bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy from the phase 1 SURPASS trial of ADP-A2M4CD8, a next-generation T-cell receptor T-cell therapy, in patients with advanced esophageal, esophagogastric junction, or gastric cancer.
Authors: Blum Murphy Mariela A. , Ajani Jaffer A. , Van Tine Brian Andrew , Clarke Jeffrey Melson , Butler Marcus O. , Lawrence Donald P. , Johnson Melissa Lynne , Cervantes Andres , Moreno Victor , Hong David S. , Brophy Francine Elizabeth , Navenot Jean-Marc , Lin Quan , Saro Jose , Norry Elliot 
Published: January 2023

349 Background: ADP-A2M4CD8 is a specific peptide enhanced affinity receptor mixed CD4+ and CD8+ T-cell therapy targeting the cancer testis antigen MAGE-A4 and modified with addition of a CD8α co-receptor designed to provide additional functionality to CD4+ T-cells. ADP-A2M4CD8 has demonstrated a favorable benefit to risk profile in the Phase 1 SURPASS trial (NCT04044859) in HLA A*02–eligible patients (pts) with unresectable or metastatic tumors positive for MAGE-A4 (Hong DS, et al. E-poster 540P: ESMO 2021; Virtual). Here we report updated clinical outcomes in pts with esophageal, esophagogastric junction (EGJ), or gastric cancer. Methods: SURPASS is a first-in-human trial consisting of a modified 3+3 dose-escalation design and an expansion cohort. Autologous T-cells are obtained by leukapheresis, transduced with a self-inactivating lentiviral vector expressing the MAGE-A4-specific T-cell receptor and the CD8α co-receptor, and infused back to the pts as ADP-A2M4CD8 following lymphodepleting chemotherapy. Primary and secondary objectives are safety and anti-tumor activity, respectively. Results: As September 6, 2022, 13 pts (11 male, 2 female) with esophageal (3), EGJ (8), and gastric cancer (2) received ADP-A2M4CD8 (range: 1.02–9.9x109 transduced T-cells). All pts had adenocarcinoma, median age was 55 years (range: 31–71), median MAGE-A4 expression H-score was 245 (range: 160–300), and pts received median of 2 lines of prior therapy (range 1–5). Adverse events (AEs) were consistent with those typically associated with lymphodepleting chemotherapy, cellular therapy, and/or disease. One pt had a Grade 5 (fatal) AE of pancytopenia. Overall response rate per RECIST v1.1 by investigator review was 15% (2 partial response [PR]). Disease control rate was 77% (2 PR+8 stable disease). This trial is ongoing, and additional data will be presented. Conclusions: Results indicate an acceptable benefit to risk profile and encouraging anti-tumor activity of ADP-A2M4CD8. An additional treatment cohort has been included in the updated SURPASS trial protocol to evaluate ADP-A2M4CD8 combined with nivolumab. A Phase 2, open-label trial in advanced esophageal and EGJ cancers has been initiated (SURPASS-2; NCT04752358). Clinical trial information: NCT04044859 .
A phase 1a dose-escalation, multicenter trial of anti-claudin 18.2 antibody drug conjugate CMG901 in patients with resistant/refractory solid tumors.
Authors: Xu Rui-hua , Wei Xiaoli , Zhang Dongsheng , Qiu Miaozhen , Zhang Yang , Zhao Hongyun , Chen Bo , Yan Joy 
Published: January 2023

352 Background: CMG901, an anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate, has demonstrated potent preclinical anti-cancer activity through monomethyl auristatin E (MMAE)-mediated cytotoxicity with bystander killing, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. Methods: This Phase 1a trial uses a modified 3+3 dose-escalation design to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity in subjects (ages 18-75 years) with advanced gastric, gastroesophageal junction (GEJ), pancreatic cancers, and other solid tumors. Eligible subjects are refractory and/or intolerant to standard therapies. CLDN18.2 expression was not required for study entry, but was retrospectively tested by the central lab. CMG901 was administered intravenously on Day 1 in 3-week (Q3W) cycle at doses of 0.3, 0.6, 1.2, 1.8, 2.2, 2.6, 3.0, and 3.4 mg/kg. Primary endpoints include safety and tolerability. Major efficacy endpoints include objective response rate (ORR) and disease control rate (DCR) based on RECIST v1.1. Pharmacokinetics (PK) and immunogenicity are also assessed. Results: As of August 4, 2022, 27 subjects (13 gastric/GEJ cancer and 14 pancreatic cancer patients) received CMG901 at dose levels up to 3.4 mg/kg. The median prior lines of systemic therapy were 2 (range: 1 to 5). Drug-related grade ≥3 adverse events (AEs) occurred in 3/27 (11.1%) patients. No drug-related grade 4 or 5 AEs were reported. MTD was not reached. In CLDN18.2-positive gastric/GEJ cancer patients, ORR and DCR were 75.0% and 100%, respectively, with ORR of 100% in the 2.6, 3.0, and 3.4 mg/kg Q3W dose cohorts. Median progression-free survival (mPFS) and median overall survival (mOS) were not reached yet. PK data showed that patients had low systemic exposure to unconjugated MMAE. Subsequent results will be presented. Conclusions: CMG901 was well-tolerated with preliminary promising clinical efficacy in patients with CLDN18.2-positive gastric/GEJ cancer. The Phase 1b dose-expansion trial in gastric/GEJ adenocarcinoma, pancreatic cancer, and other solid tumors is rapidly enrolling, with multiple pivotal (Phases 2 and 3) trials planned. Clinical trial information: NCT04805307 . [Table: see text]
First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Chinese subgroup analysis with 3-year follow-up.
Authors: Shen Lin , Bai Yuxian , Lin Xiaoyan , Li Wei , Wang Jufeng , Zhang Xiaochun , Pan Hongming , Bai Chunmei , Bai Li , Cheng Ying , Zhang Jingdong , Zhong Haijun , Ba Yi , Hu Wenwei , Xu Rui-hua , Guo Weijian , Qin Shukui , Wang Rui , Sullivan Kendall , Liu Tianshu 
Published: January 2023

353 Background: NIVO + chemo demonstrated clinically meaningful improvement in overall survival (OS) and an acceptable safety profile vs chemo in previously untreated Chinese pts from CheckMate 649, consistent with the overall study population with advanced GC/GEJC/EAC. Results from CheckMate 649 led to approval of 1L NIVO + chemo in multiple countries, including China. We report 3-year follow-up results in Chinese pts. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2-positive GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. 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 progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 37 month (mo) minimum follow-up, NIVO + chemo continued to demonstrate clinically meaningful improvement in OS and PFS vs chemo in pts with PD-L1 CPS ≥ 5 and in all randomized pts. The 36-mo OS rate was 31% with NIVO + chemo vs 11% with chemo in pts with PD-L1 CPS ≥ 5 and 26% vs 9% in all randomized pts, respectively. Objective response rate (ORR) (95% CI) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 68% (56-79) with NIVO + chemo and 48% (36-60) with chemo, and in all randomized patients was 66% (55-76) and 45% (35-56), respectively. Responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, with median duration of response (mDOR) (95% CI) of 12.5 mo (7.2-23.4) vs 6.9 mo (3.9-8.5); in all randomized pts, mDOR was 12.5 mo (7.2-17.7) vs 5.6 mo (4.4-8.3), respectively. No new safety signals were identified. Conclusions: After 3 years of follow-up, NIVO + chemo continued to demonstrate clinically meaningful survival benefit and durable objective responses vs chemo in Chinese pts, with an acceptable safety profile, consistent with the overall study population with advanced GC/GEJC/EAC. These results further support NIVO + chemo as a 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . [Table: see text]
Relevance of adjuvant chemotherapy in elderly patients with low rectal tumors.
Authors: Adeleke Sola , Davies Aaron , Okoli Somto , Wang Kaiwen , Brown Nicholas Fraser , Galante Joao R , Elwes Flora , Choy Adrian , Karova Mariya , Dahal Luna , George Sneha , Durve Meeta , Mikropoulos Christos , Edwards Albert , Raman Rakesh , Clarke Amanda 
Published: January 2023

37 Background: The balance between the benefits and toxicities of adjuvant systemic chemotherapy is crucial in the elderly, and often co-morbid patients who have undergone total mesorectal excision (TME) surgery for carcinomas of the lower rectum (1). Tumour distance from the anal verge is a known prognostic factor in rectal cancer (2, 3) and it may influence the effectiveness of adjuvant chemotherapy (AC) (4). This study evaluated the differences in the survival outcomes between patients on surveillance(S) and those who received AC in a multi-centre, real-world setting with a focus on the elderly cohort. Methods: Data was extracted from electronic patient records from 4 NHS trusts in Kent, UK. We retrospectively analysed records of patients between 1 Jan 2014 and 31 Dec 2019, who had neoadjuvant chemoradiotherapy, were down-staged and then offered either S or AC based on clinician’s judgement. The tumour distance from the anal verge was measured through high resolution MRI. The patients were downstaged following assessment as their pTNM staging was lower than their cTNM staging. Results: 589 patients treated for rectal cancer were identified. Of these, 168/589(28%) had non-metastatic disease, were later down-staged at TME and were offered S or AC. 95/168 (57%) of these patients received AC. Patients who received AC were younger (median age 63 vs 70 years, p< 0.001) and with additional poor prognostic factors such as extramural venous invasion EMVI+ (74 vs 39%, p= 0.001), circumferential resection margin CRM+ (89 vs 70% p = 0.001) and pathological nodal involvement (AJCC stage III disease) ( p< 0.001) (table) compared to those on S. Our findings did suggest that patients on surveillance with tumours < 5cm from the anal verge had a longer disease-free survival(DFS) than those who received chemotherapy; this was especially the case in the elderly patient cohort (HR 0.13 95% CI 0.02-0.99, p= 0.049).Our findings also showed that the DFS benefit for patients under surveillance increased with age. Surveillance was most effective in patients over 60 years old compared to those under 60. However, age or distance from anal verge did not have an impact on overall survival (HR 1.01 95% Cl 0.95-1.08 p= 0.70). Conclusions: Although patients treated with AC were younger than patients on S, their tumours had additional poor prognostic factors. Patients on surveillance with tumours <5cm from the anal verge enjoyed a longer DFS but no OS benefit. Elderly patients with tumours < 5cm from the anal verge with no poor prognostic features could derive a benefit from surveillance and avoid chemotherapy-related toxicity. However, our findings will need to be corroborated in prospective studies. [Table: see text]
Long-term survival outcome of multi-institutional prospective phase II trial of conversion surgery: CCOG1403.
Authors: Ito Seiji , Ito Yuichi , Kobayashi Daisuke , Matsushita Hidenobu , Tanaka Yuri , Kodera Yasuhiro ,   Chubu Clinical Oncology Group (CCOG)
Published: January 2023

380 Background: From the result of CONVO-GC-1, safety and efficacy of conversion surgery are shown. But there are few prospective studies about conversion surgery. We conducted multi-institutional prospective study of conversion surgery (CCOG1403). Methods: The patients (pts) with gastric cancer, who were initially regarded as non-curable and curably resectable after at least one course of chemotherapy, were enrolled. After diagnostic laparoscopy or laparotomy, pts were performed gastrectomy in case of curably resectable. The primary endpoint was 3-year survival from the start of first line chemotherapy. The planned sample size was 30, with one-sided alpha of 5%, power of 90%, expected 3-year survival rate of 27%, and threshold of 7%. Secondary endpoints were 5-year survival from the start of first line chemotherapy, the proportion of R0 resection, 3-year survival from the conversion surgery, pathological response, and adverse events. This study was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000014251. Results: From April 2014 to March 2019, 30 pts were enrolled from 7 institutions. The mean age was 66.7. Non-curable factors were PER(11), LYM(9), HEP(6), T(4), CY(1), PUL(1), BRA(1), and other(1), respectively. Four pts had more than one non-curable factors. The categories of Yoshida’s classification were Cat.1(3), Cat.2(16), Cat.3(8), and Cat.4(2). Regimen of chemotherapy were SOX (11), SP (8), XP+HER (8), PTX ip containing regimen (6), and others (12). Clinical responses of preoperative chemotherapy were PR in 24 and SD in 6. Operative procedures were TG (18), DG (7), and PG (1). Median operative time was 278.5min. and median blood loss was 417.5ml. Twenty-four (80%) pts achieved R0 resection. Five pts suffered >= C-D Grade III postoperative complication but all pts recovered. The pathological finding revealed major response, defined as disappearance more than two third of the primary tumor, in 26.7% (8/30) pts. Twenty-seven (90%) pts received postoperative chemotherapy. Among 24 pts with R0 resection, 16 pts experienced recurrence in PER(5), LYM(4), HEP(4), PUL(3), BRA(1), and others(4). In 30 pts accrued, 19 (66.3% 43.9-80.1), 16 (55.3% 34.3-71.7) survived more than 3 years from the start of first line chemotherapy and the conversion surgery, respectively. Conclusions: Conversion surgery is effective and worth for testing in the following randomized trial. Clinical trial information: UMIN000014251 .
Clinical outcomes of endoscopic resection of gastric GIST.
Authors: Park Jong-Jae , Joo Moon Kyung , Lee Beom Jae , Kim Sunsuk , Chun Hoon Jai 
Published: January 2023

383 Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in stomach. We evaluated the long-term clinical outcomes of endoscopic treatment for gastric GISTs. Methods: This is a retrospective study that enrolled 135 cases of gastric subepithelial tumors (SETs) resected by endoscopic procedures and confirmed as GISTs by histopathology from 2005 to 2019. The immediate and long-term clinical outcomes were analyzed retrospectively. Results: The mean age was 57.9 years, and the mean tumor size was 2.1 cm. Of the tumors, 43.0% were located in the corpus, followed by the fundus (26.7%) and cardia (17.0%). Most tumors (85.2%) were resected by endoscopic submucosal dissection. Macroperforation occurred in 4.4% and microperforation in 6.7% of the cases. The R0 resection rate was 15.6%. However, complete resection by the endoscopic view was 90.4%, of which 54.8% were in the very-low-risk group, followed by the low (28.1%), intermediate (11.9%), and high-risk groups (5.2%). During 36.5 months of follow-up, recurrence was found in four (3.4%) of the 118 patients who were monitored for more than six months (low risk group:1/37, 2.7%; intermediate risk group: 2/11, 18.2%; high risk group: 1/6, 16.7%). Conclusions: Endoscopic treatment of a GIST appears to be a feasible procedure in selected cases, however, additional surgery should be considered if pathologic result is corresponding to intermediate or high risk group.
Efficacy of fecal microbiota transplantation in patients with anti-PD-1–resistant/refractory gastrointestinal cancers.
Authors: Peng Zhi , Zhang Xiaotian , Xie Tong , Cheng Siyuan , Han Zihan , Wang Shulin , Ban Zongwen , Xu Xiaomin , Zhu Zhengnong , Zhu Jing , Yin Xiaochen , Li Sumin , Shen Lin 
Published: January 2023

389 Background: Gut microbiome that changed the response to anti-PD-1 therapy (aPD-1) against melanoma by fecal microbiota transplantation (FMT) has been reported. To investigate whether resistance to aPD-1 against gastrointestinal (GI) cancers can be overcome by FMT, this single arm, open label, investigator-initiated trial explored the efficacy of combination of FMT + nivolumab in patients with aPD-1 resistant/refractory (aPD-1r)-GI cancers. Methods: Ten patients were planned to be enrolled. Interim analysis was planned when at least one patient demonstrated effective outcome. FMT capsules were from healthy donors. FMT capsules (CFU≥1×1012) were administered in the first week. Nivolumab (3mg/kg, q2w) combined with a maintenance dose of FMT capsules (CFU≥1.5×1011) were started at Week 2 and continued for 6 cycles or until progress of disease (PD) after 3 cycles of treatment. If patient responded to the treatment and would be benefit from the treatment beyond 6 cycles, patients would enter the Expended Excess Program to continue the therapy. RECIST v1.1 evaluation was performed every 3 cycles. Stool samples were collected every 2 weeks for metagenomic analysis of gut microbiota. Results: 8 aPD-1r patients were enrolled and finished the study by the time of this analysis. Nivolumab + FMT therapy was well tolerated. No serious adverse reaction was observed. 8 patients completed 3 cycles of treatment. Metagenomic analysis of gut microbiota from Responders (R) and Non-Responders (NR) groups revealed the gut microbial composition of R group is significantly closer to that of the donor than NR group, which indicated much better colonization of donor microbiota in R. Alpha diversity was significantly higher in R than that in NR, along with a set of differential bacterial species and biological process functions including dTMP biosynthetic process enriched, suggesting gut microbiome’s potential role in the treatment. The flow cytometry analysis indicated a significant increase of IFN-ϒ+ cells in PBMCs in R at Day 8 after FMT (the highest increase during the study), before combination therapy had started. A significant increase in Ki-67+ cells in PBMCs was also observed in the R group. Relative abundance of differential bacterial species enriched in R were found to be significantly negative correlated with tumor markers like CA199 and tumor volume, and some were positively correlated with expression of CD3+CD4+ cells and CD3+CD8+ cells. Conclusions: FMT+aPD-1 may overcome the resistance to aPD-1 against GI cancer via changing gut microbiota structure. Trial registration number: NCT04130763. Keywords: gastrointestinal cancers; fecal microbiota transplantation; anti-PD-1 therapy. Clinical trial information: NCT04130763 .
Long-term outcomes from adding durvalumab to neoadjuvant treatment of operable gastroesophageal cancers: Results from a multicenter study LUD2015-005.
Authors: Middleton Mark R. , Karydis Ioannis , Lu Xin , Ryan Aileen , Venhaus Ralph Rudolph , Ramirez Kristen Auferio , Macri Mary , Ricciardi Toni , Lawrence Megan , Scott-Brown Martin , Griffiths Gareth Owen , Collins Linda , Griffiths Lucinda , Wilding Sam , Lord Simon , Owen Richard , Petty Russell D. 
Published: January 2023

398 Background: Phase III studies have shown a survival benefit for the addition of immune checkpoint inhibitors to conventional chemotherapy for patients with gastroesophageal cancer (GEC). Large scale studies of chemoimmunotherapy prior to and after surgery are under way. We sought to characterise the effects of the PDL1 inhibitor durvalumab (D) with standard neo-adjuvant chemo(radio)therapy regimens in an open label phase I/II study in patients (pts) with operable GEC (LUD2015-005, NCT02735239, EudraCT 2015-005298-19). Methods: In pts identified as suitable for potentially curative surgery we gave D (750mg q2w) alongside their standard treatment. Pts had D only at first then Oxaliplatin and Capecitabine (CapOx) q3w or fluorouracil, leucovorin, oxaliplatin and taxotere (FLOT) starting with the third cycle of D. Chemotherapy and further D were given for 6 (CapOx) or 8 (FLOT) weeks before pts had surgery and for up to 12 further infusions of D after operation. Patients on FLOT could also have more chemotherapy. Pts suitable for chemoradiotherapy (CXRT, CROSS regimen) were offered two cycles of D before starting their treatment, and were able to have up to 12 further cycles after recovering from surgery. Participants were followed for toxicity, response and survival from the time of study enrolment until death, for 3 years or until June 2022 when the study ended. Results: 11 pts received D-CapOx, 9 D-FLOT and 15 D-CXRT. All were evaluable for safety and efficacy. Treatment side effects were as expected for the agents used with diarrhoea, nausea and fatigue the most commonly reported and no new safety signals. 156 of 160 planned pre-op D doses were given. Only 2 out of 35 patients did not have surgery, both due to progressive disease on D-CXRT. 23 of the 33 patients having surgery had post-operative treatment. Amongst 33 evaluable pts 2 (5.7%) and 6 (17.1%) had complete or partial pre-op responses (RECIST) and 3 (8.6%) progression prior to surgery. Tumor regression at surgery (Mandard 1-3) occurred in 24/33 pts. Median recurrence free survival was 25.4 months (mo) (D-CapOx), 32.0 mo (D-FLOT) and not reached (D-CXRT). 2 year survival was 81.8%, 77.8% and 77.8% respectively in the 3 arms. Conclusions: Adding D to standard neo-adjuvant regimens for GEC is well tolerated. Survival times and response rates exceeded those expected for the regimens used (2 year survivals with FLOT 68% and CROSS 67%) in this non-randomised multi-centre trial. Clinical trial information: NCT02735239 .
Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study.
Authors: Tabernero Josep , Prager Gerald W. , Fakih Marwan , Ciardiello Fortunato , Van Cutsem Eric , Elez Elena , Cruz Felipe Melo , Wyrwicz Lucjan , Stroyakovskiy Daniil , Papai Zsuzsanna , Poureau Pierre-guillaume , Liposits Gabor , Cremolini Chiara , Bondarenko Igor , Modest Dominik Paul , Benhadji Karim A. , Fougeray Ronan , Leger Catherine , Amellal Nadia , Taieb Julien 
Published: January 2023

4 Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (Bev) demonstrated promising efficacy in a randomized phase 2 trial of heavily pretreated patients (pts) with metastatic colorectal cancer (mCRC). SUNLIGHT was conducted to confirm these findings. Methods: The global phase 3 SUNLIGHT study enrolled pts aged ≥18 years with histologically confirmed mCRC, ECOG PS 0/1, and treated with 1-2 prior chemotherapy regimens in an advanced setting, including fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (if medically considered) and/or anti-EGFR monoclonal antibody for RAS wild-type tumors. Pts were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) alone or combined with Bev (5 mg/kg on days 1 and 15). Primary endpoint was overall survival (OS). Results: Between Nov 2020 and Feb 2022, 492 pts were randomised to receive FTD/TPI + Bev (n = 246) or FTD/TPI (n = 246). Baseline characteristics were balanced between arms. FTD/TPI + Bev significantly extended OS over FTD/TPI, median OS was 10.8 months vs 7.5 months, respectively (HR, 0.61; 95% CI, 0.49, 0.77; P< 0.001). OS rates at 12 months were 43% in the FTD/TPI + Bev arm and 30% in the FTD/TPI arm. Median progression-free survival was 5.6 months in the FTD/TPI + Bev arm and 2.4 months in the FTD/TPI arm (HR, 0.44; 95% CI, 0.36,0.54; P< 0.001). Grade ≥3 adverse events (AEs) were not significantly increased in the FTD/TPI + Bev arm vs the FDT/TPI arm (72.4% vs 69.5%). No new safety signals were noted. Conclusions: FTD/TPI + Bev provided a statistically significant and a clinically meaningful 3.3-month improvement in OS, extending mOS up to 10.8 months, with a 39% reduction in the HR of death in pts with refractory mCRC and with a predictable and acceptable safety profile. Clinical trial information: NCT04737187 .