-2 have shown a benign safety profile. Immunologically stimulating host immunity using IRX-2, while simultaneously blocking PD-1/PD-L1-mediated immune suppression, may have the potential to enhance the outcome of current immunotherapy using IRX-2 alone. Methods: Healthy C3H mice were inoculated with SCC7 murine head and neck cancer cells. Fourteen days after inoculation, the tumor-bearing mice were treated with subcutaneous injection of IRX-2 once a week for 3 weeks, followed with anti-mPD-L1(i.p.) injection after each IRX-2 administration. Tumor size and survival were monitored for the therapeutic efficacy evaluation. Two weeks after the last IRX-2 administration, all mice were sacrificed and spleen, blood and residual tumor samples were harvested for immune function assays. Results: High levels of PD-L1 were expressed on SCC7 cell line and fresh tumors. The FCM data suggested that PD-L1 was preferentially expressed on the ALDHhigh SCC7 cancer stem cells. IRX-2 alone significantly inhibited SCC7 tumor growth, and the anti-tumor efficacy of IRX-2 was significantly enhanced by anti-mPD-L1 injection in a dose dependent manner in the immunocompetent hosts. Serum IgG from animals subjected to IRX-2 plus anti-mPD-L1 treatment mediated significantly (p < 0.05) higher cytotoxicity on SCC7 cells via ADCC than the IgG from animals treated with IRX-2 alone. CD8+ lymphocytes isolated from purified, activated and expanded CD3+ splenic T cells harvested from the animals subjected to IRX-2+anti-mPD-L1 treatment mediated significantly (p < 0.05) higher cytotoxicity than those subjected to IRX-2 or anti-PD-L1 mono-therapy against SCC7 tumor cells. Conclusions: Co-administration of IRX-2 and anti-PD-L1 promoted more powerful antitumor immunity with both B cell and T cell modulation. The combination treatment increased the specific IgG production that could kill tumor cells via ADCC, and enhanced the T cell CTL activity. Therefore, IRX-2 therapy plus anti-PD-L1 administration may represent a promising novel strategy to treat cancer patients.
DNA repair pathway alterations and correlation with immunotherapy response.
Authors: Hernandez-Guerrero Tatiana , Pedregal Manuel , Rubio Jaime , Ruiz-Hispán Eva , Fernandez Marina , Martinez Imanol , Doger Bernard , Lage Alfranca Yolanda , Ruperez Ana Belen , Zenzola Victor , Casado Victoria , Martin-Valades Jose Ignacio , Carvajal Nerea , Chamizo Cristina , Domine Manuel , García Foncillas Jesús , Moreno Victor
Published: May 2019

e14150

Background: Over the past decade, a better understanding of cancer biology has led to a revolution in immunotherapy. Checkpoint inhibitors (ICI), bispecific antibodies and agonistic agents have shown benefit in cancer treatment. Unfortunately, not all patients benefit and, despite the advances achieved in discovering markers of response, the selection of patients can still be challenging in everyday practice. Methods: We conducted a retrospective analysis of potential prognostic and predictive factors of survival in a cohort of 186 patients enrolled into Phase I Trials testing immunotherapeutic agents at our institution. We computed univariate and multivariate analysis (MVA) of demographics, clinical and molecular characteristics to assess their prognostic and predictive potential of clinical benefit (defined as achieving Complete or Partial Response (CR/PR) as best response or disease stabilization lasting > 120 days) and survival. Molecular testing included Next Generation Sequencing (NGS - Oncomine Comprehensive Assay) grouped in DNA repair, Transcription regulation, Signal Transduction and Cell-Cell interaction pathways. Results: A total of 186 patients (Male/Female: 81/105; median age 61yo) received treatment with either immune checkpoint inhibitors (122 (65,6%)), checkpoint agonists (37 (19.9%)); bispecific antibodies (19 (10.21%) or other immunotherapies (8 (4.29%)) between November 2015 and July 2018. Royal Marsden Score (RMH) was assessed and correlated with progression free survival and overall survival in the total cohort. Median Overall Survival (mOS) was 422 days (CI95%: 345-500 days), 387 (CI95%: 297-478 days), 235 (CI95%: 131-338 days), and 167 (CI95% 64-270 days) for RMH 0, 1, 2 and 3, respectively (p = 0.007). Among 57 patients with NGS results, those with pathogenic mutations in DNA repair pathways (n = 26) showed a trend towards a higher response rate (69% vs 30% p = 0.064) and clinical benefit (65% vs 35%; p = 0.034). Conclusions: Alterations in DNA repair pathways are a potential predictor of benefit of immunotherapy and warrants further studies. A larger cohort of patients is currently being explored in our center to further validate these findings.