bluuebunny/crossref_metadata_2025_split huggingface dataset:
Performance characteristics of a tissue-agnostic genome-wide methylome enrichment MRD assay for head and neck malignancies.
Authors: Liu Geoffrey , Pienkowski Martha , Huang Shao Hui , Ailles Laurie , Rey-McIntyre Katrina , Min Jun , Wang Yarong , Burgener Justin , Jones Joshua T. , Brown Ben , Zhang Junjun , Hall Owen , Shen Shu Yi , Provance Jeremy B. , Sosa Eduardo , Zhang Jing , Licon Abel , Allen Brian , Hartman Anne-Renee , De Carvalho Daniel D. 
Published: June 2024

3009 Background: Plasma cell-free DNA (cfDNA) tests have emerged as a promising approach for cancer management. cfDNA methylome approaches are well-suited for molecular residual disease (MRD) detection. Here we present data using a tissue-agnostic, genome-wide methylome enrichment platform based on cell-free methylated DNA immunoprecipitation and high throughput sequencing (cfMEDIP-seq) in head and neck cancer (HNC) to predict relapse for purposes of guiding adjuvant therapy after completion of curative-intent treatment and to detect early relapse. Methods: The cohort is comprised of biobanked samples from individuals diagnosed with stage I-IVB human papillomavirus (HPV)-negative and HPV-positive HNC with longitudinal data collection and sampling. The full cohort includes 325 unique patients with 1,155 samples. Samples were split into distinct sets to train and test a classifier consisting of differentially methylated regions. Blood collection time points include at diagnosis, and approximately 3 (landmark), 12 and 24 months after curative intent treatment. 5-10 ng of cfDNA isolated from each plasma sample was used for cfMEDIP-seq. MRD signals were quantified from average normalized counts across informative methylated regions and binarized into a positive (above the threshold) and negative groups. Recurrence-free survival (RFS) was compared for patients who tested positive to those who tested negative at 3 months post-curative treatment (i.e., landmark timepoint) and longitudinally. Results: A total of 196 post-treatment samples from 80 unique patients [stage I (35%), II (15%), III (24%), IV (26%)] were analyzed and correlated with recurrence, in this interim training result. At the landmark timepoint, patients who tested positive showed significantly worse RFS than those who tested negative (Hazard ratio (HR) 9.69; 95% CI, 4.39-21.4, P<0.001). Incorporating serial longitudinal samples, recurrence-free survival was worse in patients who tested positive compared to those that tested negative (HR 14.52; 95% CI, 5.78-36.46, P<0.001). Conclusions: Interim analysis demonstrates that MRD detection with a tissue-agnostic, genome-wide methylome enrichment platform in HNC patients after curative intent treatment correlates strongly with RFS with hazard ratios consistent with tumor-informed assays previously described. Updated analyses from the cohort will be presented at the meeting.
Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.
Authors: Halperin Daniel M. , Morris Michael , Ulaner Gary A. , Strosberg Jonathan R. , Mehr Samuel H. , Li Daneng , Soares Heloisa P. , Anthony Lowell Brian , Kotiah Sandy Diana , Jacene Heather , Tesselaar Margot ET , Kunz Pamela L. , Ferreira Denis Vasconcelos , Li Joanne , Ma Kimberly , Rearden Jessica , Moran Susan , Hope Thomas A. , Singh Simron 
Published: June 2024

3091 Background: RYZ101 (225Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improved therapeutic index. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177Lu-SSA therapy. Herein, we report updated results from the phase Ib portion of the trial. Methods: The phase Ib portion of the trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level –1 90 kBq/kg; Level –2 60 kBq/kg. DLT was assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions/safety data were overseen by a Data Review Committee. Tumor response was assessed locally by RECIST v1.1. Results: 17 patients have received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 30 June 2023, the most frequent TEAEs were nausea (58.8%) and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (none were treatment related); grade ≥3 AEs occurred in 9 patients (5 were treatment related). No AEs led to treatment discontinuation. 4 patients had TEAEs leading to dose modification, dose hold, and/or delays. The confirmed objective response rate was 29.4% (n=5; all partial responses); 1 patient had an unconfirmed partial response. 8 patients (47.1%) had stable disease and 3 patients (17.6%) had progressive disease. Updated safety and efficacy data, including duration of response and progression-free survival, will be presented. Conclusions: RYZ101 was well tolerated and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy. Longer-term safety and efficacy data will be presented. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576 .
Phase II study to evaluate safety and efficacy of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, and trastuzumab biosimilar in patients with HER2 mutated advanced solid tumors (KCSG AL20-17).
Authors: Lee Kyoungmin , Lee Kyung-Hun , Kim Dong-Wan , Yoon Jeesun , Choi Wonyoung , Lee Youngjoo , Choi Yoon Ji , Lee Soohyeon , Kim Ju Won , Ryu Hyewon , Koo Dong-Hoe , Lee Yun-Gyoo , Jeung Hei-Cheul , Lee Min-Young , Lee Namsu , Kang Myoung Joo , Lee Ji Eun , Hong Sook Hee , Kang Eun Joo , Park Inhae 
Published: June 2024

3134 Background: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has single agent clinical activity in HER2 mutated cancer. This open-label single arm phase 2 trial investigated the efficacy and safety of the dual anti-HER2 therapy, neratinib plus trastuzumab in heavily pretreated patients with HER2 mutated solid tumors excluding HER2 amplifications. Methods: Neratinib was administered 240mg p.o. daily with trastuzumab biosimilar (Herzuma) every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Secondary endpoints were duration of response (DoR), progression free survival (PFS), and safety. An exploratory biomarker study was also conducted. Results: Forty patients were enrolled with a median follow-up of 11.08 months (range, 0.39-21.63 months) and a median of 3 (range 1-9) lines of prior systemic therapy. Tumor types included lung (42.5%), colorectal (20%) biliary (12.5%), and breast (7.5%). Sixty percent (60%) of patients (n=24) had HER2 mutation in the kinase domain. Among evaluable patients (n=39), the ORR was 23.1% (CR=0, PR=9) with a median DoR of 11.18 months (95% CI 0-22.63). Median PFS was 3.42 months (95% CI 1.57-5.27) and median overall survival was 9.47 months (95% CI 2.93-16.01). Grade ≥3 adverse events (AEs) occurred in 47.5% of patients (n=19) and diarrhea was the most frequently reported AE (n=10; 25%) followed by bilirubin elevation (n=2; 5%), and anemia (n=2; 5%). Conclusions: In heavily pretreated patients with HER2 mutated solid tumors, neratinib plus trastuzumab showed a moderate response rate, with a durable duration of response. Most AEs were manageable, highlighting the need for prophylactic diarrhea management. Exploratory biomarker results will be presented at the upcoming meeting. Clinical trial information: NCT06083662 .
Fruquintinib plus capecitabine versus capecitabine as first-line maintenance treatment of metastatic colorectal cancer (mCRC): Update results from the randomized, controlled, phase Ib/II study.
Authors: Li Wenhua , Chang Jinjia , Wang Chenchen , Peng Junjie 
Published: June 2024

3567 Background: Capecitabine (Cap) is a standard first-line maintenance treatment option for colorectal cancer. Fuquinitinib (Fru) is a highly selective small molecule tyrosine kinase inhibitor that inhibits VEGFR1/2/3, which has been approved by the U.S. Food and Drug Administration (FDA) for adults with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and has recommended by NCCN guidelines as a standard treatment. Preliminary research results found that adding Fru to Cap as maintenance treatment was safe and improved progression-free survival (PFS, primary endpoint) for mCRC patients (pts). Methods: Eligible pts had been confirmed mCRC who achieved disease control (including CR/PR and SD) after at least six cycles of first-line standard chemotherapy. During phase Ib, pts received Fru (4 mg p.o. qd, 3 weeks on/1 week off, q4w]) plus Cap (850 mg/m2, p.o. bid, d1-7 and d15-21, q4w). In phase II, pts were randomized in a 1:1 ratio to receive either Fru (RP2D, 3mg, 3 weeks on/1 week off) plus Cap or Cap alone. The primary outcome was PFS 1 (defined as time from randomization to disease progression or death). Secondary were PFS 2 (defined as time from first time receiving 1L treatment to disease progression or death), ORR and DCR. Results: At data cutoff (Jan 23, 2024), 46 pts were enrolled and 38 pts who had at least one tumor assessment post treatment were randomly assigned in Fru plus Cap arm (n=20) and Cap arm (n=18). Of these pts, the median age was 59.5 (39-78) and 58.5 (32-75) years, 11 (55.0%) and 10 (55.6%) had left-sided tumors, respectively. Most pts had previously received bevacizumab therapy (65.0% /66.7%) or cetuximab (30% /22.2%). The median cycles of first-line treatment were 8 (5-12) and 8 (4-13), 8 (40.0%) and 8 (44.4%) achieved PR in the pts who had received first-line therapy, respectively. The median PFS 1 was 9.2 mo in Fru plus Cap arm and 3.1 mo in Cap arm (HR=0.385 [95% CI: 0.163 - 0.906], p=0.024). And PFS 2 was also significantly prolonged in Fru plus Cap vs Cap (16.8 vs 8.5 mo, HR=0.314 [95% CI: 0.125 - 0.788], p=0.0098). Consistently, ORR (15.0% vs 5.6%) and DCR (80% vs 55.6%) were improved in Fru plus Cap arm. The safety was similar to the previous results without new safety signals appearing. Conclusions: PFS was significantly prolonged and ORR was improved in mCRC pts treated with Fru plus Cap as first-line maintenance treatment. This trial is ongoing and updated data will be presented in the future. Clinical trial information: NCT05451719 .
Neoadjuvant long-course chemoradiation plus PD1 blockade for locally advanced rectal cancer: Results of a phase 2, open-label, randomized controlled trial.
Authors: Yang Yingchi , Pang Kai , Lin Guole , Liu Xinzhi , Zhou Jiaolin , Kong Yuanyuan , Chen Guangyong , Wang Xin , Ye Yingjiang , Li Ang , Han Jiagang , Wu Guoju , WU Aiwen , Xiao Yi , Yao Hongwei , Zhang Zhongtao ,   Polarstar Trial Collaboration Group
Published: June 2024

3611 Background: Several single-arm trials have reported pathological complete response (pCR) rates of 23-50% after combining neoadjuvant radiotherapy with immune checkpoint inhibitors in locally advanced rectal cancer (LARC). We aim to further clarify the efficacy and safety of adding PD1 inhibitors to the neoadjuvant long-course chemoradiation of LARC patients with this phase 2, randomized, controlled trial. Methods: Patients with mid-low, locally advanced rectal cancer were randomly allocated to receive neoadjuvant chemoradiation plus concurrent Tislelizumab (experiment group A), or neoadjuvant chemoradiation plus sequential Tislelizumab (experiment group B), or neoadjuvant chemoradiation only (control group). Patients of all three groups are scheduled to receive radical surgery after neoadjuvant treatment. The primary endpoint is pCR rate. Results: A total of 186 patients were enrolled. In the modified intention-to-treat population, which consist of patients having received chemoradiation and at least 1 cycle of PD1 blockade for the experiment groups and patients having received chemoradiation only for the control group, the pCR rates were 33.9% and 34.5% for experiment group A and B respectively, both significantly higher than the pCR rate of 15.5% in the control group (p=0.021 and 0.019). There were no significant differences between either one of the experiment groups and the control group regarding disease progression rate, grade 3-4 treatment-related adverse event rate and grade 3-4 surgical complication rate. Conclusions: For patients with mid-low locally advanced rectal cancer, the addition of PD1 inhibitors to neoadjuvant long-course chemoradiation, whether concurrently or sequentially, increases pCR rate, meanwhile raises no significant safety concerns. For the next step, phase 3 trials with larger sample sizes are encouraged. Clinical trial information: NCT05245474 .
A novel and uniquely designed bispecific antibody (LBL-024) against PD-L1 and 4-1BB in patients with advanced malignant tumors and neuroendocrine carcinoma: A report of safety and robust efficacy of LBL-024 monotherapy in phase I/II, first-in-human, open-label, multicenter, dose escalation/expansion study.
Authors: Lu Ming , Zhang Panpan , Luo Suxia , Chen Jie , Yang Jianwei , Song Zhengbo , Li Yongsheng , Tang Ying , Zhao Peng , Liu Baorui , Li Junhe , Hu Sheng , Zhang Zhiye , Wu Lin , Song Lijie , Feng Xielin , Shan Yunfeng , Liu Tao , Cai Shengli , Shen Lin 
Published: June 2024

4010 Background: LBL-024 blocks the immunosuppressive pathway of tumor cells by targeting PD-L1 and effectively localizes 4-1BB co-stimulation to the tumor microenvironment, to improve the anti-tumor immune response. Here we report the safety and efficacy of LBL-024 in patients with advanced malignant tumors, particularly the robust clinical benefit in extrapulmonary neuroendocrine carcinoma (EP-NEC). Methods: Patient population: Phase Ⅰ, advanced malignant tumors exhausted standard cares and phase Ⅱ, EP-NEC failed at least one line of chemotherapy. Seven dose levels of LBL-024 were evaluated (0.2, 0.8, 3.2, 6, 10, 15 and 25 mg/kg, i.v. Q3W) and 15 mg/kg was selected for phase Ⅱ. The primary endpoints were tolerability, safety and efficacy (RECIST 1.1) and the second objectives were pharmacokinetics, pharmacodynamics, and other efficacy parameters. Results: By October 31, 2023, 162 patients were enrolled (64 in phase Ⅰ, and 98 in phase Ⅱ). Tumor types include EP-NEC (46, 28.4%), NSCLC (33, 20.4%), biliary tract cancer (31, 19.1%), and other tumors (52, 32.1%). During the dose escalation stage, no DLT was observed, and the MTD was not reached. The median follow-up was 4.2 months (95%CI: 3.9, 4.9). 126 out of 162 patients (77.8%) experienced TRAEs of all grades, with 34 (21.0%) having grade ≥3 TRAEs. The most common TRAEs (≥15%) included anemia (31.5%), AST increased (30.9%), ALT increased (25.3%), and white blood cell count decreased (22.2%). Out of 146 who underwent efficacy evaluation, the ORR and DCR were 15.1% and 46.6%, respectively. Robust efficacy signals were observed in 41 patients with EP-NEC (Table 1). 6 months of DoR will be available for report in ASCO. Conclusions: LBL-024 has showed good safety profile and very promising antitumor effects in patients with advanced malignant tumors, particularly EP-NEC patients who failed at least one line of chemotherapy. The efficacy observed in EP-NEC is significantly higher than the historic reports with immunotherapy (≤10%) and chemotherapy (about 18%). The extremely robust efficacy and good safety profile support a pivotal study for accelerated development of EP-NEC, the highly unmet medical needs and deadly disease. Clinical trial information: NCT05170958 . [Table: see text]
Use of artificial intelligence–based digital pathology to predict outcomes for immune checkpoint inhibitor therapy in advanced gastro-esophageal cancer.
Authors: Eweje Feyisope , Li Zhe , Gopaulchan Matthew , Attaranzadeh Armin , Kloker Leon , Jiang Yuming , Diehn Maximilian , Li Guoxin , Li Ruijiang 
Published: June 2024

4013 Background: Accurate prediction of response and survival outcomes with anti-PD-1/PD-L1 immune checkpoint inhibition (ICI) remains a significant challenge in gastro-esophageal cancers. In this study, we use an artificial intelligence (AI)-based single-cell analysis of digitized whole-slide H&E images (WSIs) to predict objective response and survival benefit of ICI in two independent cohorts of gastro-esophageal cancer patients. Methods: WSIs were obtained from 82 ICI-treated advanced gastroesophageal cancer patients (gastric, esophageal, and gastro-esophageal junction adenocarcinoma and squamous cell carcinoma) at Stanford University for discovery, and 189 ICI-treated advanced gastric adenocarcinoma patients at Southern Medical University for external validation. Deep learning models were deployed for automated tumor area detection and segmentation of cell nuclei within WSIs. We developed a fully automated cell annotation approach by leveraging multiplex immunofluorescence and trained a deep learning model to classify nuclei into four cell types from H&E (tumor cells, lymphocytes, neutrophils, and macrophages). A total of 66 features were computed to quantify cell composition and cell-cell interactions within the tumor microenvironment. Treatment outcomes were assessed using progression-free survival (PFS) and best objective response per the Response Evaluation Criteria in Solid Tumors (v1.1), with statistical significance reported at the 95% confidence level. Results: In the training cohort, a spatial feature characterizing lymphocyte and neutrophil interaction had the strongest association with PFS (hazard ratio = 0.44, 95% CI 0.24-0.79, P = 0.0046). In the validation cohort, the spatial biomarker positive population had significantly improved PFS compared to the spatial biomarker negative population (hazard ratio = 0.41, 95% CI 0.27-0.61, P < 0.0001; median time to event: 19 months vs 9 months). For predicting objective response in the validation cohort, a multivariate model combining the spatial features achieved AUROC = 0.81 compared to AUROC = 0.65 for PD-L1 CPS (P = 0.0014), while combining the multivariate model with PD-L1 CPS achieved AUROC = 0.84. Conclusions: A single-cell computational pathology approachidentifies spatial biomarkers with predictive utility for determining ICI treatment outcomes in advanced gastro-esophageal cancer. Further validation of these findings is being pursued in additional cohorts.
First-line regorafenib with nivolumab and FOLFOX or CapeOX in patients with advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: A single-arm, phase Ib/II trial (REGONIVOCTx, EPOC2104).
Authors: Kawazoe Akihito , Hashimoto Tadayoshi , Itahashi Kota , Irie Takuma , Ono Hiromi , Tamura Hitomi , Hongo Kyoko , Ikeno Takashi , Wakabayashi Masashi , Sato Akihiro , Nakamura Yoshiaki , Fujisawa Takao , Nakayama Izuma , Koyama Shohei , Yoshino Takayuki , Nishikawa Hiroyoshi , Shitara Kohei 
Published: June 2024

4052 Background: We previously reported anti-tumor activity of regorafenib plus nivolumab for advanced gastric cancer (AGC) patients at a third or later line (1). Recently, first-line regorafenib with nivolumab and FOLFOX in AGC showed promising results in a phase 2 in the United States. CapeOX requires less frequent outpatient visits than FOLFOX and is preferred in Asian countries. We investigated the safety and efficacy of regorafenib with nivolumab and chemotherapy including CapeOX for AGC in the first-line treatment. Methods: Enrolled patients received regorafenib with nivolumab and CapeOX (Cohort A) or FOLFOX (Cohort B) in the phase Ib part (safety lead-in) to determine the recommended dose. Additional patients were enrolled in the phase II part. Regorafenib of 90 mg was administered once daily for 21 days on/7 days off with nivolumab 360 mg every 3 weeks (Cohort A) or 240 mg every 2 weeks (Cohort B) and chemotherapy. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks in the phase Ib part and objective response rate (threshold 60%, expected 80%, α = 0.1, β = 0.2) in patients with the recommended dose in the phase Ib/II part. The primary endpoint would be met if at least 22 of 30 patients showed objective tumor response. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 30 patients (14 in Cohort A and 16 in Cohort B) were enrolled from June 2022 to April 2023. All patients had MSS/pMMR tumors. No DLTs were observed in both cohorts. Objective tumor response was observed in 22 of 30 (73%; 80%CI 60.3-83.8) patients, thus the primary endpoint was achieved. Disease control rate was 97%. Six-month progression-free survival was 66.7% (95%CI 46.9-80.5). The most common grade 3 or worse treatment-related adverse events included neutropenia (33%), AST/ALT increased (13%), hypertension (13%), and leucopenia (7%) without unexpected safety signals. Conclusions: First-line regorafenib with nivolumab and chemotherapy including CapeOX showed anti-tumor activity with acceptable safety profiles in AGC patients. The results of biomarker analysis will be presented. A randomized, phase III trial is planned. 1. Fukuoka S, J Clin Oncol 2020. Clinical trial information: NCT05394740 .