bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I safety and preliminary efficacy of PM1009, a bispecific antibody targeting TIGIT and PVRIG, in patients with advanced solid tumors.
Authors: Xue Liqiong , Wu Lihua , Tang Wenbo , Wang Zhuoyi , Xue Junli , Li Qun , Ge Xiaoxiao , Lin Fengjuan , Zhao Wei , Zhou Jiuli , Guo Ye 
Published: June 2024

e14695 Background: PM1009 is an anti-TIGIT x PVRIG bispecific antibody containing a fully human anti-TIGIT IgG1 fused with a fully human anti-PVRIG scFv at the C terminus. PM1009 can potently block the TIGIT/CD155/CD112 and PVRIG/CD112 signaling pathways, and supports the depletion of TIGIT-positive Treg cells in the tumor microenvironment through FcγR engagement. This leads to the enhancement of T cell and NK cell activity towards the killing of tumor cells. PM1009 showed robust in vitro and in vivo efficacy with good safety in preclinical studies. Methods: This is the first-in-human study of PM1009, which includes a dose escalation stage (accelerated titration & 3+3 design) followed by dose expansion. In the dose escalation stage, PM1009 was administered as flat doses of 120, 300, 600 and 1200 mg for DLT evaluation after 3 weeks followed by administration Q2W. Primary endpoints were safety and tolerability, and the secondary endpoints were PK, ORR and DCR (per RECIST 1.1). Results: As of February 1, 2024, a total of 12 patients were enrolled for dose escalation and received at least one dose of PM1009, with 3 patients in each of the 120, 300, 600 and 1200 mg dose-levels. Median number of prior therapies was 5 lines (range 1- 9). No DLTs were observed up to 1200 mg. Any-grade TRAEs occurred in 11 patients (91.7%), and ≥ Grade 3 TRAEs occurred in 2 patients (16.7%). Any-Grade irAEs occurred in 7 patients (58.3%), and ≥ Grade 3 irAEs occurred in 1 patient (8.3%). Treatment interruption due to TRAE occurred in 2 patients (16.7%), with infusion related reaction (the main symptom was nausea, and the single infusion was eventually completed), and neutrophil count decrease respectively. Treatment discontinuation due to TRAE occurred in 2 patients (16.7%), with acute myocardial infarction, and neutrophil count decrease respectively. The most common TRAEs were ALP elevation (33.3%) and AST elevation (25.0%). 12 patients completed at least one tumor evaluation. The DCR per RECIST 1.1 by investigator was 33.3% (4/12; 95% CI: 9.92 - 65.11), best overall response was SD. Pharmacokinetics were dose-proportional with a terminal half-life of 5.2-7.4 days across the dose range of 120-1200 mg. Conclusions: PM1009 was well-tolerated up to 1200 mg with signs of anti-tumor activity. These findings support further clinical investigation of PM1009 especially for the combination with chemotherapy or PD-1/L1-based checkpoint inhibitors. Clinical trial information: NCT05607563 .
Prediction of immune-related adverse events in urological cancer during checkpoint inhibitor immunotherapy through immunohistochemical analysis of tumorous LCP1/ADPGK.
Authors: Xu Liqing , Ying Yicen , Yang Kaiwei , Tang Qi , Li Xuesong 
Published: June 2024

e14699 Background: The expanded utilization of immune checkpoint inhibitors (ICIs) have successfully improved the outcome of cancer patients, yet the concomitant immune-related adverse events (irAEs) can lead to fulminant unfavorable consequences. Currently, a comprehensive approach to predict irAEs is lacking. Some relevant biomarkers derived from database analyses are still in the early stages of investigation and lack robust validation in clinical samples, including LCP1/ADPGK. Herein, we validated the performance of LCP1 and ADPGK in a retrospective patient cohort with advanced urological cancers undergoing ICIs treatment, while comparing the predictive efficacy between different algorithmic models. Methods: We retrospectively collected clinical data of patients with renal cell carcinoma (RCC), upper urinary tract epithelial carcinoma (UTUC), bladder cancer (BC) receiving anti-PD-1/PD-L1 treatment from 2020 to 2023 in Peking University First Hospital. Patients were categorized into irAEs and non-irAEs groups, with irAE assessments conducted by two expert urological oncologists. Immunohistochemistry (IHC) was performed on 5-µm-thick pre-treated FFPE tumor tissue sections. Results: A total of 112 patients were included in the study, comprising 60 with RCC, 21 with UTUC, and 31 with BC. Among them, 51 (45.5%) patients experienced irAEs, with 9 exhibiting severe irAEs of grade III-IV. Immunohistochemical analysis revealed higher expression levels of LCP1 and ADPGK in patients with irAEs compared to those without irAEs. The area under the receiver-operating characteristic curve (AUC) for predicting irAEs using LCP1 and ADPGK individually was 0.82 (p < 0.0001, 95%CI = 0.74-0.90) and 0.86 (p < 0.0001, 95%CI = 0.80-0.93), respectively. The combination of LCP1 and ADPGK demonstrated an improved AUC of 0.89 (p < 0.0001, 95%CI = 0.83-0.95). Among different algorithms, the bivariate linear-regression and the geometric mean model show similar prediction effects. Notably, the combined LCP1+ADPGK model successfully predicted irAEs in RCC (AUC = 0.89, p < 0.0001, 95%CI = 0.81-0.98), UTUC (AUC = 0.81, p = 0.0063, 95%CI = 0.63-0.99), and BC (AUC = 0.88, p = 0.0004, 95%CI = 0.75-1.00). The expression of LCP1/ADPGK was not associated with the type of cancers. Conclusions: The bivariate linear-regression model of LCP1 and ADPGK could accurately predict irAEs in patients with urological cancers, which may allow us to improve the risk-benefit balance for individuals considered for ICIs therapy.
Comparative efficacy of six programmed cell death protein-1 inhibitors in first-line treatment for advanced non-small cell lung cancer: A retrospective cohort study.
Authors: Chen Siyuan , Qin Yuhui , Du Zhijuan , Qiao Yu , Hu Yi , Liu Zhefeng 
Published: June 2024

e14702 Background: All six programmed cell death-1 (PD-1) inhibitors (nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and camrelizumab) have been used as first-line therapy in Chinese patients with advanced non-small cell lung cancer (NSCLC), but the comparative efficacy of these different drugs remains unclear. Methods: Retrospective collection of patient data from the First, Third, and Fifth Medical Centers of the Chinese PLA General Hospital who received PD-1 inhibitors (monotherapy or combination therapy) from June 2015 to April 2023. Analysis of patient clinical characteristics, treatment response, and survival outcomes was conducted, with the primary endpoints being overall survival (OS) and progression-free survival (PFS). Secondary endpoints include objective response rate (ORR) and disease control rate (DCR). Results: 913 patients were included and divided into 6 groups: nivolumab (123, 13.5%), pembrolizumab (421, 46.1%), sintilimab (239, 26.1%), tislelizumab (64, 7.0%), toripalimab (39, 4.3%), and camrelizumab (27, 3.0%). Median PFS was 16.0, 16.1, 18.4, 16.9, 23.7, and 12.8 months, and median OS was 33.7, 36.1, 32.5, not reached, 30.9, and 46.0 months for the nivolumab, sintilimab, pembrolizumab, tislelizumab, toripalimab, and camrelizumab groups, respectively. PFS and OS did not differ among the different PD-1 inhibitor groups (all P>0.05). There were differences in ORR among the different PD-1 inhibitors (P<0.05), but no differences in DCR (P>0.05). Conclusions: Nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and camrelizumab exhibit similar efficacy in first-line treatment for patients with advanced NSCLC.
Effect of common medications on immune checkpoint inhibitor efficacy.
Authors: Falvello Virginia , Brinzevich Daria , Bryant Alex , Green Michael D 
Published: June 2024

e14710 Background: Previous studies have suggested that certain common medications could impact immune checkpoint inhibitor (ICI) efficacy and survival. These studies lacked non-ICI control groups, raising the possibility that survival differences could be explained by confounding. Methods: We developed a pan-cancer cohort of 27,998 patients who received ICIs in the national Veterans Health Administration (VHA) from 2010 to 2023. ICI patients were matched to 66,488 historical control patients treated with chemotherapy or targeted therapy before initial ICI regulatory approval in each cancer. We ascertained baseline use of drugs from 15 common medication classes within 1 year before therapy start and performed propensity-weighted Cox regression analyses to assess the impact of each medication class on overall survival (OS) and time to next treatment (TTNT). Interaction tests measured whether the impact of each medication class was significantly different in ICI versus historical control patients. Results: In the ICI cohort, the most common cancer types were NSCLC (46%) and melanoma (10%). After adjustment for multiple comparisons, only statins (adjusted hazard ratio [aHR] 0.93), PPIs (aHR 1.06), and loop diuretics (aHR 1.19) were associated with overall survival differences among ICI patients; nearly identical associations were observed in historical control patients (interaction p-values > 0.4 for all; Table). Similar results were seen for TTNT and in sensitivity analyses limiting to more recent medication users. Conclusions: Common medications do not appear to impact ICI efficacy. Previously described survival effects are likely the result of confounding. [Table: see text]
Predictors of endocrine immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICI) in routine clinical practice.
Authors: Kozhevnikov Alexander , Mkrtumyan Ashot , Feoktistova Polina Serrgeevna , Filonenko Daria , Polshina Natalya , Volkova Ekaterina , Grechukhina Katerina , Bykonya Irina , Zhukova Lyudmila 
Published: June 2024

e14713 Background: Endocrine irAEs have been reported in association with various ICI and are characterized by their correlation with improved survival outcomes. A growing clinical comprehension of endocrine irAEs has facilitated the development of effective treatment strategies involving hormone replacement, which has been shown to enhance patients' quality of life. This study aims to evaluate outcomes in patients (pts) experiencing endocrine irAEs and identify predictive factors for their occurrence. Methods: This retrospective cohort study comprised 214 adult pts with solid malignant tumors who underwent ICI, either as monotherapy or in combination with other chemotherapeutic agents, at the SBIH Moscow Clinical Scientific and Practical Center named after A.S. Loginov of DHM. Results: Between June 2016 and January 2023, 214 pts were included in the study (46.3% female, 53.7% male). The median age was 62.6 years (range 32–91). At the data cut-off (1 February 2024) the median overall survival (OS) for the analyzed population was 34,5 months (95%CI 21,15-43,91). No significant difference in median OS was observed between pts with overall endocrine irAEs and those exhibiting specific manifestations, such as hypocortisolism and destructive diabetes mellitus. However, thyroid irAEs were associated with improved median OS: 27.5 months compared to 22.6 months in those without (p=0.037); RR=1.39 (95%CI 1.025-1.89; p=0.036). The grade of endocrine irAEs did not impact the survival benefit. A significant association was observed between age group and endocrine irAEs (Pearson’s χ2=9.92, p=0.019), with a left-skewed age distribution due to a higher proportion of participants aged 32–44 years among those developing endocrine irAEs. Pts with nodular goiter had a 2.91 times higher risk of developing thyroiditis (95%CI 1.03–8.25), although this did not reach statistical significance (p=0.067). Calcium channel blockers were associated with an increased risk of developing thyroid irAEs (RR=1.54, 95%CI 1.09–2.19; p=0.036). Antihistamine use was a robust predictor of hypothyroidism with a RR=1.68 (95%CI 1.05–2.7, p=0.04). Initial derived neutrophil-to-lymphocyte ratio (dNLR) ≥3 predict the development of endocrine irAEs (Pearson χ2=4.02; p=0.045) as well as dNLR>2.2 (Pearson χ2=4.22, p=0.04). Conclusions: Thyroid irAEs are correlated with improved OS. Predictors of endocrine irAEs may include young age (32-44 years), calcium channel blocker or antihistamine use, dNLR ≥3, or dNLR >2.2. Prospective trials are warranted to validate these findings.
Enhancing liquid biopsy potential: The impact of the R3CE 3D culture platform.
Authors: Wu Yi-Chun , Pegram Mark D. , Kuo Wen-Hung , Chou Hsu-Huan , Huang Yen-Jang , Chen Jia-Yang , Han Hao-Wei , Zong Yu , Chen Chia-Chun , Chang Ying-Chih 
Published: June 2024

e15032 Background: The ability to expand and preserve tumor cells ex vivo has been an important aspect of cancer research, offering insights into tumor biology and the advancement of personalized therapies. However, expanding rare tumor cells, such as circulating tumor cells (CTCs) and needle biopsies, remains challenging. Methods: We present the R3CE (Reproducible, Rapid, Rare Cell Expansion) 3D culture platform, a novel system that enhances the conventional tissue culture plate with a coating of polyelectrolyte multilayer. This approach can reliably cultivate various tumor specimens, including CTCs, needle biopsies, and surgical tissues, into tumor spheroids. Results: Our platform achieved over a 90% success rate (n = 305) in producing tumor spheroids with uniform size and preserved mutational profiles across diverse cancer types such as breast, lung, and colorectal cancers. In comparison to traditional tissue biopsies, liquid biopsies are less invasive and contain CTCs that offer a more comprehensive representation of heterogeneous tumor cell populations. We show that the proliferative capacity of cultured CTCs, rather than the initial CTC counts, have a strong correlation with lung adenocarcinoma prognosis (n = 124), highlighting the clinical potential of the R3CE platform (1). Furthermore, we have successfully employed cultured CTCs for drug screening for various cancers (breast cancer, cholangiocarcinoma, colon cancer, EMPD, gastric cancer, hepatoma, lung cancer, mucosal melanoma, pancreatic cancer, and urinary bladder cancer, n = 80), resulting in measurement of ex vivo response to chemotherapy and targeted drugs. For instance, R3CE-cultured CTCs have been used in predicting response to neoadjuvant chemotherapeutic drugs in breast cancer, as evidenced by an ROC curve analysis with an AUC of 0.963, 100% sensitivity, 87.5% specificity, P=0.02. Also in an exploratory analysis of immunotherapy efficacy, involving co-culture of R3CE-cultured CTCs (n = 6) and tumor tissue-derived organoids (n = 6) with immune cells such as CAR-T and autologous NK cells, has shown promising outcomes for selected cancers. Conclusions: The R3CE 3D culture platform represents a potentially transformative tool above and beyond CTC enumeration, significantly enhancing 1) the expansion of tumor cells ex vivo and, more importantly, informing phenotypic and genotypic characterization of CTCs, thereby holding promise for advancing cancer care and treatment efficacy. 1. Che et al., Lung Cancer, 2023; 178:198-205.
Development of a prediction model for lung metastasis by using postoperative circulating tumor DNA binding clinicopathological risk factors in patients with colorectal cancer.
Authors: Han Bohan , Li Weiyao , Li Jianxia , Hu Huabin , Zhang Jianwei , Xie Xiaoyu , Mo Qinli , Deng Yanhong 
Published: June 2024

e15035 Background: Lung metastasis is common in patients with colorectal cancer (CRC). However, diagnosing lung metastasis in CRC is challenging due to slow-growing pulmonary lesions. Circulating tumor DNA (ctDNA) testing provides a direct indication of the presence of minimal residual disease (MRD) which contributing to cancer recurrence. Yet, there are no reports on the potential indications of ctDNA for the site of metastasis. The objective of this study is to develop a predictive model for lung metastasis in CRC patients who have received adjuvant therapy by integrating ctDNA with clinicopathological factors. Methods: Two independent cohorts' series were evaluated including 299 patients from China as training cohort and 134 patients from Spain as validation cohort from 2012-2020. We specifically focused on the detection of ctDNA in these patients. We employed LASSO regression for optimal feature selection and built a predictive model by multivariable logistic regression. Results: In training cohort, 59/299(19.7%) patients have detectable ctDNA. In validation cohort, 24/134 (18.6%) patients have detectable ctDNA. Patients who tested ctDNA-positive had a significantly higher incidence of lung metastasis (33.9% vs. 11.2%, P<0.001) compared to ctDNA-negative patients. A predictive model for lung metastasis was developed by multivariable logistic regression analysis. The model incorporated factors such as ctDNA status, preoperative carcinoembryonic antigen (CEA) level, presence of cancerous nodes, and the mutation status of Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) in plasma. The lung metastasis prediction nomogram demonstrated a favorable ability to distinguish with a concordance index of 0.775 (95% CI: 0.706-0.775) during internal validation. The Hosmer-Lemeshow test, with p-value of 0.967, indicated that prediction nomogram model had a good fit. In addition, the prediction model of validation cohort demonstrated a discriminative performance with a concordance index of 0.724(95% CI: 0.698-0.724). Furthermore, the DCA (Decision Curve Analysis) and CIC (Clinical Impact Curve) in both cohorts indicated that the lung metastasis nomogram exhibited a favorable clinical net benefit. Finally, through multi-model comparison, it was found that the predictive performance of the model, which includes ctDNA and blood PIK3CA mutation status, was significantly superior to all clinical prediction models. Conclusions: A lung metastasis prediction nomogram was developed by integrating postoperative ctDNA and clinicopathological risk factors. The purpose of this nomogram is to assist clinicians in predicting the probability of lung metastasis in patients who have undergone surgery for CRC, with the aim to facilitate prompt intervention.
The NAVigate-HPV Registry: A comprehensive biomarker evidence base for HPV-driven cancers.
Authors: Roof Scott , Hanna Glenn J. , Rettig Eleni M. , Routman David M. , Holsinger Floyd Christopher , Kalman Noah , Bhatia Aarti K. , Patel Mihir R. , Jabalee Jamie , Yom Sue S. , Baliga Sujith , Raben Adam , Sims John , Kaczmar John M. , Bhayani Mihir K , Berger Barry , Del Vecchio Fitz Catherine 
Published: June 2024

e15045 Background: Human papillomavirus (HPV) is an oncogenic driver of several human cancers, including those of the anal canal, uterine cervix, and head and neck (predominantly oropharynx). Despite advancements in our understanding of HPV-related cancers, there remains an unmet need for a comprehensive biomarker-driven registry to establish correlations between biomarker detectability and clinicopathologic features in patients diagnosed and treated for HPV-driven cancers. To address this need, the NAVigate-HPV Registry has been established to systematically collect and analyze integrated biomarker and clinical data from many U.S. cancer centers. Methods: NavDx (Naveris, Inc.) is a clinically validated blood-based assay detecting circulating cell-free tumor tissue modified viral (TTMV)-HPV DNA. The NAVigate-HPV Registry is a web-based data platform based on a centrally IRB approved protocol. Participating investigators will include providers that order NavDx tests in the routine clinical care of their patients and agree to the terms and conditions for use of the registry. Eligible subjects will have or have had an HPV-driven cancer (with an initial focus on HPV-driven oropharynx cancer with confirmatory tissue testing) and have received one or more NavDx blood tests during routine clinical care. Clinical data and TTMV-HPV DNA scores will be collected at enrollment and defined intervals over five years or until death. Results: In the initial phase, the registry has enlisted participation and established a steering committee composed of a representative from each of 14 institutions. These institutions are geographically diverse centers ranging from community hospitals to clinics and academic medical facilities. An IRB protocol governing the registry will maintain ethical standards, ensuring compliance and ethical conduct throughout the registry process. Data extraction methods have been previously established to evaluate an initial cohort of 543 patients (Hanna GJ, Roof SA, et. al 2023). Conclusions: Naveris and collaborators have together successfully launched the NAVigate-HPV registry with the aim of creating a robust database linking tumor biomarker results from NavDx with clinical outcomes data for HPV-related cancers. The NAVigate-HPV database is expected to encompass more than 1,000 patients within 1 year and grow to > 5,000 patients within 5 years, serving as a powerful tool for precision cancer medicine in this patient cancer population. Establishing this registry will deepen insights into HPV-related cancers and advance diagnostic and therapeutic approaches to improve patient outcomes.
MSK-ACCESS powered with SOPHiA DDM: Performance analysis of a decentralized MSK-ACCESS solution.
Authors: Klemm Florian , De Martino Fabio , Mohammad Fuad , Wenger Yvan , Casanova-Murphy Jacklyn , Bowman Anita S. , Houck-Loomis Brian , Brannon Angela Rose , Berger Michael F. , Xu Zhenyu 
Published: June 2024

e15063 Background: Blood plasma cell-free DNA (cfDNA) testing of cancer patients allows for genomic profiling when tissue sampling is too invasive or of insufficient quality. This approach has demonstrated clinical utility to identify treatment targets, screen for resistance and monitor disease burden. MSK-ACCESS (Memorial Sloan Kettering – Analysis of Circulating cfDNA to Evaluate Somatic Status) is a validated, high sensitivity cfDNA assay employed at MSK to identify biologically actionable tumor alterations in clinical care. SOPHiA GENETICS is developing a decentralized solution of this assay that incorporates major features of MSK-ACCESS such as molecular barcoding, duplex-based variant calling, the inclusion of tumor-informed prior knowledge and identification of somatic alterations through the removal of both germline and clonal hematopoiesis (CH) variants. Here, we present the results of a performance study obtained during product development. Methods: A cohort of 24 plasma cfDNA and matched white blood cell (WBC) DNA samples were collected from patients with solid tumors and processed at MSK according to the validated standard operating procedures and bioinformatic analyses. In parallel, for the same set of materials libraries were constructed at SOPHiA GENETICS using the proprietary CUMIN molecular identifiers, captured with probes targeting the updated MSK-ACCESS v2 set of 146 genes and sequenced on an Illumina NovaSeq 6000. Variants were called using a duplex-aware approach by SOPHiA GENETICS and germline and CH variants were identified and filtered by paired cfDNA – WBC DNA analysis. Accuracy of the decentralized “MSK-ACCESS powered with SOPHiA DDM” solution was assessed through concordance to the orthogonal results obtained by MSK. Results: A total of 104 somatic SNV/Indels were detected with variant allele fractions (VAF) ranging from 0.1% to 97.0% with a median of 5 variants per sample. The positive percent agreement (PPA) for all variants above the limit of detection of the original MSK-ACCESS assay was 98.9% with 99.98% specificity. For the subset of prior-knowledge variants PPA was 95.6% down to 0.1% VAF. A total of additional 59 variants with ≤ 15% VAF were found both in cfDNA and WBC and assigned as CH-derived. Importantly, these occurred not only in CH-associated genes but also in common oncogenes such as BRCA1/2 and ERBB2, highlighting the utility of matched WBC analysis to correctly identify somatic variants. Conclusions: The results demonstrate that the decentralized “MSK-ACCESS powered with SOPHiA DDM” solution exhibits a high degree of agreement to the results achieved by MSK. Further studies will be conducted to expand the analytical performance evaluation.