bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4-year follow-up of CheckMate 649.
Authors: Elimova Elena , Shitara Kohei , Moehler Markus H. , Ajani Jaffer A. , Shen Lin , Garrido Marcelo , Gallardo Carlos , Wyrwicz Lucjan S. , Yamaguchi Kensei , Cleary James M. , Bruges Maya Ricardo Elias , Karamouzis Michalis , Skoczylas Tomasz , Bragagnoli Arinilda , Liu Tianshu , Tehfe Mustapha , Feeney Kynan , Wang Rui , Nathani Raheel , Janjigian Yelena Y. 
Published: June 2024

4040 Background: NIVO + chemo demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit vs chemo and an acceptable safety profile in previously untreated, advanced non-HER2+ GC/GEJC/EAC, leading to approvals in many countries. NIVO + chemo continued to demonstrate clinically meaningful improvement in efficacy at 2 and 3-yr follow-ups. We present 4-yr follow-up results for NIVO + chemo vs chemo from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. HER2+ patients (pts) were excluded. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 1581 pts were randomized to NIVO + chemo or chemo. At the 48-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). OS benefit with NIVO + chemo was observed in most prespecified subgroups. Objective response rates (ORR) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). In the exploratory analysis of OS by response at the 18-week landmark timepoint, there were numerically more pts achieving response with NIVO + chemo vs chemo, and median OS (95% CI) with NIVO + chemo was numerically longer in responders vs non-responders both in pts with PD-L1 CPS ≥ 5 (20.5 [17.5–25.0] vs 14.0 [11.6–15.7]) and all randomized pts (19.4 [17.5–21.7] vs 13.1 [11.6–14.4]). No new safety signals were identified, consistent with the 3-yr follow-up. Conclusions: NIVO + chemo is the first PD-1 inhibitor/chemo combination to demonstrate long-term efficacy and acceptable safety after 4 yrs of follow up in previously untreated advanced GC/GEJC/EAC. These results are consistent with earlier follow-ups, further supporting NIVO + chemo as a standard 1L treatment in these pts. Clinical trial information: NCT02872116 . [Table: see text]
Enfortumab vedotin (EV) in previously treated gastric/esophageal cancers cohorts of EV-202.
Authors: Muro Kei , Chin Keisho , Maron Steven Brad , Braiteh Fadi S. , Mitani Seiichiro , Hara Hiroki , Kuboki Yasutoshi , Mulcahy Mary F , Baranda Joaquina Celebre , Gardner Faithlore Patrice , Jin Ning , Hamauchi Satoshi , Kaplan Jason , Gorla Seema Rao , Liu Shubin , Wozniak Michele , Meng Changting , Kondo Shunsuke 
Published: June 2024

4046 Background: Gastric/esophageal cancers have moderate/high Nectin-4 expression. EV is a Nectin-4–directed antibody–drug conjugate approved for use in locally advanced or metastatic (la/m) urothelial carcinoma. We report antitumor activity and safety of EV monotherapy in esophageal and/or gastric cancer in EV-202 (NCT04225117). Methods: This open-label, multicohort, phase 2 study enrolled adults with la/m solid tumors and ECOG performance status 0–1. In the esophageal squamous cell carcinoma (ESCC) and gastric/esophageal adenocarcinoma (GEA; gastric cancer, gastroesophageal junction/esophageal adenocarcinoma) cohorts, patients (pts) had prior treatment with 1 platinum-based and ≤2 lines of cytotoxic therapy in the la/m setting and disease not amenable to curative intent. Inclusion required prior HER2-directed therapy if HER2-positive and prior PD-1/L1 inhibitor. Nectin-4 expression was assessed retrospectively. Pts received EV 1.25 mg/kg intravenously on days 1, 8, and 15 per 28-day cycle. Primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1; ≥7 out of 40 responders are needed to conclude promising antitumor activity. Secondary endpoints were investigator-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) per RECIST v1.1; overall survival (OS); and safety/tolerability. Results: Of the 44 (as of June 2, 2023) and 42 pts (as of Mar 3, 2023) in the ESCC and GEA cohorts, respectively, median age was 66 and 62 y, 82% and 71% of pts were male, and 68% and 69% had ≥2 prior lines of systemic therapy in the metastatic setting. Efficacy data are shown in the table. Efficacy was generally better in pts with <3 (n=22) vs ≥3 (n=21) prior therapy lines in the ESCC cohort. Common treatment-related adverse events (TRAEs) were pruritus (n=12, 27%), maculopapular rash (n=12, 27%), and dysgeusia (n=11, 25%) for ESCC and pruritus (n=16, 38%), alopecia (n=15, 36%), and dysgeusia (n=13, 31%) for GEA. Grade ≥3 TRAEs (>1 pt) were hypercalcemia, hyperglycemia, maculopapular rash, and decreased neutrophil count (each n=2, 5%) for ESCC and maculopapular rash (n=3, 7%), decreased neutrophil count (n=2, 5%), and hyperglycemia (n=2, 5%) for GEA. For ESCC and GEA, respectively, TRAEs of special interest included skin reactions (n=27, 61%; n=23, 55%), peripheral neuropathy (n=9, 20%; n=7, 17%), and hyperglycemia (n=3, 7%; n=3, 7%). Conclusions: In pts with pretreated gastric/esophageal cancers, EV demonstrated safety consistent with the known profile of EV. Promising antitumor activity was observed in pts with ESCC. Clinical trial information: NCT04225117 . [Table: see text]
First-line osemitamab (TST001) plus nivolumab and capox for advanced g/GEJ cancer (TranStar102): Results of cohort G from a phase I/IIa study.
Authors: Zhang Xiaotian , Guo Zengqing , Zhang Jingdong , Guo Weijian , Sun Meili , Xu Nong , Qi Charlie , Zhu Xuelian , Zhang Lijuan , Qian Xueming , Germa Caroline , Shen Lin 
Published: June 2024

4048 Background: TST001 is a humanized monoclonal antibody with improved affinity to claudin 18.2 (CLDN18.2) and enhanced ADCC activity. In vivoanti-tumor activity of TST001 plus an anti-PD-1 antibody and chemotherapy is significantly stronger than chemotherapy plus anti-PD-1 antibody or chemotherapy plus anti-CLDN18.2 antibody, regardless of the CPS PDL1 levels. Promising efficacy of osemitamab plus CAPOX chemotherapy as 1st line treatment of G/GEJ cancer has been observed in cohort C of TranStar102, making the triple combination of TST001, nivolumab and CAPOX an attractive combination to explore. Methods: Cohort G from TranStar102 (NCT04495296) is designed to evaluate the safety and preliminary efficacy of TST001 (at 2 doses: 3mg/kg or 6mg/kg Q3W) plus nivolumab and CAPOX as 1st line treatment in patients with G/GEJ cancer, with a safety lead-in and expansion phase. 40 patients were planned to be enrolled in each dose cohort. Eligible patients include HER2 negative or unknown, unresectable locally advanced or metastatic G/GEJ cancer, regardless of CLDN18.2 or PD-L1 expression. CLDN18.2 and PD-L1 status are analyzed retrospectively using IHC 14G11 LDT assay and PD-L1 IHC 28-8 pharmDx. Results: As of Jan 19, 2024, 82 patients have been dosed with a median follow-up of 9.7 months, 40 patients at 3mg/kg, 42 patients at 6mg/kg. All patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were hypoalbuminemia (67.1%), nausea (63.4%), and vomiting (59.8%). The incidence of nausea (69% vs 57.5%) and hypoalbuminaemia (76.2% vs 57.5%) was higher at 6mg/kg than 3mg/kg. Most of the TRAEs are grade 1 or 2. The most common TRAE grade 3 or higher were neutrophil decreased (n=10), platelet count decreased (n=8), nausea (2 at 3mg/kg, 1 at 6mg/kg) and vomiting (2 at 3mg/kg). No new safety signal was detected when nivolumab was added to TST001 in combination with chemotherapy. 79 patients had measurable disease at baseline including 25 CLDN18.2 negative patients. 51/79 patients had partial response as of cut-off date, out of which 45 were confirmed (ORR 57%), with no significant difference between the 2 dose levels. 17 patients had stable disease. The disease control rate (DCR) was 91.9% in all patients across CLDN18.2 expression levels and CPS PD-L1 levels. The progression-free survival (PFS) and duration of response (DoR) are immature and need longer follow-up. Conclusions: Preliminary data indicate that the combination of TST001 6mg/kg Q3W plus nivolumab and CAPOX for the 1st line treatment of patients with G/GEJ cancer is safe and well tolerated with encouraging preliminary anti-tumor activities. Updated clinical data, including PFS and DoR will be reported at the time of the conference. Clinical trial information: NCT04495296 .
The use of micronuclei DNA from erythrocytes for the detection of early-stage gastrointestinal cancers.
Authors: Sun Haobo , Yao Xingyun , Han Yuehua , Jiao Yurong , Kong Xiangxing , Liu Chengcheng , Guo Qingqu , Meng Fei , Liang Honghao , Fan Xiuqin , Li Jun , Ding Kefeng , Gao Xiaofei 
Published: June 2024

4085 Background: Gastrointestinal (GI) cancers account for over a third of cancer deaths. However, their early detection remains a challenge. Micronuclei (MN) are extranuclear bodies containing damaged chromosome segments indicative of genomic instability. Increased MN frequency in hematopoietic cells is observed in patients with solid tumors. We have developed a method (WO2021/228246 A1) for purifying and characterizing micronuclei DNA (MN-DNA) in erythrocytes from peripheral blood. By comparing MN-DNA from healthy donors (HDs) and GI cancer patients, we identified significant changes in read densities at specific genomic locations in patients, which were termed as tumor-associated MN-DNA (taMN-DNA) signatures. Here, we evaluated the potential of these signatures for early-stage GI cancer detection, including colorectal (CC), gastric (GC) and esophageal (EC) cancers. Methods: Peripheral blood (1-2 ml) was collected from healthy donors (HD) and cancer patients MN-DNA isolation and purification from erythrocytes. Participants were randomly divided into training, validation and independent test cohorts in a 7:2:1 ratio, maintaining similar cancer types, CC/GC/EC/HD ratio, gender and age distribution. Distinct MN-DNA features between cancer patients and HDs were identified using sequencing data. Logistic regression algorithms were applied using these features for cancer detection. Results: The study enrolled 1753 participants, including 987 HDs, 420 CC, 282 GC and 64 EC cases. Of these, over half were diagnosed with early-stage diseases; TNM stage 0-I accounted for 40.57%, stage II for 23.32%, stage III for 29.25% and stage IV for 6.87%. The cancer detection model with MN-DNA features yielded an overall accuracy of 87.43%, with a sensitivity of 83.66% and specificity of 90.36%. For individual caner types, sensitivity was 85.37% for CC, 79.31% for GC and 92.31% for EC. For early-stage (stage 0-II) CC, GC and EC, the model demonstrated sensitivities of 95.12%, 86.05% and 100.00%, respectively, at 90.36% specificity. Conclusions: Unlike cell-free DNA, MN-DNA are chromosomal fragments in the cytoplasm. The abundance of erythrocytes in peripheral blood provides an easily accessible source for MN-DNA enrichment. This pilot study illustrates the potential of MN-DNA as a tool for early GI cancer detection, contributing to large-scale efforts towards developing an effective GI cancer screening test.
Genomic signature analysis and survival outcomes in cholangiocarcinoma (CCA) using oncology research information exchange network (ORIEN) database.
Authors: Patel Riya Jayesh , Rosario Spencer , Sonti Sahithi , Hsiao Hua-Hsin , Pawlik Timothy M. , Tsilimigras Diamantis I , Siegel Erin M. , Berim Lyudmyla Derby , Turk Anita Ahmed , Masood Ashiq , Salhia Bodour , Kolesar Jill , Davis S. Lindsey , Le Tri Minh , Nevala-Plagemann Christopher Duane , Chan Carlos H.F. , Churchman Michelle , Thanikachalam Kannan , Iyer Renuka V. 
Published: June 2024

4101 Background: Immunotherapy (IO) is standard of care for advanced CCA patients (pts) regardless of PD-L1 expression. Lack of biomarkers that predict prolonged benefit or resistance to therapies are unmet gaps in this field that we attempted to fill using transcriptional and survival data in the ORIEN dataset. Methods: Through an ORIEN intermember project, we accessed an avatar dataset for clinical characteristics and transcriptional data of the CCA cohort. We first identified clinical factors highly associated with transcriptional variability and conducted principal component analysis (PCA), focusing on factors linked to the first principal component (PC1). Both specimen site and type (p<0.01) were found highly associated with PC1 and were included as co-variates in subsequent models. Then, immune deconvolution using XCell was performed on the ORIEN-CCA RNA-sequencing cohort to determine the transcriptome portion attributed to effector T cell (Teff) and regulatory T cell (Treg) for each patient. Teff:Treg ratios were calculated and used to divide patients into cold (low Teff:Treg) and hot (high Teff:Treg) cohorts based on their median (mTeff:Treg = 0.0004). Differential gene expression analysis comparing hot and cold tumors yielded 72 significantly differentially expressed genes (FC <1.5, adjusted p<0.05). Gene Set Enrichment Analysis (GSEA) of transcriptomic changes revealed enrichment for immune and metabolic pathway alterations. Results: The ORIEN avatar dataset comprised of 78 pts, with 39 designated as immune hot and 39 as immune cold (demographics in Table). Median overall survival (mOS) was 3.17 years in hot and 2.65 years in cold group . These groups exhibited significantly different Teff:Treg ratio (p<0.0001). Differential gene expression identified 72 altered genes, including upregulated immune genes (e.g., IL2RA, CD80, GBP5) in the hot group and metabolic genes (e.g., AZGP1) in the cold group. GSEA of these genes revealed immune pathway enrichment in hot tumors, with increased antigen presentation, NK cell function, and B-cell activation. Surprisingly, cold tumors were enriched of pathways involved in lipogenesis, oxidation, and proliferation. Conclusions: ORIEN-CCA cohort analysis revealed immune hot and cold tumors with distinct transcriptional alterations and differences in mOS. Correlating these alterations with IO use, and further studies of enriched pathways in cold tumors are warranted. [Table: see text]
Genomic and transcriptomic biomarkers of nab-paclitaxel plus gemcitabine-cisplatin in patients with advanced biliary tract cancer.
Authors: Woo Seonjeong , Kang Beodeul , Lee Sung Hwan , Kim Jung Sun , Kang Haeyoun , Yang Seok Jeong , An Chansik , Kim Gwangil , Hwang Sohyun , Kim Chan , Chon Hong Jae 
Published: June 2024

4104 Background: Nab-paclitaxel plus gemcitabine-cisplatin (GemCis/nab-P) showed promising clinical outcomes in phase II trials for advanced biliary tract cancer (BTC) but did not demonstrate superiority over the control treatment in subsequent phase III clinical trials.In this study, we investigated predictive biomarkers of response to GemCis/nab-P in patients with advanced BTC using comprehensive genomic and transcriptomic analyses. Methods: This prospective cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received GemCis/nab-P at CHA Bundang Medical Center, Korea from July 2021 to December 2022. Targeted genomic (Oncomine Comprehensive Assay) and whole-transcriptome sequencing data for tissue samples collected before the initiation of systemic chemotherapy were used for biomarker discovery (n = 108). To identify genomic and transcriptomic features related to overall survival (OS) and progression-free survival (PFS), the log-rank test, Cox proportional hazards model, and Lasso Cox regression model were used. Results: Among the 119 enrolled patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% had extrahepatic cholangiocarcinoma, and 23.5% had gallbladder cancer. Most patients had metastatic or recurrent disease (68.9%). The median follow-up duration was 23.7 months (range 0.8–30.2), median PFS was 8.3 months (95% Confidence interval (CI), 7.0–11.5), and median OS was 19.8 months (95% CI, 15.3–not reached). The most common genetic aberrations were TP53 (53.7%), KRAS (29.6%), and ARID1A (16.7%) alterations. TP53 mutations were associated with a poor OS (p = 0.001) and PFS (p = 0.005). In the transcriptome analysis, genes associated with immune responses, especially tumor-associated macrophages, were upregulated in patients with worse OS and PFS. We constructed a Lasso-Cox regression model and identified VSIG4 (hazard ratio (HR): 3.0, p = 2.0 × 10-4 for OS; HR: 2.4, p = 4.0 × 10-4 for PFS), ITGA3 (HR: 2.6, p = 0.001 for OS; HR: 1.7, p = 0.020 for PFS), and CCL8 (HR: 1.6, p = 0.110 for OS; HR: 1.6, p = 0.039 for PFS) as effective predictors of poor clinical outcomes during GemCis/nab-P treatment. Conclusions: GemCis/nab-P showed promising survival outcomes in advanced BTC. Further, patients with TP53 mutations or high tumoral levels of VSIG4, ITGA3, and CCL8 showed a poor prognosis after GemCis/nab-P treatment. Clinical trial information: NCT04871321 .
Efficacy and safety of envafolimab plus lenvatinib combined with TACE in initially unresectable hepatocellular carcinoma: An open-label, single-arm, phase II study.
Authors: Bai Xueli , Chen Yiwen , Zhang Junlei , Hu Wendi , Li Xiang , Shen Yan , Zhang Min , Wu Jian , Gao Shunliang , Yu Jun , Que Risheng , Zhang Yun , Yang Fuchun , Xia Weiliang , Zhang Aibin , Tang Xiaofeng , Liang Tingbo 
Published: June 2024

4108 Background: TACE-based conversion therapies are warranted for over 70% of patients with intermediate-advanced unresectable hepatocellular carcinoma (uHCC). This study aimed to investigate the efficacy and safety of envafolimab plus lenvatinib and TACE as conversion therapy in uHCC. Methods: This is an open-label, prospective, single-arm, phase II study. Eligible patients with uHCC (Barcelona Clinic Liver Cancer Stage B or C) were consecutively enrolled. Patients will receive envafolimab subcutaneously (300 mg, Q3W) and Lenvatinib orally daily (12 mg/day (body weight ≥ 60 kg) or 8 mg/day (<60 kg)) during TACE sessions. TACE will be conducted every 6 weeks on demand according to investigators’ evaluation, mainly based on the proportion of viable tumors. The primary endpoint was the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version1.1 (RECIST 1.1). Secondary endpoints were disease control rate (DCR) and duration of response (DoR) per RECIST 1.1 and mRECIST, progression-free survival (PFS), overall survival (OS), and safety. Results: Between February 2022 and July 2022, 38 patients were enrolled and included for primary efficacy and safety analysis. As of December 13, 2023, the median follow-up of 16.9 months (95CI, 6.7 to 24.2). The ORR and DCR were 47.4% (95%CI, 31.0% to 64.2%) and 78.9% (95%CI, 62.7% to 90.5%) per RECIST 1.1, respectively (with ORR and DCR of both 78.9% per mRECIST). The median PFS (mPFS) was 8.78 months (95CI, 5.23 to not avaliable (NA)), and the median OS (mOS) was immature with 1-year OS of 88.9%. The median DoR assessed per RECIST 1.1 was 6.7 months (7.7 months per mRECIST). Of 38 patients, 17 patients were assessed as successful conversion with a conversion success rate of 44.7%. Sixteen patients underwent surgery with the R0 resection rate of 100%, the pathological complete response (pCR) rate of 31.3%, and major pathological response (MPR) rate of 56.3%. Of 38 patients, overall incidences of AEs of any grade was 97.4%. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 20 (52.6%) patients, which mainly included increased AST (34.2%), increased ALT (18.4%), and decreased platelet count (15.8%). No treatment-related death occurred. Conclusions: Envafolimab combined with lenvatinib and TACE yielded promising survival outcomes and conversion rate with a manageable safety profile in uHCC, representing a potential and feasible conversion therapy regimen for this population. Clinical trial information: NCT05213221 .
Sorafenib plus hepatic arterial infusion of oxaliplatin and fluorouracil vs sorafenib plus transarterial chemoembolization for advanced hepatocellular carcinoma: A biomolecular exploratory, randomized, phase III trial (SHATA-001).
Authors: Lai Zhicheng , Kan Anna , He MinKe , Du Zefeng , Shi Ming 
Published: June 2024

4113 Background: Several recent studies had demonstrated the superiority of Sorafenib/lenvatinib plus transcatheter arterial chemoembolization (TACE) over sorafenib/lenvatinib alone in advanced hepatocellular carcinoma (HCC). Herein, we compared the efficacy and safety between sorafenib plus TACE (SoraTACE) and sorafenib plus hepatic arterial infusion chemotherapy (SoraHAIC) in advanced HCC. Additionally, we validated a predictive model from our previous phase III trial (NCT02973685, cohort1). Methods: In this phase III trial (NCT02856126), patients with advanced HCC were enrolled. Eligible patients were randomly assigned (2:1) to receive Sorafenib (400mg orally twice daily) plus HAIC with oxaliplatin & fluorouracil per 3 weeks or TACE (50mg of epirubicin and lobaplatin mixed with lipiodol and polyvinyl alcohol) until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). Whole-Exome Sequencing and RNA Sequencing of tumor biopsy samples were performed for predictive biomarker exploration (cohort 1) and validation (SHATA-001). Results: Between August 4, 2016, and October 25, 2020, 207 patients were assigned to treatment (SoraHAIC, n=141; SoraTACE, n=66). Primary endpoint was met, with the median OS of 15.6 (95% CI, 12.7-18.6) months in SoraHAIC group and 11.2 (7.6-14.6) months in SoraTACE group (HR, 0.53 [0.38-0.74], p<0.001). Median progression-free survival was 6.9 (5.4-8.5) months and 4.2 (2.9-5.3) months in the respective groups (HR, 0.51[0.37-0.69], p<0.001). Safety analyses (n=200) showed frequencies of grade 3-4 elevated alanine aminotransferase (5% vs 21.7%; p<0.001) and elevated aspartate aminotransferase (16.4% vs 35%; p<0.001) significantly higher with SoraTACE than SoraHAIC. Serious adverse events occurred more frequently with SoraTACE (56.7%) than SoraHAIC (39.3%) (p=0.023). In cohort 1, we analyzed the metabolic activity of fatty acid degradation (FAD) pathway using FAD score, which was positively correlated with longer OS, especially in patients received TACE. Furthermore, we found a down regulation of FAD activity in patients enrolled in SHATA-001. And higher FAD score showed a better tumor response to SoraTACE, while FAD had no difference between responders and non-responders in SoraHAIC. Conclusions: This trial demonstrated SoraHAIC significantly improved OS over SoraTACE in patients with advanced HCC. However, patients with high FAD activity might have a better tumor response and survival benefit to SoraTACE than SoraHAIC. Clinical trial information: NCT02856126 .