bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human, phase I study of AK109, an anti-VEGFR2 antibody, in patients (pts) with advanced or metastatic solid tumors.
Authors: Xu Nong , Zheng Yulong , Zhong Haijun , Zhao Fuyou , Zhou Huan , Mao Chenyu , Lv Wangxia , Yuan Meiqin , Qian Jiong , Jiang Haiping , Wang Zishu , Xiao Cheng , Liu Ting , Liu Wei , Li Baiyong , Xia Yu 
Published: June 2022

3021 Background: AK109 is a fully-human monoclonal antibody that specifically binds to vascular endothelial growth factor receptor 2 (VEGFR2), thereby block vascular endothelial growth factor (VEGF)/VEGFR2 signaling pathway to inhibit angiogenesis, endothelial cell migration and proliferation of tumor cells. This phase I study is the first-in-human trial of AK109, which was designed to evaluate safety, tolerability of AK109, to determine the maximum tolerated dose (MTD), recommend phase II dose (RP2D) and to gain preliminary data on pharmacokinetics (PK), pharmacodynamics, immunogenicity and clinical activity for AK109 in pts with advanced or metastatic solid tumors resistant to standard therapies (NCT04547205). Methods: This open-label, multi-center, phase I study included a dose escalation phase (part 1) using a 3+3 design to determine MTD and potential RP2D (n = 36 max), with planned dosing of 2, 4, 8, 12 and 18 mg/kg q2w and 15mg q3w, followed by a dose expansion phase (part 2), at 2 potential RP2Ds in q2w or q3w respectively (n = 24-30). The PK characteristics, dose limiting toxicity (DLT), adverse events per CTCAE 5.0 and efficacy (ORR, DCR, DoR, PFS per RECIST v1.1, OS, etc.) of AK109 were evaluated. Results: As of December 30th, 2021 (median follow-up: 6.0 months), 40 pts (median age: 59.5 years) were enrolled, 16 pts in part 1 and 24 pts in part 2. No DLT was observed AK109 in part 1. Tumor types included gastric cancer (n = 9), non-small cell lung cancer (n = 8), hepatocellular carcinoma (n = 8), colorectal cancer (n = 5), pancreatic carcinoma (n = 2) and oesophagus cancer (n = 2), etc. Preliminary PK analyses showed systemic exposure in Cmax and AUClast increased dose proportionally at doses of 8 mg/kg and above, with a mean half-life of 8.5 to 10 days. 12mg/kg q2w and 15mg/kg q3w were selected as RP2Ds. Average exposure of AK109 was 6.9 cycles. Eight pts received over 10 cycles of AK109. Treatment related adverse events(TRAE) occurred in 38 (95%) of all pts. Grade 3 and 4 TRAE occurred in 16 (40%) of all pts. The most common TRAEs were proteinuria (22/40, 55%), hypertension (13/40, 32.5%) and AST increased (11/40, 27.5%). Serious adverse event (SAE) occurred in 11 (27.5%) pts, 2 (5%) of which were AK109 related. ORR and DCR were 10.0% and 62.5%, respectively. The median PFS of non-small cell lung cancer (n = 8) and gastric cancer (n = 9) were 5.6 months (95% CI, 1.3, NE) and 5.5 months (95% CI, 1.4, NE), respectively. Conclusions: AK109 showed manageable safety and promising anti-tumor activity. Two phase II studies of AK109 combined with AK104 (anti PD-1/CTLA-4 bi-specific antibody) are ongoing to evaluate the efficacy of AK109 combined with AK104 in patients with multiple solid tumors (NCT05142423, NCT04982276). Clinical trial information: NCT04547205.
Multicancer early detection with a spectroscopic liquid biopsy platform.
Authors: Baker Matthew , Cameron James Munro , Sala Alexandra , Antoniou Georgios , Butler Holly , Brennan Paul , Conn Justin , Connal Siobhan , Hegarty Mark , Palmer David , Smith Benjamin 
Published: June 2022

3034 Background: A rapid, low-cost, sensitive, multi-cancer early detection (MCED) test would be transformational in the diagnostics field. Earlier cancer detection and instigation of treatment can increase survival rates. An effective test must accurately identify the small proportion of patients with typically non-specific symptoms who actually have cancer. Such symptoms don’t easily segregate by organ system, necessitating a multi-cancer approach. Methods: In this large-scale study ( n = 2094 patients) we applied the Dxcover Cancer Liquid Biopsy to differentiate cancer against non-cancer, as well as organ specific tests to identify cancers of the brain, breast, colorectal, kidney, lung, ovary, pancreas, and prostate. The test uses Fourier transform infrared spectroscopy to analyze all macromolecules in a minute volume of patient serum, and machine learning to build a classifier of the resultant spectral profiles for calling the likelihood of cancer. Results: For the overall cancer classification, our model achieved 90% sensitivity with 61% specificity when tuned for sensitivity, with detection rates of 93% for stage I, 84% for stage II, 92% for stage III and 95% for stage IV. We also tuned for maximum sensitivity or specificity, whilst the other statistic was fixed above a minimum value of 45%. This resulted in 94% sensitivity with 47% specificity, and 94% specificity with 48% sensitivity, respectively. For organ specific cancer classifiers area under the curve values were calculated for all cancers: brain (0.90), breast (0.74), colorectal (0.91), kidney (0.91), lung (0.90), ovarian (0.85), pancreatic (0.81) and prostate (0.85). Conclusions: Cancer treatment is often more effective when given earlier and this low-cost strategy can facilitate the requisite earlier diagnosis. With further development, the Dxcover MCED test could have a significant impact on early detection of cancer, which is vital in the quest for improved survival and quality of life.
Test performance and clinical validity of circulating tumor DNA (ctDNA) in predicting relapse in solid tumors treated with curative intent therapy.
Authors: Mittal Abhenil , Molto Consolacion , Tamimi Faris , Di Iorio Massimo , Al-Showbaki Laith , Cescon David W. , Amir Eitan 
Published: June 2022

3036 Background: Studies have explored the prognostic value of ctDNA in predicting relapse in solid tumors treated with curative intent. These studies have evaluated ctDNA at specific ‘landmark’ timepoint or over numerous ‘surveillance’ time points. However, variable results have led to uncertainty about the clinical validity of this tool. Here, we quantify the predictive and discriminatory accuracy of ctDNA and explore sources of heterogeneity at both landmark and surveillance time points across different tumor sites. Methods: A search of MEDLINE (host: PubMed) identified studies evaluating ctDNA after curative intent therapy in solid tumors. Odds ratios (OR) for disease recurrence at both landmark and surveillance time points for each study were calculated and pooled in a meta-analysis using the Peto method. Pooled sensitivity and specificity weighted by individual study inverse variance were estimated and meta-regression utilizing linear regression weighted by inverse variance was performed to explore associations between patient and tumor characteristics and the OR for disease recurrence. Results: Of 23 studies identified; 16 (750 patients) and 14 studies (853 patients) reported on landmark and surveillance time points respectively. The median time from completion of definitive therapy to landmark testing was 51.5 days (range 3-120). The pooled OR for recurrence at landmark was 22.22 (95% CI 14.82-33.30) and at surveillance was 27.51 (95% CI 19.1-39.63). The pooled sensitivity for ctDNA at landmark and surveillance time points were 59.9% and 73.2%. The corresponding specificities were 90.9% and 86.6%. Subgroup results are shown in the table. There was lower predictive accuracy with the use of tumor site specific panels, in patients receiving adjuvant chemotherapy and in lung cancer. Meta-regression showed that longer time to landmark and higher number of surveillance blood draws were associated with higher prognostic accuracy, as was a history of smoking. Conclusions: Although ctDNA at both landmark and surveillance time points shows high prognostic accuracy, it has low sensitivity, suboptimal specificity and therefore weak discriminatory accuracy to predict relapse in patients with solid tumors treated with curative intent. Testing methodology, time points and patient populations need to be optimized before it can be incorporated routinely in clinical practice.[Table: see text]
Increasing targeted therapy options for patients with relapsed cancer with broader somatic gene panel analysis from the primary tumor: The Profiler02 randomized phase II trial.
Authors: Tredan Olivier , Pouessel Damien , Penel Nicolas , Chabaud Sylvie , Gomez-Roca Carlos A. , Pannier Diane , Brahmi Mehdi , Fabbro Michel , Garcia Marie-Eve , Larrieu-Ciron Delphine , Ray-Coquard Isabelle Laure , Viala Marie , Italiano Antoine , Cassier Philippe Alexandre , Dufresne Armelle , Attignon Valéry , Treilleux Isabelle , Viari Alain , Pérol David , Blay Jean-Yves 
Published: June 2022

3130 Background: PROFILER-02 is a multicenter randomized prospective study comparing the proportion of metastatic cancer patients (pts) with Targeted Agent (TA) recommendation provided by large NGS panel (FOne panel, 324 genes) vs home 87-gene NGS panel (CTRL) (PMID 30865223). Methods: Adult pts with advanced/metastatic cancer during 1st or 2nd line of therapy without known targetable gene alteration were eligible and randomized (1:1) to FOne vs CTRL panel. Both panels were performed for each patient. The randomization arm defined the first panel reviewed by dedicated Molecular Tumor Board (MTB) at disease progression while the 2nd panel remained blinded. The primary objective was the pts rate with at least one TA recommendation by the MTB using either FOne or CTRL panel. The study was designed in order to detect difference in proportions of 10% between the two panels. A sample size of 289 pts with both panels were requested to show this difference with an expected proportion of discordant pairs of 20% using a McNemar's test with 98% power and 5% two-sided significance level. Secondary endpoints included number of pts receiving at least one TA, progression free survival (PFS) and overall survival (OS). Results: From June 2017 to June 2019, among the 339 included pts 171 and 168 pts were randomized in FOne or CTRL panels’ first use, respectively. Median age was 57 years [19.0 - 85.0]; 54.9% were female. The median time from randomization to first MTB was 7.62 months [range 0.80 - 48.1]. Among the 339 pts, 147 pts (43.4%) had no TA recommendation, 108 pts (31.9%) had at least one TA recommendation according to both panels, 67 pts (19.8%) had one or more TA recommendation according to FOne panel only and 17 pts (5%) according to CTRL panel only (McNemar p < 0.001). At the time of the analysis, 51/339 (15%) pts started recommended treatment: 27 pts (8%) with TA recommendation from both panels, 21 pts (6.2%) from FOne only and 3 pts (0.3%) from CTRL only. Main initiated TA were PARP inh. (FOne n = 12; CTRL n = 9), PI3K/AKT/mTOR inh. (FOne n = 10; CTRL n = 9) and immunotherapy (ICI) (FOne n = 7; CTRL n = 0). Median PFS following first MTB were 3.2 months (95% CI 2.5-3.8) and 2.6 months (95% CI 2.0-3.8), median OS were 8.7 months (95% CI 6.6-10.8) and 8.4 months (95% CI 6.4-9.7), in the FOne and CTRL arm, respectively. Conclusions: Larger NGS panel including Tumor Mutational Burden increased the number of recommended options (TA and ICI), as well as the number of treatment initiation. Clinical trial information: NCT03163732.
Pan-cancer landscape of CD274 (PD-L1) and PDCD1LG2 (PD-L2) structural variations.
Authors: Hoskins Emily Louise , Samarodnitsky Eric , Wing Michele , Reeser Julie , Hopkins Julia , Murugesan Karthikeyan , Kuang Zheng , Stein Leah , Risch Zachary , Vella Raven , Abedola Serifat , Yu Lianbo , Paruchuri Anoosha , Huang Richard S.P. , Albacker Lee A. , Roychowdhury Sameek 
Published: June 2022

3133 Background: PD-1 receptor and PD-L1 ligand interactions are the target of immunotherapies across multiple tumor types. Established biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden, and PD-L1 immunohistochemistry. Structural variations in CD274 (PD-L1) and PDCD1LG2 (PD-L2) have been observed in cancer, but the comprehensive landscape is unknown. Here we describe the genomic landscape of CD274 and PDCD1LG2 structural variations, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. Methods: We analyzed sequencing data from 514 cancer cases with CD274 and PDCD1LG2 structural variations across 25 publications and data sources, including large pan-cancer sources: Foundation Medicine, Inc (FMI), The Cancer Genome Atlas (TCGA), and Oncology Research Information Exchange Network. To evaluate immune signature enrichment, we ran the software ImSig on gene expression data. We curated literature reporting clinical outcomes of patients harboring structural variations in CD274 and PDCD1LG2. Results: From 25 studies and datasets, we curated 514 cancer cases with structural variations in PD-L1 and PD-L2, including 158 duplications, 126 deletions, 97 inversions, 178 translocations, and 96 unclassified structural variations, totaling to 655 events. We observed breakpoint ‘hotspots’ in the 3’-untranslated regions (UTRs) of PD-L1 and PD-L2. Leveraging TCGA data, we observed, in CD274-rearranged tumors, significant upregulation in PD-L1 and PD-L2 expression and signatures for interferon signaling, macrophages, monocytes, T cells, and immune cell proliferation (each p < 0.001, compared to CD274 non-rearranged, copy neutral tumors). Furthermore, retrospective review of 12 studies that included patients with structural variations in CD274 or PDCD1LG2, including duplications, inversions and copy number amplifications, revealed a 73% (52/71) response rate to PD-1 immunotherapy with durable responses. Conclusions: Our evaluation of CD274 and PDCD1LG2 structural variations shows that the 3’-UTR is frequently affected and is associated with increased expression of ligands and immune signatures. Enriched interferon signaling in CD274-rearranged tumors is of particular interest, as interferon exposure is known to drive PD-L1 and PD-L2 expression. Retrospective evidence from curated studies suggests that these genomic alterations could identify candidates for PD-1 or PD-L1 immunotherapy. We expect that these findings will better define CD274 and PDCD1LG2 structural variations in cancer and support our pan-cancer prospective clinical trial to target these alterations.
Combining autophagy and immune characterizations to predict prognosis and therapeutic response in lung adenocarcinoma.
Authors: Li Qiaxuan , Zhou HaiYu 
Published: June 2022

3140 Background: As a key regulator of programmed cell death, autophagy is critical for maintaining the stability of the intracellular environment. Increasing evidences have found that the clinical importance of the interaction between autophagy and immune status in LUAD. Reliable prognostic signatures based on combination of autophagy and immune status have not been well-established. We aimed to explore the potential autophagy-immune-derived biomarkers to predict prognosis and therapeutic response in lung adenocarcinoma. Methods: Patients from GSE72094 dataset were randomized 7:3 to a training set or an internal validation set. Three independent cohorts, TCGA, GSE31210 and GSE37745, were used as the external verification. Unsupervised hierarchical clustering was used to identify the autophagy-associated and immune-associated molecular patterns for LUAD based on autophagy-genes and immune-genes. The LASSO analysis, univariate and multivariate cox regression analysis were performed to filtrate significant prognostic autophagy-immune-based genes, followed with model construction and patient stratification. Tumor immune microenvironment and functional pathways were investigated. The potential therapeutic responses were explored by GDSC database, TIDE algorithm, and immunotherapy clinical cohorts. Results: We found that autophagy cluster A had the better survival prognosis (p < 0.001) and high immune status (p < 0.001) was identified as favorable factors for patients’ overall survival. We merged autophagy and immune subtype into a two-dimensional index to characterize the combined prognostic classifier 535 genes were defined as autophagy-immune-related DEGs. Four genes (C4BPA, CD300LG, CD96, and S100P) were identified to construct the autophagy-immune-related prognostic risk model. Survival analysis and receiver operating characteristic curve showed significant prognostic efficacy. Through ssGSEA and CIBERSORT analysis, the majority of immune infiltrating cells were shown to be enriched in the low-risk group. What’s more, the expression of crucial immune checkpoint molecules, such as PD-1, PD-L1 and CTLA-4, was observed highest in low-risk group (p < 0.001). TIDE and immunotherapy clinical cohorts’ analysis showed that low-risk group was predicted with more potential responders to immunotherapy. In addition, there are different patterns of autophagy between low- and high- risk patients. GO, KEGG and GSEA function analysis focus on cell cycle, MAPK, apoptosis, MTORC1 and selective autophagy pathway. Docetaxel, rapamycin and sorafenib may be the potential drugs candidate in high-risk group (p < 0.01). Conclusions: In summary, the autophagy-immune-based gene signature represents a promising tool for risk stratification tool in lung adenocarcinoma, which can regard individualized treatment and follow-up scheduling for patients.
Construction of a near-term predictive model for irAEs induced by PD-1 inhibitors.
Authors: Zhang Ying , Zhao Jun , Hu Wenqing , Du Yunyi , Zhang Xiaoling , Ma Ning , Yang Wei , Yang Bo , Gao Yangjun , Wang Yu , Liu Min , Wang Mei , Wang Hui , Feng Tingting , Cai Linlin , Li Weiling , Lu Jing 
Published: June 2022

3147 Background: Immune checkpoint inhibitors have opened a new chapter in cancer therapy, but the incidence of irAEs caused by them is high, and severe irAEs can be fatal. The current research on irAEs is almost focused on early predictions, and there is a lack of near-term predictions (the cycle before the occurrence of irAEs). Absolute eosinophil count (EO#) has been reported to be associated with immune-related pneumonia, but its association with other systemic irAEs requires further exploration. The aim of this study was to explore the near-term predictive value of neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR), and EO# for PD-1 inhibitor-induced irAEs. Methods: The data are from tumor patients who received PD-1 inhibitor therapy in our department from July 2019 to May 2021. A total of 146 cases were included, of which 56 had irAEs. The data of NLR, PLR and EO# in the cycle before the occurrence of irAEs (the median number of cycles was the second cycle) were collected, and the data of the second cycle was used as the control for patients without irAEs group. Logistic method was used to analyze the correlation between NLR, PLR and EO# and irAEs, and a predictive model was constructed. The sensitivity and specificity of the model were evaluated by ROC curve. This study was registered on Chinese Clinical Trail Registry (ChiCTR2100049849). Results: A total of 146 tumor patients were included, of which 56 developed at least one irAEs. Grade 1-2 irAEs occurred in 39 cases, grade 3-4 in 12 cases (including cardiac, liver, lung and skin toxicity), grade 5 in 2 cases(including cardiac and lung toxicity), and ungraded in 3 cases. The data of the cycle before the occurrence of irAEs were analyzed. Univariate analysis showed that NLR (odds ratio [OR], 1.4, p< 0.05) and EO# (OR, 12.6, p< 0.05) were associated with irAEs, and multivariate analysis suggested NLR (OR, 1.7, p< 0.001) and EO# (OR, 20.4, p< 0.05) were independent risk factors for irAEs. The prediction model composed of NLR, PLR and EO# had a correct rate of 76.7% (AUC = 0.752) in predicting the occurrence of irAEs in the near-term cycle, with a sensitivity of 51.8% and a specificity of 92.2%; the correct rate of predicting irAEs of grade 3 and above was as high as 91.9% (AUC = 0.778), the sensitivity was 14.3% and the specificity was 99.2%. Conclusions: The model composed of NLR, PLR and EO# may predict the occurrence of irAEs in the near-term cycle, especially the prediction of irAEs above grade 3, which can provide early warning for the occurrence of irAEs. Clinical trial information: ChiCTR2100049849.
Combination treatment of radiofrequency ablation and peptide neoantigen vaccination: Promising modality for future cancer immunotherapy.
Authors: Fang Yong , Shou Jiawei , Mo Fan , Zhang Shanshan , Lu Lantian , Han Ning , Liu Liang , Qiu Min , Li Hongsen , Han Weidong , Ma Dongying , Guo Xiaojie , Guo Qianpeng , Huang Qinxue , Zhang Xiaomeng , Ye Shengli , Pan Hongming , Chen Shuqing 
Published: June 2022

3151 Background: We previously reported the safety and immunogenicity of a personalized neoantigen-based peptide vaccine, iNeo-Vac-P01, in patients with a variety of cancer types. The current study investigated the synergistic effects between radiofrequency ablation (RFA) and neoantigen vaccination in cancer patients and tumor-bearing mice. Methods: 28 cancer patients were enrolled in this study, including 10 patients who had received RFA treatment within 6 months before scheduled for vaccination, and 18 patients who had not. Individualized neoantigen peptide vaccines were designed, manufactured, and delivered for all patients, followed by subcutaneous administration of GM-CSF as an adjuvant. Mouse models were used to validate the synergistic efficacy of combination treatment of RFA and neoantigen vaccination. Results: Longer median progression free survival (mPFS) and median overall survival (mOS) were observed in patients receiving RFA prior to vaccines compared to patients only receiving vaccines (4.42 and 20.18 months vs. 2.82 and 10.94 months). Ex vivo ELISpot assay showed that patients who received both had stronger IFN-γ responses against patient-specific neoantigens at baseline and post vaccination. Mice receiving RFA together with vaccine displayed higher antitumor immune responses than mice receiving single modality; addition of anti-PD-1 further enhanced the antitumor response. Conclusions: Neoantigen vaccination after RFA treatment led to an overall increase in clinical response and immune response among patients of different cancer types. Combination treatment of both modalities in mice further validated their synergistic antitumor potentials, which could be further enhanced by the addition of anti-PD-1. The mechanisms of their synergies require further investigation. Clinical trial information: NCT03662815.