bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated results of anlotinib combined with TQB2450 (PD-L1 blockade) as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, multicenter, open-label phase Ⅱ clinical trial.
Authors: Zhang Zhiye , Meng Xiangrui , Yang Xiuli , Hong Yong-Gui , Xia Jin , Chen Yunfang , Wu Tao , Shan Zheng-Zheng , Fan Qingxia , Wang Feng 
Published: June 2023

4041 Background: PD-1 blockades combined with chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC recently. However, the safety profile of conventional chemotherapy was still disappointing. Therefore, the chemotherapy-free regimen might be a promising strategy. As a novel multitarget TKI mainly targeting VEGFR1-3, anlotinib was a potential first-line combination therapy and second-line monotherapy for patients with ESCC in China. TQB2450 was a novel PD-L1 blockade developed by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (Nanjing, China). Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with TQB2450 as first-line therapy in advanced ESCC. The preliminary results were reported in 2023 ASCO-GI Symposium (Abs 377) and the update results were reported here. Methods: Patients with previously untreated metastatic or locally advanced ESCC, whose age was between 18 and 75 years, with ECOG PS of 0 or 1 and life expectancy of > 3 months were eligible as the inclusion criteria. Eligible patients were administered with anlotinib (12mg, po, d1~14, q3w) plus TQB2450 (1200mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 and iRECIST using CT scans every 2 cycles for the first 6 cycles, and every 3 cycles thereafter. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 46. The primary endpoint was ORR. Secondary endpoints included safety, PFS, DCR, DoR and OS. Results: From Mar 2022 to Sep 2022, a total of 46 patients were enrolled. At the data cut-off date (Dec, 2022), there were 1 CR (2.2%), 27 PR (58.7%), 14 SD (30.4%) and 4 NE (8.7%). Therefore, the preliminary ORR was 60.9% (95%CI: 45.4%~74.9%), DCR was 91.3% (95%CI: 79.2%~97.6%). The median PFS of the 46 pts was not yet available. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-related adverse events in 46 patients with the incidence > 10% were hypertension (28%), hypothyroidism (20%), leukocytosis (20%), hyperthyroidism (17%), anemia (15%), fatigue (15%), neutrophil count decreased (11%), constipation (11%), sinus bradycardia (11%) and hand-foot syndrome (11%). The common grade ≥3 treatment-related adverse events were hypertension (4%), hand-foot syndrome (2%), hyponatremia (2%), platelet count decreased (2%) and lymphocyte count decreased (2%). Conclusions: Preliminary results suggested that anlotinib combined with TQB2450 as first-line therapy in advanced ESCC exhibited encouraging efficacy and manageable adverse events. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: NCT05038813 .
A phase 2 single-arm study of berzosertib in combination with irinotecan in patients with progressive TP53 mutant gastric and gastro-esophageal junction cancer.
Authors: Stockton Shannon , Soares Heloisa P. , Dayyani Farshid , Saeed Anwaar , Kim Edward S. , Jin Ning , Yacoub George Hosni , Whisenant Jennifer , Ayers G. Dan , Gore Steven , Das Satya (Nanu) , Berlin Jordan 
Published: June 2023

4044 Background: TP53 mutations are reported in 30-70% of patients with metastatic/unresectable gastric (G) and gastro-esophageal junction (GEJ) adenocarcinoma and are associated with a poor prognosis. Novel therapeutics are needed. Gastrointestinal cancer cell lines with TP53 mutations demonstrate reliance on the ataxia telangiectasia and Rad3-related protein kinase (ATR) axis for DNA damage repair (DDR) in vitro. The ATR axis is triggered by single-strand DNA breaks and thus combining ATR inhibitors with topoisomerase I (TopI) inhibitors may have a synergistic effect, particularly in patients with TP53 mutant tumors. Irinotecan, a TopI inhibitor, is an established cytotoxic therapy for gastric and GEJ adenocarcinoma. We evaluated irinotecan in combination with the ATR inhibitor berzosertib (formerly M6620) in patients with TP53-mutated gastric and GEJ adenocarcinoma. Methods: This was a single-arm phase II study in third-line patients with G/GEJ cancers possessing TP53 mutations (exon 2 and exons 4-11). Patients received irinotecan 180 mg/m2 IV and berzosertib 270 mg/m2 IV on days 1 and 15 every 28 days. The primary endpoint was overall response rate (ORR) (Ha: 35% and Ho:15%). A subset of patients underwent biopsies on C1D1 post-irinotecan and C2D2 to evaluate the expression of DDR biomarkers Y-H2AX, KAP1 p-Ser 824, and p-ATR. Results: A total of 17 patients were enrolled. Of 16 efficacy-evaluable patients, one experienced a partial response. The ORR was 6.2% thus the primary endpoint was not met. The disease control rate was 56.2%. Median progression-free survival was 4.01 months [95% CI 2.07-Not Reached]. Median overall survival was 6.21 months [95% CI 4.83-8.61]. No new safety signals were observed with the experimental treatment combination and the most common ≥ grade 3/4 treatment-related adverse events were neutropenia (4/17, 23.5% patients), anemia (3/17, 17.6%), febrile neutropenia (2/17, 11.8%), and diarrhea (2/17, 11.8%). No grade 5 events occurred. Conclusions: Although the primary endpoint of ORR was not met, the combination of irinotecan and berzosertib in patients with TP53-mutated G/GEJ adenocarcinoma was well-tolerated and demonstrated anti-tumor activity comparable to other agents with published later-line data (e.g. ramucirumab+paclitaxel, TAS-102). Analyses of pharmacodynamic biomarkers of DNA damage repair are in process. While further clinical development of berzosertib is not planned, other ATR inhibitors are being explored in combination with irinotecan in gastrointestinal malignancies, including G/GEJ cancer. Clinical trial information: NCT03641313 . [Table: see text]
FLOT plus nivolumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: Results from the randomized phase 2 IKF-S628/AIO-STO-0417 (Moonlight) trial of the AIO.
Authors: Lorenzen Sylvie , Goetze Thorsten Oliver , Hofheinz Ralf Dieter , Thuss-Patience Peter C. , Dechow Tobias Nicolaas , Riera-Knorrenschild Jorge , Schuch Gunter , Luley Kim Barbara , Koch Christine , Goekkurt Eray , Schmalenberg Harald , Ettrich Thomas Jens , Lindig Udo , Pink Daniel , Bitzer Michael , Bolling Claus , Homann Nils , Junge Sabine , Pauligk Claudia , Al-Batran Salah-Eddin 
Published: June 2023

4045 Background: FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. FLOT is a well-established standard of care triplet regime. Some physicians may consider a triplet in patients with aggressive disease. The aim of this Arm C part of the Moonlight trial was to evaluate the safety and efficacy of the combination of FLOT plus nivo. Methods: Moonlight is a multi-cohort phase-II trial. The results for Arm C evaluating FLOT + nivo (240 mg) q2w as first-line therapy in all-comers are presented here. Primary endpoint was progression-free survival at 6 months (PFS@6), main secondary endpoints were safety, OS, and overall response rate (ORR). Results: Fifty-two patients were enrolled. Baseline characteristics were: median age 61y, GEJ 65%. Sixty-five percent had centrally assessed PD-L1 CPS≥1 (available in 96% of pts). Pts. received a median number of 8 cycles of FLOT and nivo and 42% received further line treatment. FLOT plus nivo was well tolerated and feasible with the most frequent adverse events of ≥ grade 3 being decreased neutrophils (40.4%), anemia (5.8%) and thromboembolic events (7.7%). After a median follow-up of 9.4 months, 3- and 6-month progression-free survival rates were 85% and 42%, respectively. Median PFS was 6.6 months and median OS 10.8 months. ORR and disease control rate (DCR) were 54% and 87%, respectively. Compared to the pooled study cohorts A and A1 (n = 90 pts) utilizing mFOLFOX plus nivo and ipilimumab (non-randomized comparison), FLOT plus nivo was associated with greater DCR (87% vs. 78%) and 3-months PFS (85% vs. 72%). Conclusions: FLOT and nivo is feasible and seems to be associated with improved disease control in the early course of therapy. FLOT plus nivo may represent an option for select patients with aggressive, rapidly progressive disease. Clinical trial information: NCT03647969 .
Osemitamab in combination with capecitabine and oxaliplatin (CAPOX) as a first line treatment of advanced G/GEJ cancer: Updated data of cohort C from a phase I/IIa, multi-center study (TranStar102/TST001-1002).
Authors: Shen Lin , Liu Dan , Li Ning , Guo Weijian , Liu Tianshu , Li Hongli , Li Jiayi , Bai Yuxian , Deng Yanhong , Zhuang Zhi-xiang , Sun Meili , Fan Qingxia , Zhao Fuyou , Han Liang , Xia Zhenzhong , Wang Jianming , Qi Charlie , Xu Li , Qian Xueming , Germa Caroline 
Published: June 2023

4046 Background: Adding a claudin18.2 antibody to a chemotherapy is a clinically validated approach for patients with high CLDN18.2 expressing tumors. TST001 is a best in class differentiated antibody whose improved CLDN18.2 affinity and enhanced antibody-dependent cellular cytotoxicity, leads to anti-tumor activity in low to medium CLDN18.2 expressors gastric cancer cells. Pre-clinical studies also showed that TST001 has stronger tumor regression effects than the IMAB362-analog at the same dose. Methods: The efficacy and safety of osemitamab with CAPOX as 1st line treatment with G/GEJ cancer was explored in a dose escalation and expansion phase 1/2 study in China (Cohort C, NCT04495296). Positive claudin18.2 expression (membranous staining ≥1+ intensity in≥10% of tumor cells) as assessed centrally using the LDT assay was required in the expansion phase only. Results: As of Dec 31, 2022, 64 patients were dosed with osemitamab in combination with CAPOX, 15 patients received osemitamab at doses ranging from 1 to 8 mg/kg Q3W in the dose escalation and 49 patients at 6 mg/kg in the dose expansion. The median follow up was 151 days. Patient characteristics were typical of 1st line G/GEJ cancer, with relatively higher percentage of peritoneal disease (48.4%). Nausea (65.4%), vomiting (46.2%) and hypoalbuminemia (65.4%) were the most common adverse events related to TST001 at dose of 6mg/kg in 52 patients (3 patients in dose escalation and 49 patients in dose expansion), most of them were grade 1 or 2 (only one patient experienced grade 3 nausea and vomiting, and one experienced grade 3 hypoalbuminemia). In the expansion cohort, 40 of the 45 patients with measurable lesions had at least one post-treatment tumor assessment. 27 achieved partial response (PR) of which 21 were confirmed. There was no obvious trend in improved efficacy with higher level of CLDN18.2 expression based on overall response rate (ORR). Progression free survival (PFS) and duration of response (DOR) were still immature. Conclusions: TST001 in combination with CAPOX as first-line treatment for the patients with G/GEJ cancer is safe and encouraging anti-tumor activities have been observed regardless of the CLDN18.2 expression levels above 1+ intensity in >=10% tumor cells per central LDT assay. Updated ORR, mPFS and mDOR will be presented at the time of the congress. Clinical trial information: NCT04495296 .
Multi-dimensional cell-free DNA-based liquid biopsy and early detection of gastric cancer.
Authors: Pengfei Yu , Wu Min , Ding Guangyu , Bao Hua , Du Yian , Xu Zhiyuan , Yang Litao , Fang Jingquan , Huang Xingmao , Lai Qian , Wei Jia , Yan Junrong , Yang Shanshan , He Peng , Tang Haimeng , Wu Xue , Shao Yang , Su Dan , Cheng Xiangdong 
Published: June 2023

4060 Background: Gastric cancer is one of the most common cancer types. Most patients were diagnosed at advanced stages and experienced poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing the gastric cancer-associated mortality. Methods: We prospectively collected a study cohort of 249 participants including 110 pathologically confirmed with stage I-II gastric cancer and 139 with non-cancerous conditions. A plasma sample was collected from each patient before conventional screening modalities for gastric cancer. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. We used these differential profiles to develop an ensemble model to identify gastric cancer patients from non-cancer individuals. We further collected a validation cohort consisting of 73 gastric cancer patients and 94 non-cancer individuals to validate the cfDNA-based assay. Additionally, we compared the performance of our assay and conventional gastroscopy in a hypothetical 100,000 screening population by Monte Carlo simulation. Results: The liquid biopsy assay that incorporated four types of cfDNA characteristics was able to identify early-stage gastric cancer patients from non-cancer individuals at an AUROC of 0.962 in the study cohort and 0.972 in the validation cohort. At a specificity of 92.1% (128/139), it achieved a sensitivity of 88.2% (97/110) in the study cohort. With this threshold, in the validation cohort, 91.5% (86/94) of healthy individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In both study and validation cohorts, the inferred probabilities of cancer showed consistent trends to increase with pathological stages in the cancer group and disease statuses in the non-cancer group. Of note, our approach detected all gastric tumors located in the cardia and fundus (100.0%, 19/19), which could be challenging for gastroscopic examination. Additionally, through in-silico simulations, we showed that our cfDNA-based non-invasive assay may detect 96.3% more gastric cancer cases than conventional gastroscopy owing to higher sensitivity and anticipated better participant compliance in a large hypothetical screening population. Conclusions: We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer.
Induction chemotherapy plus definitive chemoradiotherapy versus chemoradiotherapy alone in esophageal squamous cell carcinoma: Long-term results and exploratory analyses of a randomized controlled trial.
Authors: Xi Mian , Chen BaoQing , Liu Shi-Liang , Zhu Yujia , Zhao Lei , Liu Mengzhong 
Published: June 2023

4061 Background: The previous results of our trial demonstrated that the addition of induction chemotherapy (IC) prior to definitive chemoradiotherapy (CRT) failed to significantly improve response rate or 3-year survival in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Here, we report the long-term results and exploratory analyses to further evaluate the therapeutic value of IC in ESCC. Methods: This was a single-institution, open-label, randomized, phase II trial. Patients with previously untreated, unresectable, stage II–IVA ESCC were randomly assigned in a 1:1 ratio to receive induction docetaxel (75 mg/m2 on day 1) and cisplatin (75 mg/m2 on day 1) every 3 weeks for two cycles, followed by concurrent CRT, or CRT alone. The primary endpoint was overall response rate at 3 months after CRT. Second endpoints were overall survival (OS) and progression-free survival (PFS). The relationship between tumor response to IC and long-term survival was analyzed as an exploratory, post-hoc analysis. Moreover, baseline tumor biopsies were evaluated by RNA-seq to identify patients who are more likely to benefit from IC. Results: Between May 2015 and September 2017, 110 eligible patients were randomly assigned to the IC+CRT group (n=55) or the CRT group (n=55). The overall response rate was 74.5% in the IC+CRT group versus 61.8% in the CRT group (P=0.15). At a median follow-up of 74.9 months, the 5-year OS rate was 31.8% in the IC+CRT group and 29.1% in the CRT group (P=0.68; HR, 0.91; 95% CI, 0.58–1.43). Similarly, no significant differences were identified in 5-year PFS between groups (30.5% vs. 25.5%, P=0.51; HR, 0.86; 95% CI, 0.56 to 1.34). Patients who responded to IC had significantly better survival than nonresponders. Six key genes were identified based on RNA-seq and gene expression comparison between responders and nonresponders after IC. Risk-score model was constructed by these key genes and then validated. Conclusions: Addition of induction docetaxel plus cisplatin before definitive CRT still failed to provide an obvious survival benefit in ESCC based on long-term follow-up. However, this strategy did result in a significantly improved survival in IC responders. Our results also revealed potential molecular biomarkers to predict who may benefit from IC. Clinical trial information: NCT02403531 .
Development of an artificial intelligence algorithm for adjuvant chemotherapy based on a nationwide registry of patients with gastric cancer by the Japanese Gastric Cancer Association (JGCA).
Authors: Yamada Yasuhide , Kamada Ami , Kabeya Yoshinori , Yoshida Sumito , Harada Hitoshi , Urakawa Naoki , Kanaji Shingo , Nakamura Yuma , Nagashima Kengo , Takeuchi Hiroya , Doki Yuichiro , Kitagawa Yuko , Kodera Yasuhiro , Kakeji Yoshihiro 
Published: June 2023

4063 Background: Recent marked advances in machine learning have led to expectations of the clinical application of artificial intelligence (AI) to support medical care. Methods: A survival analysis model which consisted of 31 covariates was adopted for AI algorithms using machine learning and these were constructed using clinical data sets for training. The performance of AI algorithms was evaluated in order to determine the optimal chemotherapy including surgery alone without any adjuvant chemotherapy with the highest survival rate for each patient. This involved using clinical data for verification to compare survival of an AI-recommended treatment group, for which therapy recommended by AI was actually administered, with an AI-deprecated group, for which therapy recommended by AI was not administered. Results: The clinical characteristics of 23653 patients and treatment are described in the Table from 2011 to 2018 in a nationwide registry of gastric cancer patients in Japan by the Japanese Gastric Cancer Association and were made available for this study. S-1 monotherapy was used the most frequently of all adjuvant chemotherapy in this study. We used the "restricted mean overall survival time" (RMST) of all the patients as metrics. The RMST in the AI-recommended and the AI-deprecated groups were 51.4 and 47.5 months, respectively. Patient data for the verification were matched baseline characteristics by the propensity score. This model predicted effectively overall survival after gastrectomy. The RMST of over 80 years old patients were 43.9 in the AI-recommended and 38.3 months in the AI-deprecated, respectively. This AI algorithm recommended adjuvant S-1 more frequently for patients with higher age, male, American Society of Anesthesiologists – physical status 2, Eastern Cooperative Oncology Group performance status 1, pT3/pT4, pN2/pN3, more than the upper normal limit of preoperative blood urea nitrogen, macroscopic types 2/3, differentiated adenocarcinoma, Roux-en-Y reconstruction, and Clavien-Dindo classification grade II/III. The RMST for pStage IIA/IIB/IIIA/IIIB/IIIC were 55.7/53.9/50.3/45.7/42.2 months in the AI-recommended and 55.1/50.7/43.9/36.9/32.0 months in the deprecated. This AI algorithm showed a higher survival rate in pStage III patients particularly. Conclusions: The AI algorithm could readily be integrated into clinical practice to choose adequate adjuvant chemotherapy for each patient based on each patient's baseline data because it trained and verified the nationwide registry has good predictive performance. [Table: see text]
Circulating tumor DNA as a marker of recurrence risk in locoregional esophagogastric cancers with pathologic complete response.
Authors: Lander Eric Michael , Huffman Brandon , Klempner Samuel J , Aushev Vasily N. , Ferguson Jenifer , Sharma Shruti , Jurdi Adham A , Liu Minetta C. , Eng Cathy , Gibson Michael K. 
Published: June 2023

4066 Background: Following neoadjuvant therapy and definitive surgery, up to one-third of patients (pts) with gastroesophageal adenocarcinoma with a pathologic complete response (pCR; tumor regression grade 0 [TRG0]) will recur, while up to one-half of pts with a near-pCR (TRG1) experience recurrence. Our study aims to evaluate postoperative circulating tumor DNA (ctDNA) as a prognosticator of recurrence in pts with pCR or near-pCR after curative-intent neoadjuvant chemotherapy (NAC) or chemoradiation (CRT) and surgery. Methods: We retrospectively identified pts from 11 institutions with stages I-III esophagogastric cancers who completed neoadjuvant therapy and had TRG0 or TRG1 scores at the time of curative-intent surgery. Postoperative plasma samples were collected for ctDNA analysis within a 16-week molecular residual disease (MRD) window after definitive surgery and serially during follow-up from 9/19/19 to 2/21/22. MRD by ctDNA was assessed using a personalized, tumor-informed ctDNA assay (Signatera mPCR-NGS assay). The primary outcome was recurrence-free survival (RFS), measured from the date of surgery to the first documented sign of radiographic recurrence. Survival analysis was performed using the maximum likelihood bias reduction method for Cox regression. Results: We obtained 250 blood samples from 45 pts with esophageal (N=18), gastroesophageal junction (N=17), and gastric (N=10) adenocarcinomas who received either NAC or CRT. The median follow-up for this cohort was 22.8 months (range: 0.3-81.7 months). Despite pts achieving pCR (N=12) or near-pCR (N=33), ctDNA-positivity in the 16-week MRD window (N=21) correlated with higher rates of recurrence (66.7%; 2/3) compared to the absence of ctDNA (11.1%; 2/18). Detectable ctDNA was associated with a significantly shorter RFS (HR 23.0, 95% CI 2.0-268.1; p=0.012). 35 pts had ctDNA analyzed at any post-surgical time point, where the recurrence rate was 87.5% (7/8) in ctDNA-positive pts compared to 7.4% (2/27) in ctDNA-negative pts, exhibiting a further reduction in RFS (HR 44.8; 95% CI 5.4-369.7; p<0.0001). Out of 8 ctDNA-positive pts, two (25%) converted from ctDNA-positive to ctDNA-negative with subsequent treatment. Conclusions: Within the subgroup of pts with esophagogastric adenocarcinoma and favorable pathologic responses (TRG 0-1) following neoadjuvant treatment, the presence of post-operative ctDNA identified pts with elevated recurrence risk. If validated in larger cohort studies, testing for ctDNA may be a useful biomarker to select pts at risk for recurrence with potential to inform prospective clinical trials for direction of adjuvant therapy.