bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal and personalized detection of circulating tumor DNA (ctDNA) for monitoring efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma (HCC).
Authors: Hsu Chih-Hung , Lu Shan , Abbas Alex , Guan Yinghui , Zhu Andrew X. , Aleshin Alexey , Lee Kyung-Hun , Lee Michael Sangmin , Mahipal Amit , Ryoo Baek-Yeol , Ding Beiying , Spahn Jessica , Verret Wendy , He Aiwu Ruth , Wang Yulei 
Published: May 2020

3531 Background: ctDNA has emerged as a promising biomarker for noninvasive monitoring of treatment response and disease progression in many tumor types. However, the clinical use of ctDNA in patients with HCC has not been established. Here, we evaluated longitudinal and personalized detection of ctDNA for monitoring the treatment response to atezolizumab (atezo) + bevacizumab (bev) in patients with unresectable HCC not previously treated with systemic therapy. Methods: A subset (n = 48) of 104 patients with HCC who enrolled in Arm A of GO30140 (NCT02715531; Phase 1b) and received atezo + bev treatment were included in this study. These patients had 10 CR, 11 PR, 12 SD and 15 PD per IRF-assessed RECIST 1.1. Serial plasma samples were collected at baseline (Cycle [C]1 Day [D]1), during treatment (C2D1, C4D1) and at disease progression. Somatic mutations in individual tumors were identified via whole exome sequencing of archival tumor tissues or fresh biopsies collected before treatment. Personalized ctDNA assays (Signatera 16-plex multiplex PCR next-generation sequencing assay) specific to each patient’s tumor mutational signatures were successfully designed for 47 of 48 patients. Results: At C1D1, a median of 25.7 ng of cell-free DNA was extracted from 2-mL plasma samples. ctDNA was detected in 45 of 47 patients (96%), with a median of 70.6 mean tumor molecules/mL of plasma (MTM/mL) and a median of 1.8% mean variant allele frequency (mean VAF) in plasma. Higher ctDNA levels detected at C1D1 appeared to be associated with increased tumor burden ( P < 0.03). Dynamic changes in ctDNA levels post-treatment were associated with response at C4D1. ctDNA status changed from positive at baseline to negative in 7 of 10 CR (70%), 3 of 11 PR (27%), 1 of 11 SD (9%) and 0 of 11 PD (0%) patients. Longer PFS was observed in patients whose ctDNA became undetectable post-treatment. The median PFS in patients with ctDNA present vs cleared at C4D1 was 6.5 months and not reached, respectively (HR, 12 [1.7-93], log-rank P < 0.00029). Conclusions: Our study showed that Signatera, a personalized and tumor-informed ctDNA assay, could be used as a sensitive method for detecting ctDNA in patients with unresectable HCC. More importantly, our results illustrate the promise of ctDNA as an emerging biomarker that may potentially help to monitor treatment responses and disease progression in patients with HCC.
Comprehensive genomic profiling of 216 Chinese patients with renal cell carcinoma.
Authors: Zhang Congwang , Yang Chunhe , Chen Jie , Xu Xiaohong , Wang Lingyu , Lin Rongbo , Yang Yining 
Published: May 2020

3532 Background: Renal cell carcinoma (RCC), a global public health problem, has exhibited a gradual rise in incidence. Unfortunately, the scarcity of effective biomarkers in the clinical became a major limitation of the progress of biological therapies. Therefore, it is imperative to accurately comprehend RCC genomic profiling for exploring its clinical treatment strategies. Methods: Formalin Fixed Paraffin Embedded (FFPE) tumor and matched blood samples of 216 Chinese RCC patients were obtained for next-generation sequencing (NGS)-based 620 cancer genes panel assay and RCC genomic profiling was evaluated. Results: In our Chinese RCC cohort, multiple histological subtypes, encompassing clear cell (96/216, 44.44%), papillary (14/216, 6.48%), chromophobe (2/216, 0.93%), and undefined subtypes (104/216, 48.15%) were included. The top ranked genomic alterations in Chinese RCC patients were VHL (45.83%), PBRM1 (17.1%), BAP1(13.89%), TP53 (10.65%), SETD2 (9.29%), MTOR (8.67%), ARID1A (5.6%), PTEN (5.09%). Interestingly, BAP1, PBRM1 were co-mutated with VHL, and MET, NF2 were mutually exclusive with VHL (all p < 0.05). Of these patients, 87.9% (190/216) of RCC patients had at least one genomic alteration, indicating the potential clinical benefits of targeted therapies. Out of 15 most common canonical pathways, potentially targetable genomic alterations were mainly identified in HIF (45.83%), chromatin remodeling (42.59%), PI3K/AKT (24.07%), DNA damage response (19.44%), RTK-RAS (18.06%), TP53 (15.74%), NOTCH (9.72%), Hippo (9.72%), and WNT (5.56%) pathway. Additionally, HIF pathway was commonly co-altered with chromatin remodeling pathway, and WNT and NOTCH pathways were significantly co-altered with TP53 pathway. Rare mutation types such as CDKN2A-DMRTA1 and HOOK1-ALK were also detected. Across samples, the median TMB was 2.2 (0-18.6) mutations/Mb. Only 2 Chinese RCC patients had TMB-high (> 10 mutations/Mb). Conclusions: Our results displayed the landscape of genomic alterations in 216 Chinese RCC patients. The genomic alterations identified in our study may provide an opportunity to discover potential strategies for targeted and immunotherapy in RCC. Future studies should account for these genomic alterations.
The predictive role of plasma mutant allele fraction to antiangiogenic drugs in patients with mCRC: An expanded analysis of surrogate biomarkers of response to first-line treatment with bevacizumab.
Authors: Martini Giulia , Elez Elena , Mancuso Francesco M , Gomez Maria Auxiliadora , Caratu Ginevra , Matito Judit , Argiles Guillem , Mulet Nuria , Baraibar Iosune , Ros Javier , Garcia Ariadna , Comas Raquel , Ligero Marta , Santos Cristina , Nuciforo Paolo , Dienstmann Rodrigo , Tabernero Josep , Aranda Enrique , Perez-Lopez Raquel , Vivancos Ana 
Published: May 2020

3541 Background: So far, no biomarkers of response to anti-angiogenic drugs are available in colorectal cancer (CRC) treatment. Liquid biopsy tracks dynamic mutational changes in CRC patients (pts). RAS mutant allele fraction in plasma (plMAF) is an independent prognostic marker in metastatic CRC (mCRC). We explored the predictive value of plMAF in RAS mutant pts treated in 1st line with chemotherapy +/- bevacizumab (bev). Methods: A multicentric prospective/retrospective analysis was conducted. We collected data from 226 mCRC pts and selected the subset not eligible for metastasis resection with basal plMAF sample evaluable for RAS mutant MAF quantification with digital PCR (BEAMing). Pts were stratified as high (≥ 5.8%) or low ( < 5.8%) plMAF. We investigated associations between clinicopathological variables and progression-free survival (PFS) stratified by plMAF RAS levels using Cox regression models and survival data were calculated by Kaplan-Meier method. Computational analysis of baseline CT scan data extracted 93 radiomics features of all the lesions per patient including 1) 1st class from density histogram distribution and texture analysis by 2) 2nd order and 3) higher order feature classes. The radiomic features distribution between pts with high and low pIMAF was assessed with Student’s t-test analysis. Results: From October 17 to May 19, 63 basal plasma samples were analysed with BEAMing. 42 pts (67.7%) were classified as high and 21 pts (32,3%) as low plMAF. In high plMAF subgroup, a statistically significant longer PFS favouring FOLFOX+bev was observed, compared to FOLFOX alone (10.7 vs 6.9 mts; HR: 0.30; p = 0.002). In low RAS plMAF subgroup, no differences in terms of PFS were observed in either arm (8.9 vs 8.7 mts; HR: 0.7; p = 0.6). Multivariate PFS model showed no association between RAS plMAF and clinicopathological variables, except for high RAS plMAF and treatment benefit with FOLFOX+bev. The CT-radiomics signature, that may translate tumor vascularization, differentiated patients with high vs low pIMAF (p = 0.002). 58 patients (92%) had similar radiomic score; 5 patients with high plMAF (8%) presented very heterogeneous radiomic score distribution. Conclusions: Tumor-borne RAS plMAFs may constitute a potential predictive biomarker of efficacy for anti-angiogenic drugs in mCRC. Next steps will include the identification of -histological, transcriptomic and radiomic- surrogate biomarkers of response that reflect tumor irrigational status.
First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/refractory solid tumors.
Authors: Xu Rui-hua , Qiu Miao-Zhen , Zhang Yang , Wei Xiao-Li , Hu Chaohong 
Published: May 2020

3550 Background: MRG003 is a novel antibody drug conjugate (ADC) composed of a fully human anti-EGFR IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG003 is presently being tested in an ongoing phase I study for safety, pharmacokinetics, and preliminary antitumor activity in patients (pts) with solid tumors (CTR20180310). Methods: In the phase I dose escalation study of a traditional (3+3) design, pts with relapsed or refractory cancers received single agent MRG003 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. The starting dose of MRG003 is 0.1 mg/kg, followed by 0.3, 0.6, 1.0, 1.5, 2.0, 2.5, and 3.0 mg/kg. Observations included adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity which is assessed every two cycles. Results: A total of twenty-two pts with colorectal (CRC, n = 15), nasopharyngeal (NPC, n = 3), head and neck (H&N, n = 2), esophageal (EC, n = 1), and duodenal (DC, n = 1) cancer were enrolled in the dose escalation. The median age of pts was 56.5 years. The MTD identified was 2.5 mg/kg. Commonly observed adverse events were anemia (50%), AST increase (41%), decreased appetite (41%), rash (36%), pruritus (36%), asthenia (36%), and proteinuria (32%). Majority of AEs were mild to moderate in severity. EGFR expression in patients’ tumor samples was determined retrospectively by a validated IHC method in a central laboratory. Nine out of 22 pts tested were EGFR positive. Among these 9 EGFR positive pts, one with NPC in the 2.5 mg/kg cohort had partial response, four had stable disease (one with H&N in the 1.5 mg/kg, one each with NPC and H&N in the 2.0 mg/kg, and one with EC in the 2.5 mg/kg cohorts). The disease control rate (DCR) at doses ≥1.5 mg/kg was 100% for the EGFR positive pts. Conclusions: The dose escalation study of MRG003 showed manageable safety profiles and encouraging preliminary antitumor activity in pts with EGFR-positive solid tumors. MRG003 is currently being evaluated as a single agent in phase I dose expansion cohorts to further assess safety, PK, and antitumor activity. Clinical trial information: CTR20180310 .
First-in-human phase I study of ALT-P7, a HER2-targeting antibody-drug conjugate in patients with HER2-positive advanced breast cancer.
Authors: Park Yeon Hee , Ahn Hee Kyung , Kim Ji-Yeon , Ahn Jin Seok , Im Young-Hyuck , Kim Seol-Hee , Lee Sunbae , CHUNG HYE-SHIN , Park Soon Jae 
Published: May 2020

3551 Background: ALT-P7 is an antibody-drug conjugate, in which two molecules of monomethyl auristatin E (MMAE) are site-specifically conjugated to a cysteine-containing peptide motif of trastuzumab variant. This is the first-in-human study evaluating safety and pharmacokinetics of ALT-P7 in patients with HER2-positive advanced breast cancer. Methods: This was an open label, 3+3 dose-escalation phase 1 trial. Eligible patients were with HER2-positive advanced breast cancer progressive to at least two kinds of prior anti-HER2 treatment. ALT-P7 at doses from 0.3mg/kg to 4.8mg/kg were intravenously administered once every 3 weeks. Dose limiting toxicities were evaluated over the first cycle of 21 days. Primary objective was to define the maximum tolerated dose. Results: ALT-P7 were administered in 27 patients (n=4 at 0.3mg/kg, n=3 at each of 0.6, 1.2, 2.4, 3.6, 4.2, 4.5 mg/kg, n=5 at 4.8mg/kg) between Jan 2018 and Feb 2020. The median number of previous line of systemic therapy was six, including median four prior anti-HER2 agents. The most common grade (G) 3/4 adverse event (AE) was neutropenia (n=4). The other common drug-related AEs of all grade were myalgia (n=9), fatigue (n=7), sensory neuropathy (n=6), alopecia (n=6), pruritus (n=6), and neutropenia (n=6). Dose limiting toxicities(DLTs) were observed in three patients at 4.8mg/kg (G4 febrile neutropenia, G4 thrombocytopenia, G4 hyperbilirubinemia, G3 myalgia, G4 hyponatremia). No DLTs have been observed up to 4.2mg/kg, and safety evaluation at 4.5mg/kg is currently ongoing. Toxicokinetic analysis for total antibody, drug-conjugated antibody, and free payload suggested that there were no accumulation of ALT-P7 upon repeated injection. In 22 patients with response evaluation, disease control rate at 6 weeks of ALT-P7 treatment was 77.3%(17/22) and partial response was achieved in two out of fifteen patients with measurable lesion. The median PFS at doses from 2.4 to 4.8mg/kg was 6.2 months (95% CI 2.5-9.9 months). Conclusions: ALT-P7 was well tolerated to a dose of 4.2mg/kg in heavily pretreated HER2-positive advanced breast cancer. DLTs were observed at 4.8mg/kg, and 4.5mg/kg is under evaluation. The observed clinical activity warrants further evaluation in a phase 2 trial. Clinical trial information: NCT03281824. Clinical trial information: NCT03281824 .
Anaplastic lymphoma kinase (ALK) partners identified by next-generation sequencing in Chinese patients with solid tumors.
Authors: Yang Sheng , Gong Fuyu , Wang Guoqiang , He Xiaohui 
Published: May 2020

3555 Background: Anaplastic lymphoma kinase (ALK) rearrangement is a validated therapeutic driver gene in non-small cell lung cancer (NSCLC). More than 30 different fusion partner genes of ALK in NSCLC have been reportedand most of these ALK fusions respond well to ALK inhibitors crizotinib. With the development of next-generation sequencing (NGS), more novel partners for ALK rearrangement have been identified. Here, we aimed to report the landscape of ALK rearrangement in Chinese patients with solid tumors. Methods: Tissue or blood samples were subjected to NGS in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for ALK arrangement. Results: In total, we profiled more than 40,000 patients, among which 72 cases with 52 ALK fusion partner, harboring 17 reported partners and 35 novel partners. The average ALK rearrangement patients' age was 53 years (range, 17-76 years). Among all the ALK fusion cases (n = 72), lung cancer were the largest proportion with 77.8% (n = 56), colorectal cancer accounted for, 5.5% (n = 4), liver cancer accounted for 4.2% (n = 3), biliary cancer, melanoma, carcinosarcoma and inflammatory myofibroblastic tumor accounted for 2.8% (n = 2) respectively, and only one case (n = 1) was malignant peritoneal mesothelioma. The most common ALK fusion partners were KIF5B (n = 6), DCTN1 (n = 5) and STRN (n = 5). In 38 cases, 35 novel ALK fusion partners were discovered. The novel CLIP4-ALK, EHBP1-ALK, PLB1-ALK occurred twice in 6 patients, which were two lung cancer patients with CLIP4-ALK fusion, two lung cancer patients with PLB1-ALK fusion, one hepatic cellular cancer patients with EHBP1-ALK, and one melanoma patients with EHBP1-ALK. There were two special lung cancer cases with two ALK fusions. One case detected the novel LRIG1-ALK fusion and novel PLB1-ALK fusion, the other case detected novel GLI3-ALK fusion and reported HIP1-ALK fusion. Conclusions: Novel ALK fusions are detected in patients with not only NSCLC but also other solid tumors. NGS fusion assay is an optional method for screening novel fusions.
Comparison of the clinical interpretation of high-dimensional molecular data by two molecular tumor boards.
Authors: Rieke Damian Tobias , de Bortoli Till , Horak Peter , Lamping Mario , Jelas Ivan , Rüter Gina , Berger Johannes , Glimm Hanno , Brors Benedikt , Stenzinger Albrecht , Fröhling Stefan , Keilholz Ulrich 
Published: May 2020

3564 Background: The clinical interpretation of molecular data is a bottleneck of precision oncology. High-dimensional molecular data, such as RNA sequencing (RNA-seq) and whole-exome sequencing (WES), will likely increase the complexity of clinical interpretation. We compared the recommendations by two molecular tumor boards (MTBs) that independently interpreted the same high-dimensional molecular profiles. Methods: Patients with advanced solid tumors, no available standard therapy, an ECOG performance status of 0-1, and available fresh-frozen tissue underwent WES of tumor tissue and normal blood as well as RNA-seq of tumor tissue within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program of the German Cancer Consortium (DKTK). Data from 46 patients (WES and RNA-seq, n = 41; WES alone, n = 5) were independently discussed by two MTBs. Treatment recommendations were compared with regard to levels of evidence, therapeutic baskets, and types of biomarkers. Results: A total of 51,610 aberrations (median, 393 per patient) were considered for clinical interpretation (34,314 mutations/single-nucleotide variants, 7,115 mRNA expression changes, 6,144 DNA copy number variations, 4,037 gene fusions). 110 and 132 treatment options were identified by the two MTBs, respectively, with an overall agreement rate of 44.1%. The highest agreement rates were identified for treatment options based on clinical levels of evidence (Level 1, 60%; Level 2, 49.6%) and for poly(ADP-ribose)-polymerase inhibition (57.1%). The lowest agreement rates were identified when MTBs opted for traditional chemotherapy (0%), combination therapies (6.9%), therapies based on preclinical levels of evidence (Level 3, 35.9%; Level 4, 32%), and MAPK inhibition (35%). Similar agreement rates, ranging from 39% (gene fusions) to 54% (loss of heterozygosity), were observed for different types of biomarkers. Conclusions: Reproducible, evidence-based annotation of high-dimensional molecular data is feasible. Our experience provides a basis for ongoing harmonization and standardization efforts within the MTBs of the DKTK.
Ultrasensitive multiplex detection of structural rearrangements in ALK, RET, ROS1 and PD-L1 using a comprehensive next-generation sequencing assay.
Authors: Ngeow Kao Chin , Choudhury Yukti , Tan Kian-Hin , Pek Michelle , Ng Kim-Tien , Lim Soon Thye , Lim Jing Quan , Huang Dachuan , Ong Choon Kiat , Tan Min-Han 
Published: May 2020

3572 Background: Oncogenic structural rearrangements (SR) in ALK, RET and ROS1 are well-described in lung cancer, and confer sensitivity to targeted therapy. SR disrupting the 3’UTR of PD-L1 gene have been reported in multiple cancer types and can potentially predict response to checkpoint immunotherapy. An amplicon-based next-generation sequencing (NGS) platform technology (AmpliMARK), previously optimized for detection of single nucleotide variations (SNVs), microsatellite instability and viral DNA, was extended to the multiplex detection of SR in ALK, RET, ROS1 and PD-L1 in cell-free DNA (cfDNA) and tumor tissue DNA. Methods: A hybrid primer-extension and adapter-ligation based method allowing detection of SR in a fusion-partner agnostic manner was utilized for multiplex target capture of genomic regions of ALK, RET, ROS1 and PD-L1 SR. Analytical validation was performed using admixtures of fragmented genomic DNA from an ALK SR-positive cell line, commercial standards containing RET and ROS1 SR, and synthetic PD-L1 SR gene constructs. Clinical performance was assessed in cfDNA samples from lung cancer patients and tumor tissue DNA samples from natural killer(NK)/T-cell lymphoma patients. Results: Detection of SR could be achieved to an allele frequency detection limit of 0.5% with sensitivity of 89.5% and specificity of 100% in admixture samples mimicking cfDNA. In an unselected series of 374 lung cancer cases, actionable SR for ALK, RET and ROS1 were detected in cfDNA of 9 samples, for an overall detection rate of 2.4%, and 1.8% (3 out of 168) when restricted to treatment-naive lung cancer cases only. In 29 NK/T-cell lymphoma tumor tissue samples, 9 samples were positive for PD-L1 SR, which were orthogonally confirmed by whole-genome sequencing, targeted sequencing or Sanger sequencing for a concordance rate of 100% across all samples. For 1 NK/T-cell lymphoma tumor tissue sample where matched plasma was available, the same PD-L1 SR was also detected in cfDNA. Conclusions: We have demonstrated and validated a comprehensive amplicon-based NGS assay for ultrasensitive multiplex detection of structural rearrangements in ALK, RET, ROS1 and PD-L1 across both cfDNA and tumor tissue DNA in analytical and clinical contexts. Ongoing studies will further evaluate the performance and utility of this assay across a larger number of clinical samples for the detection of these SR as well as additional cancer-associated SR involving NTRK1/2/3, FGFR2/3 and TMPRSS2.
A phase Ib study of oral Chk1 inhibitor LY2880070 as monotherapy in patients with advanced or metastatic cancer.
Authors: Miller Wilson H. , Chu Quincy S. , Bouganim Nathaniel , Jonker Derek J. , Batist Gerald , Buhlaiga Najwa J , Lheureux Stephanie , Spratlin Jennifer L. , Alcindor Thierry , Smith Patricia S , Owen Joel , Zaknoen Sara L. , Stille John R. , Fortier Caroline , Vincett Darcy , Oza Amit M. 
Published: May 2020

3579 Background: LY2880070 (LY) is an orally-administered, selective adenosine triphosphate-competitive inhibitor of checkpoint kinase 1 (Chk1). LY blocks the checkpoint response, and Chk1 inhibition results in mitotic catastrophe to produce apoptosis. Methods: This 2-part, open-label multi-center study explores the safety, pharmacokinetics (PK) and anti-tumor activity of LY in patients with advanced or metastatic cancers. The primary objective of this study was to determine the maximum tolerated dose (MTD) for multiple escalating oral doses of LY. Secondary objectives were to: 1) Characterize the dose-limiting toxicities (DLTs) and overall safety profile for LY; 2) Evaluate the PK of LY; and 3) Evaluate the anti-tumor activity of LY. Patients received LY orally in 21-day cycles in two treatment arms: 1) A multiple ascending dose (MAD) arm in patients with normal/intermediate CYP2D6 metabolism; or 2) An arm with LY administered as monotherapy to CYP2D6 poor metabolizers. Results: The MTD in normal/intermediate CYP2D6 metabolizers was 200 mg BID daily. A dose of 400 mg QD was not tolerated even with the use of anti-emetics. However, BID administration (same total daily dose) made LY tolerable. Dose-limiting toxicities were predominantly vomiting, nausea, and fatigue, and appeared to be correlated with Cmax. The mean half-life was 5.35 (+/- 2.3) hours. BID dosing provided maintenance of the AUC (3271.4 h∙ng/mL 200 mg BID vs 3377.9 h∙ng/mL 400 mg QD) while lowering Cmax (350.0 ng/mL 200 mg BID vs 691.9 ng/mL 400 mg QD) and increasing Cmin, compared to QD dosing of the same total daily dose. Importantly, BID administration of 200 mg LY resulted in a median Cmin at steady-state that remains above the IC80 for 12 h/day and above the IC50 for 24 h/day. Five patients had a best response of SD for a duration of ≥ 6 cycles. Conclusions: LY was tolerated in a daily BID schedule. The toxicity profile can be modulated by changing the dosing frequency from QD to BID while administering the same daily dose. LY may be a potential combination therapy with DNA damaging agents. Study #: NCT02632448 . This study is sponsored by Esperas Pharma Inc., 1255 boul. Robert-Bourassa #1610, Montreal, Qc, H3B 3X3. Clinical trial information: NCT02632448 .