bluuebunny/crossref_metadata_2025 huggingface dataset:
Unveiling survival strategies: The impact of treatment modalities on patients with esophageal cancer and the role of racial disparities.
Authors: Castillo Dani Ran , Jeon Won Jin , Chong Esther G , Kim Jae Y. , Wu S.Peter
Published: January 2024

257

Background: Managing esophageal cancer (EC) involves neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy as the standard of care. However, some patients may remain unsuitable for esophagectomy. This study explores real-world outcomes in EC patients across different treatments, considers prognostic factors, and examines potential racial disparities. Methods: Data from 44,181 patients diagnosed with locally advanced EC between 2004-2017 were extracted from the National Cancer Database. The cohort was stratified into three groups: nCRT followed by esophagectomy, definitive RT (dCRT), single-modality RT. The dataset included 24,676 patients who received nCRT with esophagectomy or dCRT (N=17,534) and 1,971 patients who received single-modality RT. Endpoints included overall survival (OS). Cox Proportional Hazards Model was employed for multivariate survival analysis. Chi-square test was applied to the covariate demographic data. Results: nCRT followed by esophagectomy significantly improved OS compared to dCRT (mOS 43.5 vs. 20.1 months, p < 0.001). Single-modality RT had an mOS of 14.4 months. In the RT group, 73% were over 65 years old compared to 59% in the dCRT group (p < 0.001). Over 60% of patients had node-positive disease in both RT and dCRT groups (69% vs. 61.4%). More privately insured patients received multimodal treatment compared to publicly insured patients (27.3% vs. 16.8%, p < 0.001). Over 70% of patients were willing to travel within 20 miles for treatment, 60% underwent treatment in community programs. Racial disparities were observed, with Black patients experiencing worse outcomes compared to all other groups, while Asian and Hispanic patients had better outcomes (table1). In the squamous cell histology subset treated with dCRT, mOS was 22 (20.6 – 23.6 months) for Black patients, 27 (26 – 28) months for White patients, 36 (30-46) months for Hispanic patients, and 37 (30-44) months for Asian/Pacific Islander patients (p < 0.001). Conclusions: This real-world data analysis underscores the effectiveness of nCRT followed by esophagectomy in providing the best survival benefit for EC patients compared to dCRT or RT alone. Racial disparities emerged as significant factors influencing cancer survival outcomes. These identified factors including race and age can assist clinicians in making better-informed decisions regarding treatment pathways for specific patient populations. [Table: see text]
INTERCEPT Program of circulating tumor DNA (ctDNA) testing for minimal residual disease (MRD) in colorectal cancer (CRC): Results from a prospective clinical cohort.
Authors: Maddalena Giulia , Pellatt Andrew Jared , Eluri Madhulika , Parseghian Christine Megerdichian , Aziz Kathryn , Alfaro Kristin , Kell Robert J. , Bent Alisha Heather , Huey Ryan W , Uppal Abhineet , Konishi Tsuyoshi , Overman Michael J. , Morelli Maria Pia , Willis Jason , Shen John Paul Y.C. , Raghav Kanwal Pratap Singh , Newhook Timothy E. , Morris Van K. , Dasari Arvind , Kopetz Scott
Published: January 2024

27

Background: Minimal residual disease, defined by ctDNA+ in the absence of macroscopic of disease, represents a new and clinically poorly defined subset of patients (pts). While observational cohorts have been reported on the prognosis of MRD, there is little information on the impact of returning and acting on ctDNA results on the subsequent ability to detect radiographic disease. Here we provide real-world evidence form a large prospective cohort where ctDNA testing was routinely performed and returned to pts and providers, providing opportunities to understand the prognostic performance of ctDNA in practice, including the rate of false negatives defined as radiographic recurrence without detectable ctDNA. Methods: The INTERCEPT program enrolled pts undergoing curative intent surgery for stages II-IV CRC at MD Anderson Cancer Center. A tumor-informed MRD assay (Signatera) was drawn post-operatively and every 3 months as per established reimbursement guidelines. Pts enrolled between Jan-Dec 2022 were included with follow up through Aug, 2023. Post-op timepoint was defined as any test within 6.5 months of surgery to include adjuvant therapy. A false negative result was defined as a negative test but with radiographic detection of recurrence within the subsequent 4 months. Results: A total of 1,140 pts were included, with 44.7% female and 39% with advanced disease. At least one ctDNA+ result was obtained in 338 patients (29.6%). When limited to pts with a post-operative/post-adjuvant timepoint (n= 520) and a median follow up of 10.4m, the 12m DFS was 94.2% for ctDNA-, and 54.3% for pts with at least 1 ctDNA+ test (median DFS of 14.9m); HR 17.67 (95% CI: 10.08 – 30.99), p<0.0001. When segregated by stage, ctDNA remained the most important predictor of outcomes [Table], such that pts with stage IV ctDNA- had better prognosis than pts with stage II ctDNA+ (38.9% vs 87.7% 12mDFS, p=.002). For 15 pts, we detected a false negative ctDNA, representing a rate of 1.3% (15/1140) corresponding to a negative predictive value (NPV) of 98.1%. Conclusions: In this first prospective real-world ctDNA program, MRD testing had a high NPV (98.1%) with very few false negative cases. The prognostic importance of ctDNA was confirmed and exceeded the risk prediction of stage alone, underlying and supporting the importance of introducing the test in practice and the need to investigate interventional studies, as are ongoing in the INTERCEPT program (crcmrd.org). [Table: see text]
Clinical risk factors for splenic hilar nodal metastasis in remnant gastric cancer after distal gastrectomy.
Authors: Sakon Ryota , Yoshikawa Takaki , Ogawa Rei , Nishino Masahi , Ishizu Kenichi , Watanabe Masahiro , Kinoshita Takahiro , Wada Takeyuki , Hayashi Tsutomu , Yamagata Yukinori
Published: January 2024

270

Background: Splenectomy is usually considered to be required for complete dissection of splenic hilar lymph node (#10 LN) in gastric cancer (GC). Although spleen-preserving D2 was established for the advanced GC not invading the grater coverture based on the JCOG0110 clinical trial, D2 gastrectomy with splenectomy remains the standard procedure for the advanced GC involving grater coverture in Japan. However, the applicability of this treatment for remnant gastric cancer (RGC) is unclear because the lymphatic flow and lymphatic metastatic pattern may have been changed after initial gastrectomy. There are no guidelines for splenic hilar nodal dissection for RGC. In this study we evaluated risk factors for #10 nodal metastasis in RGC. Methods: This study retrospectively examined RGC patients who received gastrectomy with #10 nodal dissection after distal gastrectomy at two high-volume cancer centers in Japan between 1998 and 2015. Results: 99 patients were entered in this study. The #10 nodal metastatic rate was 12.1% (12/99). Initial gastrectomy was performed for benign in 42 patients and for malignant in 52 patients. The median duration from the initial gastrectomy was 20 (1-55) years. Main tumor location was lesser curvature in 46 patients, anterior wall in 11, greater curvature in 19, posterior wall in 11, and the whole in 12. Large type 3(≥8cm) and type 4 were found in 18 cases. The median tumor size was 50 (10-232) mm. The depth of invasion was cT1 in 31 patients, cT2 in 19, cT3 in 11, cT4a in 28, and cT4b in 10. Histology was differentiated type in 46 patients and undifferentiated type in 56. Completion gastrectomy was performed in 98 patients and partial gastrectomy in 1. 89 patients underwent splenectomy. The univariate analysis showed that tumor location (lesser curvature vs others, p=0.027) and depth of invasion (cT1-3 vs cT4, p=0.032) were significant risk factors for #10 nodal metastasis. By multivariate analysis, these two factors remained significant. Metastasis to #10 nodal metastasis was 0% (0/28) in patients without both risk factors, 11-12% in those with at least one risk factor, and 30% (6/20) in those with both risk factors. Conclusions: The tumors not confined to the lesser curvature and cT4 were significant risk factors for #10 nodal metastasis of RGC after distal gastrectomy. Splenectomy should be considered for complete splenic hilar nodal dissection when these risk factors are positive.
Retrospective cohort study to evaluate the efficacy and safety of T-DXd in HER2-positive unresectable advanced or recurrent gastric or gastroesophageal junction cancer: EN-DEAVOR study.
Authors: Nakanishi Koki , Kodera Yasuhiro , Kawakami Hisato , Makiyama Akitaka , Konishi Hirotaka , Morita Satoshi , Narita Yukiya , Sugimoto Naotoshi , Minashi Keiko , Imano Motohiro , Inamoto Rin , Kume Hiroki , Yamaguchi Keita , Hashimoto Wataru , Muro Kei
Published: January 2024

274

Background: Relatively limited clinical data exists for patients who receive T-DXd treatment in the 3L+ setting for HER2-positive unresectable advanced/recurrent gastric or gastroesophageal junction cancer. Insufficient data exists on real world patient populations that are likely to be excluded from clinical trials (e.g., elderly patients, those with significant co-morbidities). Therefore, this study was designed to evaluate the real-world clinical effectiveness and safety of T-DXd in patients with HER2-positive gastric cancer. Methods: This study (UMIN000049032) was a real-world, multicenter, non-interventional, retrospective cohort study conducted in Japan. Patients with HER2-positive unresectable advanced/recurrent gastric or gastroesophageal junction cancer treated with T-DXd were enrolled. The patients were first administered T-DXd between Sep 2020, when T-DXd became available for clinical use in Japan, and Sep 2021. We followed up on these patients' records until Sep 2022. The endpoints were overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response (ORR), adverse events (AEs) of Grade ≥3, and adverse events leading to dose reduction, interruption, or discontinuation. Results: A total of 318 patients were enrolled, and 312 patients were analyzed, excluding 6 patients due to double enrollment or miss-enrollment (median age 70 years, performance status 0 or 1/≥2 [87%/12%], 43% patients with ascites). Median OS, rwPFS, and TTF were 8.90 months, 4.57 months, and 3.94 months, respectively. Overall ORR was 32.7%; it was 43.8% in the 226 patients with a target lesion. Regarding safety, the incidence of Grade ≥ 3 AEs was 48.4%. A total of 190/312 (60.9%) patients treated with T-DXd experienced dose reduction, interruption, or discontinuation of T-DXd treatment due to AEs. The most common reasons for dose reduction or interruption were neutrophil count decreased, anorexia, and malaise, while the most common reasons for discontinuation were interstitial pneumonia, anorexia, malaise, and nausea. Conclusions: This study demonstrates the effectiveness and safety of T-DXd in the 3L+ setting in real-world patients with HER2-positive gastric or gastroesophageal cancer. No new safety signals were identified on the basis of this study.
Diagnostic performance of endoscopy and MRI in identifying true response among patients with rectal cancer treated with total neoadjuvant therapy and selective watch and wait or TME.
Authors: Omer Dana Mohamed Rashid , Williams Hannah , Lin Sabrina T. , Thompson Hannah M , Verheij Floris S. , Yuval Jonathan B. , Buckley James T. , Qin Li-Xuan , Gollub Marc J. , Garcia-Aguilar Julio ,   OPRA Consortium
Published: January 2024

28

Background: The success of a watch-and-wait (WW) strategy for rectal cancer relies on restaging endoscopy and MRI to correctly identify a true response (TR) to neoadjuvant treatment. This secondary analysis of the OPRA trial is the first study to evaluate the restaging assessment’s diagnostic performance in a large cohort of WW patients. Methods: In the OPRA trial, patients with stage II/III rectal cancer were treated with total neoadjuvant therapy (TNT) and restaged with endoscopy and MRI 8±4 weeks post-treatment. Patients with a clinical complete (cCR) or near complete (nCR) response were offered WW; patients with an incomplete clinical response were recommended for total mesorectal excision. Diagnostic parameters, including accuracy, sensitivity, specificity, positive and negative predictive values, were calculated using TR as the reference standard. TR was defined as pathologic complete response for patients treated with TME or sustained cCR for ≥2 years for patients on WW. Contingency tables were prepared for two approaches: one considering either cCR or nCR positive for a TR, and one considering cCR as the only response grade positive for a TR. Results: Of the 304 patients restaged after completing TNT, 265 (87.2%) with ≥2 years of follow-up data available were included. Restaging endoscopy outperformed MRI across all parameters. Accuracy improved minimally to 66% when both modalities agreed on a cCR or nCR (Table). Restricting a positive result to cCR resulted in higher specificity, lower sensitivity, and higher accuracy (75%) (Table 1B). The positive posttest probability that a patient with a cCR had a TR was 81%, while the negative posttest probability that a patient with a non-cCR had a TR was 30%. Conclusions: Restaging endoscopy outperforms MRI in predicting TR, but the assessment’s overall accuracy even when both tests are combined remains suboptimal. Our results highlight the challenge of recognizing TR using subjective restaging exams. Opportunities to improve diagnostic accuracy include machine learning and radiomics, which have the potential to aid clinicians in identifying true responders. [Table: see text]
First-line FOLFOX therapy for advanced esophageal squamous cell carcinoma: Multicenter prospective study in Japan.
Authors: Fushiki Kunihiro , Tsushima Takahiro , Tsubosa Yasuhiro , Notsu Akifumi , Yamamoto Shun , Nakayama Izuma , Imazeki Hiroshi , Hamai Yoichi , Motoori Masaaki , Nomura Motoo , Nakachi Kohei , Fumita Soichi , Otsu Satoshi , Tanaka Yoshihiro , Murakami Kentaro , Furuta Mitsuhiro , TAKEUCHI HIROYA , Kato Ken
Published: January 2024

280

Background: Cisplatin (CDDP) plus fluoropyrimidine was the standard first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). FOLFOX is promising option especially in patients with ESCC intolerant to CDDP but there were limited data on efficacy and safety of FOLFOX. We conducted a multicenter prospective observational study of FOLFOX for Japanese patients with ESCC intolerant to CDDP. Methods: Eligible participants had clinical stage IVB ESCC, with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, intolerant to CDDP, but tolerant to FOLFOX. FOLFOX (oxaliplatin 85 mg/m², leucovorin 200 mg/m², bolus fluorouracil 400 mg/m², and infusional fluorouracil 2400 mg/m²) was administered every 14 days. The primary endpoint was the response rate (RR) by RECIST v1.1 and the null hypothesis of RR was 10%. Based on the assumption of performing a one-sided test with an α of 0.10, 29 patients were needed to ensure the statistical power of 90% assuming RR of 30%. Results: In this study, 31 patients were enrolled from 14 hospitals between Apr. 2021, and Jul. 2022 and 30 patients received FOLFOX. The patient characteristics were: median age, 77 (range 66–89); male/female, 30/1; ECOG PS 0/1/2, 16/12/3; median creatinine clearance, 49.9 ml/min (33.4–80.2); median G8 score, 12 (range 7–17); and median CARG score, 8 (range 6–13). As the data cutoff of Jul 2023, all 30 patients discontinued FOLFOX. The reason for treatment discontinuation was disease progression, 86.7%; adverse events, 13.3%. Median follow-up time (interquartile range: IQR) was 20.2 (IQR 13.7–23.1) months. Median number of cycles administered were 5 (range 1–24). The RR was 22.6% (80%CI 0.13–0.35; p = 0.031) and disease control rate was 42.0%. Median progression-free survival was 3.9 months (95% CI 2.3–6.1). Median overall survival was 13.3 months (95% CI 9.5–not reached). The incidence of grade 3 or higher adverse events was 40% (neutropenia 26.7%, anemia 3.3%, nausea 6.7%, anorexia 6.7%, infection 6.7%, peripheral sensory neuropathy 3.3%). There was no treatment related death. Twenty-three patients (76.7%) received subsequent therapies, such as nivolumab (70%). Conclusions: First-line FOLFOX showed an acceptable safety profile and the prespecified statistical efficacy target was achieved. FOLFOX might be a treatment option for advanced ESCC patients who are intolerant to CDDP. Clinical trial information: UMIN000044485 .
A phase Ib/II study of ASKB589 (anti-Claudin 18.2 [CLDN18.2] monoclonal antibody) combined with CAPOX and PD-1 inhibitor as first-line treatment for locally advanced, relapsed and metastatic gastric/gastro-esophageal junction (G/GEJ) adenocarcinoma.
Authors: Peng Zhi , Shen Lin , He Ying , Chen Jing , Hickingbottom Barbara , Lu Jianfeng
Published: January 2024

317

Background: ASKB589 is a humanized IgG1 monoclonal antibody against Claudin 18.2 (CLDN18.2) with high affinity and enhanced antibody-dependent cytotoxicity. We report preliminary safety and efficacy data from an ongoing Phase Ib/II, dose-escalation and expansion study of ASKB589 combined with capecitabine, oxaliplatin(CAPOX) and Sintilimab as first-line treatment of G/GEJ adenocarcinoma (NCT05632939). Methods: The study enrolled G/GEJ adenocarcinoma patients(pts) with CLDN18.2 positive expression. The dose-escalation phase used a 3 + 3 design to determine the maximum tolerated dose (MTD). In expansion, the dose of ASKB589 selected for expansion was based on the safety, tolerability, pharmacokinetics and antitumor activity during escalation phase. Responses were assessed by RECIST 1.1 every 2 cycles (6 weeks). Adverse events (AEs) were graded using CTCAE v5.0. In escalation, pts received ASKB589 intravenously (IV) at doses of 6 mg/kg (n = 3) and 10 mg/kg (n = 6) every 3 weeks (Q3W) combined with CAPOX and Sintilimab. In expansion, all pts received ASKB589 IV at a dose of 6 mg/kg. Results: As of July 20, 2023, 9 pts were enrolled in escalation. No DLT was observed and thus the MTD was not identified. 9(100%)pts had treatment-related adverse events (TRAEs), the most common being nausea (77.8%), hypoproteinemia (66.7%), and hyponatremia (55.6%). While the majority of TRAEs were grade 1 or 2, 1 pt (11.1%) had a grade 3 TRAE (decreased neutrophils [10mg/kg]). In expansion, 26 pts with CLDN18.2 moderate-to-high expression (≥2+ membrane staining intensity in ≥40% of tumor cells) were included in the safety set. 24(92.3%) pts had TRAEs, the most common being nausea (65.4%), vomiting (53.8%), hypoproteinemia (53.8%), anemia (50.0%), fatigue (26.9%) and decreased neutrophils (23.1%). 3 pts (11.5%) had TRAEs of grade ≥3 including hypocalcemia, hypokalemia, decreased neutrophils, fatigue and bone marrow suppression. For the 15 evaluable pts who had at least one post-baseline tumor assessment, 12 pts (80.0%) achieved PR for an unconfirmed objective response rate (ORR) of 80.0%. 3 pts (20.0%) had SD for a disease control rate (DCR) of 100.0%. The PK of ASKB589 at doses of 6mg/kg and 10mg/kg combined with CAPOX and anti-PD1 therapy was consistent with that of monotherapy. Conclusions: ASKB589 combined with CAPOX and PD-1 inhibitor has manageable safety and promising antitumor activity. 6mg/kg is chosen as the recommended dose in subsequent studies. Clinical trial information: NCT05632939 .
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 4-year (yr) 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 , McCraith Stephen , Liu Tianshu
Published: January 2024

318

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. 1L NIVO + chemo is approved for advanced GC/GEJC/EAC in multiple countries, including China. We report 4-yr results of NIVO + chemo vs chemo in Chinese pts from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2+ 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 49-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and in all randomized pts (Table). The 4-yr OS rate was 25% with NIVO + chemo vs 11% with chemo in pts with PD-L1 CPS ≥ 5 and 21% vs 9% in all randomized pts. 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 vs 48% (36–60) with chemo; corresponding ORR in all randomized pts was 66% (55–76) and 45% (35–56). Responses were more durable with NIVO + chemo vs chemo both in pts with PD-L1 CPS ≥ 5 (median duration of response [mDOR; 95% CI] 12.5 mo [7.2–23.4] vs 6.9 mo [3.9–8.5]) and in all randomized pts (mDOR [95% CI] 12.5 mo [7.2–17.7] vs 5.6 mo [4.4–8.3]). No new safety signals were identified (Table). Conclusions: After 4 yrs of follow-up, NIVO + chemo continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo in Chinese pts, with an acceptable safety profile. These results are consistent with previous reports and with the overall study population with advanced GC/GEJC/EAC and further support NIVO + chemo as a standard 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . [Table: see text]
Benefit of immune checkpoint inhibitors (ICI) for patients with advanced esophageal squamous cell carcinoma and low PD-L1 expression: A systematic review and meta-analysis.
Authors: Lopes Mario Machado , Alencar Viviane , Sousa Isadora Martins de , Marin Comini Ana Carolina , Camandaroba Marcos Pedro Guedes
Published: January 2024

346

Background: Immunotherapy has improved survival for patients with advanced esophageal squamous cell carcinoma (aESCC) and currently is the standard of care for patients with a positive PD-L1 status (CPS ≥10; TPS ≥1%) in the first-line setting. For PD-L1 negative/low, treatment options are limited, and chemotherapy is usually the first choice and associated with adverse events that may impair quality of life. Immunotherapy trials harbor conflicting results in this subgroup of patients, therefore, we performed a systematic review and meta-analysis to evaluate the potential benefit of ICI as single treatment for patients with aESCC and a PD-L1 expression negative/low. Methods: Studies that enrolled patients with aESCC treated with ICI versus chemotherapy in first and second-line settings and provided separate outcomes for patients with PD-L1 negative/low were identified by searching the EMBASE, PubMed and Cochrane databases. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and odds ratio (OR) with 95% confidence intervals (CI) for TEAE. Statistical analyses were performed using Revman 5.4 and a random-effects model. I² analysis was used to assess heterogeneity. This meta-analysis was recorded on Prospero ID CRD42023411251. Results: We included 6 randomized clinical trials with a total of 674 individuals in the final analysis. Most studies (5/6) included previously treated patients. ICI monotherapy in aESCC patients and PD-L1 expression negative/low was associated with a better OS (HR 0.86; 95% CI 0.76-0.97; p = 0.02; I² = 0%) and worse PFS (HR 1.37; 95% CI 1.10-1.71; p = 0.005; I² = 0%). Regarding the safety profile, it showed higher grade 3-5 toxicity rates (OR 1.8; 95% CI 1.17-2.78; p = 0.007; I² = 85%) for chemotherapy. Conclusions: ICI is effective for patients with aESCC and low/negative PD-L1 expression with an improvement in OS and a favorable safety profile.
Anlotinib plus TQB2450 as adjuvant therapy in patients with esophageal squamous cell carcinoma: A phase II study (ALTER-E005).
Authors: Guo Changying , Chen Shengjia , Ye Yongqiang , Li Xiao-Bing , Mao Weimin
Published: January 2024

347

Background: There is currently a limited range of therapeutic options available for postoperative patients (pts) with esophageal squamous cell carcinoma (ESCC), emphasizing the urgent requirement to investigate more efficient and safer postoperative treatment regimens for resectable ESCC. TQB2450, a novel PD-L1 blockade, has shown promising activity when combined with anlotinib, an antiangiogenic agent, in the treatment of various tumors, including advanced ESCC,1 and biliary tract cancer.2 The ALTER-E005 study aimed to evaluate the efficacy and safety of combining anlotinib with TQB2450 as adjuvant therapy in pts with ESCC. Methods: This was a single-arm, multi-center phase II clinical trial. 30 pts (≥18 years) with histologically confirmed T1-2N1-3M0 or T3-4NanyM0 ESCC who had undergone radical (R0) resection with no recurrence 6 to 12 weeks after surgery and ECOG PS ≤ 1 would been rolled. Enrolled pts received oral anlotinib 12 mg on days 1-14 and intravenous TQB2450 1200 mg on day 1every 3 weeks for up to 16 cycles, until disease recurrence. The primary endpoint was disease recurrence free (DFS). The secondary endpoints included safety, 1-year DFS rate, 3-year DFS rate, 1-year overall survival (OS) rate, and 3-year OS rate. Results: Between August 18, 2022, and August 25, 2023, a total of 12 patients were enrolled. Out of the 12 surgically resected cases of ESCC, 11 (91.7%) had an ECOG score of 1, 10 (83.3%) were male, and 6 (50%) were under the age of 65. According to the eighth edition of the AJCC Cancer Staging Manual, 7 (58.3%) were classified as stage II, and 5 (41.7%) were classified as stage III. As of the data cut-off date (August 25, 2023), the median follow-up time was 5.1 months (95% CI: 3.4-6.8). 2 pts experienced disease recurrence, and the median duration of DFS has not yet been reached. Currently, 9 pts are still undergoing therapy, with treatment durations ranging from 0.3 months to 9.6 months. 2 pts discontinued therapy due to adverse events (AE), which subsequently improved after treatment. One patient experienced immune-related myocarditis, while the other patient had mouth ulcers and hand-foot syndrome. Additionally, one patient voluntarily withdrew from the study. Out of the total 12 patients, 3 (25%) experienced grade 3 treatment-emergent adverse events (TEAEs). There was no grade 4 or higher TEAEs reported. The grade 3 TEAEs included hand-foot syndrome (16.7%), abnormal liver function (8.3%), and immune-related hepatitis (8.3%). Conclusions: The study demonstrated the preliminary efficacy and safety of combining anlotinib with TQB2450 as adjuvant therapy in patients with ESCC who had undergone radical (R0) resection and showed no recurrence 6 to 12 weeks after surgery. 1. Zhi-Ye Zhang, et al. poster 4041: ASCO 2023. 2. Zhou J, et al. Hepatology 2022. Clinical trial information: NCT05252078 .
FLOT compared to FOLFOX/XELOX as a neoadjuvant chemotherapy in locally advanced gastric cancer: Experience of two clinics.
Authors: Semenov Nikolay , Dalgatov Kamil , Izrailov Roman , Zhukova Lyudmila
Published: January 2024

361

Background: The optimal regimen of neoadjuvant chemotherapy (NCT) in locally advanced gastric cancer (GC) remains controversial, especially whether triplet (FLOT) or duplet (FOLFOX/XELOX) regimen is superior since escalation does not always lead to significant clinical improvement. The aim of this study is to assess efficacy of triplet and duplet chemotherapy regimens as a neoadjuvant approach in locally advanced GC via retrospective data. Methods: We queried the data for 334 patients with locally advanced GC (cT2-4 or cN+) diagnosed in 2016–2023 yy administered with multi-agent NCT: FLOT or XELOX/FOLFOX. The primary endpoints were the ratio of patients with disease progression on NCT, rates of ypN0, and rates of pathological complete response (pCR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). Results: 156 patients (out of total 334 included in the study) received doublet NCT (FOLFOX/XELOX, 8/6 cycles respectively), 61.5% were males, median age was 67.4 (range 21.3-85.4) years, 88.2% had cT3-4. and 22.4% had locally advanced gastroesophageal junction (GEJ) adenocarcinoma. 177 patients were treated with triple NCT (FLOT, 8 cycles), 62.1% were males, median age was 59.9 years, 89.2% had cT3-4, and locally advanced GEJ adenocarcinoma was diagnosed in 21.0%. At a median follow up of 34.7 months (mth) using FLOT regimen as NCT was associated with better clinical outcomes. The ratio of patients who have progressed on NCT was 21.5% and 31% in triplet and doublet arms, respectively (p=0.098). Rates of ypN0 were 50.5% in FLOT arm and 43.7% in XELOX/FOLFOX arm (p=0.36). pCR was achieved in 8.2% and 6.3% in FLOT and XELOX/FOLFOX arms, respectively (p=0.59). Median PFS was 20.3 mth in FLOT arm in comparison to 15.7 mth in FOLFOX/XELOX arm (p=0.012). Median OS was not reached (NR) for triplet arm and was 25.1 mth for doublet arm (p= 0.003). Patients who conversed resectable disease had median PFS of 34.5 and 23.1 months for FLOT and FOLFOX/XELOX arms, respectively (p=0.024). Median OS in these subgroups was NR and 37.0 mth (p=0.003). Conclusions: We report that triplet regimen (FLOT) in comparison with doublet (FOLFOX/XELOX) regimen is the more favorable option as a neoadjuvant setting in locally advanced gastric cancer. FLOT NCT is associated with increased ypN0, pCR and shows statistically significant difference in PFS and OS.
Safety and efficacy of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (Neo DCF) therapy for locally advanced esophageal cancer: Real world data analysis.
Authors: Tamba Mikako , Osumi Hiroki , Fukuoka Shota , Ogura Mariko , Okamura Akihiko , Kanamori Jun , Imamura Yu , Takahari Daisuke , Yoshino Koichiro , Udagawa Shohei , Wakatsuki Takeru , Shinozaki Eiji , Watanabe Masayuki , Yamaguchi Kensei , Chin Keisho , Ooki Akira
Published: January 2024

365

Background: Neoadjuvant chemotherapy with docetaxel, cisplatin plus 5-FU (Neo DCF) is one of the standard treatments for locally advanced esophageal squamous cell carcinoma (ESCC) in Japan based on the results of the JCOG1109 NExT study. As Neo DCF is both highly effective and high rate of adverse events, it is important to confirm clinical outcomes in the clinical practice and to explore clinical factors that predict treatment efficacy and adverse events (AEs) for treatment optimization. Methods: ESCC patients who were treated with Neo DCF between July 2016 and May 2023, were enrolled. Three courses of DCF (DTX [day 1]: 70 mg/m2, CDDP [day 1]: 70 mg/m2, 5-FU [continuous infusion on days 1-5]: 750 mg/m2, every 3 weeks) were planned, and prophylactic antibiotics was administered on days 5-15. We retrospectively assessed disease free survival (DFS), pathological response, AEs. Pathological response was assessed according to the Becker’s Criteria. Subgroup analyses of clinical factors related to the pathological response and AEs were also performed. Results: In total, 91 patients (median age, 62.3 years) were enrolled. Clinical stages of this cohort were 8.8% (I),16.4% (II), 69.2% (III), and 5.5% (IVA), respectively. After Neo DCF treatment, 90 patients (98.9%) underwent curative surgery. Median DFS and 3-year DFS rate were not reached and 76.9%. The incidence of pathological complete response (pCR) and major pathological response (MPR) were 11.1% (10/90) and 35.6% (32/90), respectively. There were no cases of recurrence in patients with pCR and MPR. The most common grade 3 or 4 AEs were neutropenia (58/91, 63.7 %), diarrhea (15/91, 16.5%), and thrombosis (9/91, 9.9%), respectively. Febrile neutropenia occurred in 33 patient (36.2%). Clinical T stage was significantly associated with pCR (P = 0.033). Conclusions: Neo DCF was effective and tolerable in the real-world ESCC patients in Japan.
Proportion and distribution of PD-L1 expression and associated clinicopathologic features in patients with microsatellite instability-high gastric cancer.
Authors: Lee Sun Mi
Published: January 2024

387

Background: The frequency of microsatellite instability-high (MSI-H) phenotype in sporadic gastric cancers (GCs) widely varies from 8% to 20%. From prior data, MSI-H phenotypes are significantly associated with female sex, older age, antral location of the tumor, well to moderate differentiation, intestinal type, non-signet ring cell component, mucinous histologic type, a moderate to severe lymphoid stromal reaction, and a lower TNM stage. This study investigated the proportion and distribution of PD-L1 expression of MSI-H GCs compared to microsatellite stable (MSS) GCs. Methods:The study consists of 847 cases of unselected GC. MSI analysis was performed on all GC cases by immunohistochemistry for mismatch repair proteins followed by multiplex polymerase chain reaction. Among them, 72 GCs were found to be an MSI-H phenotype. After matching the T category of GCs, 200 cases of GC with MSS phenotype were selected for a control group. Immunohistochemistry for PD-L1 (SP263) was performed on 72 MSI-H GCs and 200 MSS GCs. Results: Patients with MSI-GC were significantly associated with advanced age (p <0.001), advanced tumor (p=0.0173), antral location of the tumor(p=0.0018), and T2 and T3 category (p=0.0031) but not T1 or T4 category. Histologically, MSI-H GCs occurred frequently in ulcerofungating mass (45.8%, p < 0.0001)), intestinal type (73.6%, p=0.0102), well to moderately differentiated tumor (56.9%, p=0.0102), tubular histologic type (66.7%, p=0.0013), tumor necrosis (18.1%, p <0.0001), and peritumoral neutrophilic infiltrate (40.3%, p <0.001) compared to those of 200 MSS GCs. In the evaluation of PD-L1, 55 (76.4%) MSI-H tumors revealed PD-L1 expression with ≥ 1 CPS. The predominant PD-L1 staining was found in intratumoral and peritumoral immune cells (66.7%) than within tumor cells (9.7%). The distribution of positive immune cells was predominantly located in the periphery of the tumor (37.5%) than within the tumor (9.7%). According to the criteria for PD-L1 positivity as at least 10 CPS, approximately 50% of MSI-H GCs were considered PD-L1 positive tumors with at least 10 CPS. Conclusions: In this study, the prevalence of MSI-H phenotype is approximately 8.5% of unselected GCs. Approximately 76% of patients with MSI-H tumors showed PD-L1 expression with at least 1 CPS, and 50% revealed PD-L1 expression with at least 10 CPS, who can respond better to immune checkpoint inhibitors with promising therapeutic benefits. Due to the peritumoral expression of immune cells in PD-L1 positive GCs with MSI-H phenotype, different endoscopic approaches to obtain tumor tissues for PD-L1 evaluation would be considered, such as sampling tissues at the tumor periphery.
The usefulness of ctDNA and exosome DNA as biomarkers in esophageal squamous cell carcinoma.
Authors: Nakai Tomoki , Kitahata Yuji , Nakamura Yuki , Motobayashi Hideki , Takemoto Norio , Ojima Toshiyasu , Hayata Keiji , Iwaya Takeshi , Hiraki Hayato , Nishizuka Satoshi , Kawai Manabu
Published: January 2024

388

Background: Recently, the usefulness of exosome DNA (exo-DNA) for prognostic analysis of various solid tumors has also been reported. In this study, we investigated the usefulness of ctDNA and exo-DNA as biomarkers for esophageal squamous cell carcinoma. Methods: Patients with esophageal squamous cell carcinoma undergoing standard treatment had ctDNA and exo-DNA collected over time. NGS analysis was performed on biopsy or surgical specimens, and mutated genes in individual cases were followed by ddPCR over time. Results: NGS analysis was performed on 16 patients. 12 of 16 cases showed mutations, In 8 cases, ctDNA and exo-DNA could be measured by ddPCR over time. In one case of Stage IVA. both ctDNA and exo-DNA were useful to determine the efficacy of chemotherapy and radiotherapy, and in one case of Stage II, both ctDNA and exo-DNA were useful to predict postoperative recurrence. Conclusions: In esophageal squamous cell carcinoma, ctDNA and exo-DNA may be useful in determining treatment response and predicting recurrence. We will further investigate the usefulness of ctDNA and exo-DNA in esophageal squamous cell carcinoma, including prognostic prediction. Clinical trial information: UMIN000045311 .
Concordance among three programmed death-ligand 1 (PD-L1) scoring methods and their association with clinical outcomes of tislelizumab (TIS) monotherapy in esophageal squamous cell carcinoma (ESCC).
Authors: Shu Yongqian , Wang Jufeng , Chen Zhendong , Kim Sung-Bae , Lin Chen-Yuan , Kato Ken , Van Cutsem Eric , Du Wenting , Shi Jingwen , Xia Tianyu , Huang Ruiqi , Li Qiao , Zhang Yun , Shen Zhirong , Shen Lin
Published: January 2024

390

Background: Multiple scoring methods and cutoffs have been developed to evaluate tumor PD-L1 expression status in patients with ESCC, and PD-L1 expression level has been associated with the degree of response to anti-programmed cell death protein 1 (PD-1)/PD-L1 therapy. Here, we retrospectively investigated concordance between three PD-L1 scoring methods and their association with clinical outcomes in RATIONALE-302, a phase 3 study of the anti-PD-1 antibody TIS vs investigator-chosen chemotherapy (ICC) as second-line treatment for advanced unresectable/metastatic ESCC (NCT03430843). Methods: Patients enrolled in RATIONALE-302 with evaluable PD-L1 expression by the tumor area positivity (TAP) score (based on visual estimation of positive tumor cells [TCs] and tumor-associated immune cells [ICs]) using the VENTANA PD-L1 (SP263) assay were categorized at a 10% cutoff. Stained slides from those patients were rescored post hoc using both combined positive score (CPS; based on counting positive TCs and ICs) at cutoff 10 and TC (based on counting positive TCs only) score at a 1% cutoff, thresholds currently used in ESCC for anti-PD-(L)1 therapy. Concordance at these thresholds was investigated. Clinical efficacy (overall survival [OS]) for PD-L1 subgroups was assessed. Results: Of 512 pts enrolled, 364 had evaluable TAP scores (TIS, n=180; ICC, n=184), of whom 355 had evaluable post-hoc CPS and TC scores (TIS, n=175; ICC, n=180). TAP score and CPS showed high concordance in terms of overall percentage agreement (OPA; 90% [95% confidence interval (CI): 86, 93]) and Cohen’s Kappa (0.79 [95% CI: 0.72, 0.85]), while TAP and TC scores had lower concordance (OPA: 78% [95% CI: 73, 82]; Cohen’s Kappa: 0.56 [95% CI: 0.47, 0.64]). OS benefit with TIS vs ICC in PD-L1 subgroups defined by TAP, CPS, and TC score cutoffs were generally similar (Table). Conclusions: OS subgroup analysis showed comparable treatment effect by TAP score at 10% cutoff, CPS at cutoff 10, and TC score at 1% cutoff based on SP263 staining. TAP score and CPS at these cutoffs exhibited substantial concordance. The results indicate that the less time-consuming, visually estimated TAP score and CPS may be interchangeable for clinical measurement of PD-L1 expression in patients with ESCC. Clinical trial information: NCT03430843 . [Table: see text]
Circulating exosomal microRNA signature to predict peritoneal metastasis in patients with advanced gastric cancer.
Authors: Wada Yuma , Nishi Masaaki , Yoshikawa Kozo , Takasu Chie , Tokunaga Takuya , Nakao Toshihiro , Kashihara Hideya , Yoshimoto Toshiaki , Shimada Mitsuo
Published: January 2024

396

Background: Despite of radical operation, about half of gastric cancer (GC) patients with advanced GC develop peritoneal metastasis (PM) and the patients with PM has poor prognosis. However, because staging laparoscopy was high invasive procedure for the patients, identification of PM by using liquid biopsy can be useful in patients with GC. Methods: We analyzed two genome-wide miRNA expression profiling datasets (GSE164174 and TCGA). We prioritized biomarkers in pretreatment plasma specimens from clinical training and validation cohorts of patients with GC. We developed an integrated exosomal miRNA panel and established a risk-stratification model, which was combined with miRNA panel and currently used tumor markers (CEA, CA19-9, CA125, and CA72-4 levels). Results: Our comprehensive discovery effort identified a 4-miRNA panel that robustly predicted the metastasis, with an excellent accuracy in TCGA dataset (AUC=0.86). We successfully established a circulating exosomal miRNA panel with remarkable diagnostic accuracy in the clinical training (AUC=0.85) and validation (AUC=0.86) cohorts. Moreover, the predictive accuracy of the panel was significantly superior to conventional clinical factors (P<0.01), and the risk-stratification model was dramatically superior to the panel and currently used clinical factors for predicting PM (AUC=0.94, univariate: OR = 77.00, P < 0.01; multivariate: OR = 57.71, P = 0.01). Conclusions: Our novel risk-stratification model for predicting PM has a potential for clinical translation as a liquid biopsy assay in patients with GC. Our findings highlight the potential clinical impact of our model for improved selection and management of patients with this malignancy.
The distribution of human epidermal growth factor receptor 2 (HER2) expression and the efficacy and safety of treatments in HER2-expressing advanced or metastatic gastroesophageal cancer: A systematic literature review (SLR).
Authors: Zhen David Bing , Schwartz Naomi RM , Beckerman Rachel , Stricker-Shaver Janicec , Zhu Mingshu , Gadikota Hemanth , Scherrer Emilie
Published: January 2024

405

Background: HER2 overexpression plays an important role in determining treatment options for patients with gastroesophageal cancer (GEC). HER2 overexpression has historically been defined dichotomously as HER2-positive (HER2+) or HER2-negative. An emerging potentially clinically relevant category is HER2-low, which could be targeted with HER2-directed antibody drug conjugates. However, data on the epidemiology and outcomes associated with HER2-low GEC are limited. Methods: An SLR of PubMed, Embase, and Cochrane Central Register of Controlled Trials databases was conducted to identify clinical trials, observational studies, and meta-analyses reporting clinical outcomes or distribution of HER2 expression by IHC and ISH in advanced or metastatic (a/m) GEC. Key inclusion criteria were: English language, published between 2013-2023, and sample size ≥100 HER2-expressing patients. HER2+ was defined as IHC score of 3+ or IHC 2+ and ISH+. HER2-low was defined as IHC 1+ or IHC 2+ and ISH-. Weighted averages were calculated for the proportion of patients who were HER2+ and HER2-low to estimate of the proportion of patients in each HER2 expression category. Results were categorized by patient population (all GEC or gastric cancer [GC] only). Results: Of 2,701 non-duplicated records screened, 174 studies met inclusion criteria. Distribution of HER2 expression was reported in 111 studies, 5 of which reported on the frequency of HER2 expression of IHC 1+ and/or IHC 2+ and ISH+. HER2 expression status varied by patient population, with a weighted average of 26.9% for HER2-low and 13.1-16.5% for HER2+ across groups (Table). Different cutoffs for HER2 amplification via ISH also affected the proportion of patients in each HER2 category across studies. Efficacy and safety outcomes were stratified by HER2 status or IHC results in 74 studies. However, only 3 observational studies reported outcomes separately for the HER2-low population, and results were inconclusive. Conclusions: The distribution of HER2 expression in a/m GEC in the identified studies is highly heterogenous, likely due to variability in IHC scoring and patient populations. Few studies with sufficient samples size (≥100 patients with HER2-expression a/mGEC) reported outcomes for HER2-low a/m GEC, and those that were identified were of low quality. The HER2-low a/m GEC population constitutes an unmet need for effective therapy. There is a need for consistent use of a standardized definition of HER2-low in a/mGEC and additional studies to better evaluate treatment options and outcomes for this patient population. [Table: see text]
Cell free DNA (cfDNA) assessment of esophagogastric (EG) cancer using MSK-ACCESS.
Authors: Cytryn Samuel Louis , Phu William , Shah Ronak H. , Walch Henry S. , Chatila Walid Khaled , Vakiani Efsevia , Brannon Angela Rose , Ladanyi Marc , Srivastava Amitabh , Tang Laura H. , Strong Vivian E. , Molena Daniela , Solit David B. , Berger Michael F. , Janjigian Yelena Y.
Published: January 2024

406

Background: Treatment for EG cancer is increasingly complex and the role of predictive and prognostic biomarkers is critical in selecting the optimal therapy. Longitudinal, non-invasive methods that characterize dynamic molecular profiles and detect molecular residual disease are needed. Methods: Patients with EG cancer receiving care at Memorial Sloan Kettering (MSK) had cfDNA analysis with an ultrasensitive capture based liquid biopsy for detection of somatic alterations in 129 cancer associated genes (MSK ACCESS). Results: 98 patients with EG adenocarcinoma underwent cfDNA analysis; 18% had esophageal tumors, 44% had GEJ, and 38% had gastric. 78 (80%) patients had cfDNA obtained prior to treatment (48 [50%] metastatic; 29 [30%] locally advanced) and 21 (21%) at time of progression. 85% had matched tumor NGS performed with MSK IMPACT: median TMB was 5.3 mut/Mb (IQR 3.3-7.4) and median alterations per tumor sample was 11 (IQR 7-17). cfDNA identified a similar molecular profile compared to tumor NGS (TP53 [62 v 72%], ARID1A [12 v 20%], CDKN2A [10 v 16%], APC [10 v 13%], ATM [10 v 12%], PIK3CA [7 v 12%]), although cfDNA was detected more frequently in patients with metastatic disease compared to localized disease (p=0.02). cfDNA did not detect copy number alterations as frequently as patient-matched tumor NGS (41 v 16%, p<0.01), including ERBB2amp (22 v 10%, p=0.05), though patients with HER2 IHC 3+ tumors were more likely to have detectable ERBB2amp on cfDNA compared to HER2 IHC 2+ tumors (50 v 9% p=0.03). Additionally, those with detectable ERBB2amp on cfDNA had a higher copy number on tumor NGS compared to those with undetectable cfDNA (median 39 [IQR 23-46] v 10 [IQR 6-15] p<0.01). Baseline detection of ctDNA may indicate a poor prognosis; among patients with locally advanced disease (median follow up 20.1 months), 0 of 10 with undetectable ctDNA died compared to 5 (26%) of 19 with detectable ctDNA (p=0.08). Among patients with untreated, metastatic disease (median follow up 24.3 months), patients with undetectable ctDNA had a non-significant, improvement in PFS (HR 0.28 95% CI 0.08-1.17; p=0.08) and OS (HR 0.45 95% CI 0.10-1.96; p=0.20) compared to patients with detectable ctDNA, independent of disease burden. Conclusions: Our findings highlight the utility of cfDNA with MSK ACCESS as a complimentary tool for molecular characterization and potential prognostication in patients with EG cancer. [Table: see text]