tbuckley/cabot-search huggingface dataset:
Effectiveness and safety of first-line serplulimab in patients with metastatic/locally advanced esophageal carcinoma (EC): A real-world study.
Authors: Jingni Zhu, Changjiang Sun, Yuanyuan Ren, Xinnian Yu, Zijian Sun, Yan Sun
Journal: Journal of Clinical Oncology (2024)

e16044 Background: The prognosis of metastatic/locally advanced EC has significantly improved with the development of immune checkpoint inhibitors. Serplulimab has been approved in the treatment of various solid tumors (e.g. esophageal squamous cell carcinoma [ESCC], small cell lung cancer). Considering the lack of real-world evidence, this study aimed to explore the real-world effectiveness and safety of serplulimab as first-line therapy in patients with metastatic/locally advanced EC. Methods: Thismulticenterretrospective study included patients with metastatic/locally advanced EC who received first-line serplulimab-containing therapy from March 2022 to December 2023. The demographic and disease characteristics, chemotherapy regimens selected by physicians, treatment response and adverse events were collected from medical record. The outcomes included progression free survival (PFS), objective response rate (ORR), overall survival (OS), duration of response (DoR), time to treatment discontinuation (TTD) and safety. Results: A total of 57 patients were included, 45 (78.9%) were male with a mean age of 68 years. A majority of patients had ESCC (n=40, 70.2%) and metastatic disease (n=35, 61.4%). The most common chemotherapy regimens combined with serplulimab were paclitaxel plus cisplatin (n=27, 39.1%) and etoposide and platinum (n=13, 23.6%). With a median follow-up of 4.8 month (range: 0.7-19.7), the median PFS was 7.4 months (95% confidence interval [CI]: 3.7-11.1). The ORR and DCR were 22.8% and 96.5% in all patients, respectively. The median DoR and TTD were 4.7 months (95% CI: 4.3-not estimated [NE]) and 13.9 months (95% CI: 3.6-24.1), respectively, while the median OS was not reached (NR). The mPFS was 11.1 months (95% CI: 7.0-NE) in patients with ESCC, which was numerically longer than those with neuroendocrine carcinoma (6.5 months, 95% CI: 5.8-7.3, P=0.052). Other effectiveness outcomes in ESCC are presented in Table. Patients &gt; 65 years had a significant improved mPFS compare to those ≤ 65 years (5.9 vs. 11.1 months, P=0.001). The rate of any grade adverse events (AEs) was 26.3% (n=15), while grade 3 or higher AEs was 10.5% (n=6), thrombocytopenia (7.0%, n=4), myelosuppression and pulmonary infection (both 5.3%, n=3) being the most common. Conclusions: First-line serplulimab combined with chemotherapy demonstrated promising effectiveness and favorable safety profile in patients with metastatic/locally advanced EC, especially in ESCC. The current real-world evidence indicates that serplulimab combined with chemotherapy could provide survival benefit for patients with advanced first-line EC. [Table: see text]
Camrelizumab plus chemotherapy combined with consolidative radiotherapy as first-line treatment for oligometastatic esophageal squamous cell carcinoma (ESCORT-1st-RT): A single-arm, open-label, phase 2 trial.
Authors: Dan Han, Baosheng Li, Wei Huang
Journal: Journal of Clinical Oncology (2024)

e16043 Background: Compared to chemotherapy alone, immunotherapy combined with chemotherapy as the first-line standard treatment for esophageal squamous cell carcinoma (ESCC) can increase progression-free survival (PFS) to 5.8-7.2 months. This study aimed to explore the feasibility and safety of combining camrelizumab and chemotherapy with consolidative radiotherapy in the treatment of advanced oligometastatic ESCC. Methods: This study included newly diagnosed patients with stage IV ESCC confirmed by histopathology and imaging examination who had ≤ 5 metastatic lesions in ≤ 3 organs. All patients were treated with camrelizumab combined with albumin paclitaxel and carboplatin for 4 cycles, followed by consolidative radiotherapy. The primary esophageal lesion and metastatic lymph nodes were treated with involved-field irradiation therapy, receiving 2.0 Gy per fraction over 25 daily sessions. For distant metastases in organs like the liver, lungs, brain, or bones, radiotherapy was tailored to individual clinical needs, often employing hypofractionated radiation therapy with doses starting at 3 Gy per fraction or above. The maintenance duration of camrelizumab treatment was limited to a maximum of 12 months. The primary endpoint was PFS. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: From October 26, 2021, to September 28, 2022, 29 patients with ESCC, median age 63 (range 51-74), were enrolled; 93.1% were male. All had an ECOG score of 0 or 1 and stage IV disease. 27 (93.1%) patients completed planned radiotherapy. Of 29 evaluated patients, 23 achieved an objective response and 6 maintained stable disease. Thus, the ORR and DCR were 79.3% (95% CI 78.2-80.4) and 100% (95% CI 100-100), respectively. With 23.3 months (95%CI 21.5-25.1) of follow-up, the median PFS was13.7 months (95% CI 9.9-17.5) , the median OS has not reached and the 1-year and 2-year OS rates were established at 72.4% (95% CI 52.3-85.1) and 61.4% (95% CI 41.1-76.5), respectively. The most common treatment-emergent adverse events (TEAEs) of grade 3-4 were lymphocyte count decreased (65.5%), neutrophil count decreased (27.6%), and white blood cell count decreased (20.7%). 1 patients discontinued camrelizumab treatment due to radiation esophagitis. No grade 5 TEAEs occurred. Conclusions: Consolidative radiotherapy following camrelizumab combined with chemotherapy showed potential efficacy and manageable tolerability in patients with advanced oligometastatic ESCC.
Outstanding safety and efficacy data of IMC002, an autologous CLDN18.2-targeting CAR-T, in CLDN18.2+ advanced solid tumors.
Authors: Tianhang Luo, Zhengmao Lu, Rui Zheng, Jun Zhou, Suqiong Wang, Ruidong Hao, Minmin Sun
Journal: Journal of Clinical Oncology (2024)

e16012 Background: Claudin 18.2 (CLDN18.2) is a promising therapeutic target for advanced solid tumors with CLDN18.2 expression. IMC002 is an autologous CLDN18.2-targeting CAR-T cell directed by a CLDN18.2-specific VHH, the specificity of which was confirmed by a membrane proteome array assay. Preclinical studies showed that IMC002 exhibited high tumor specificity, anti-tumor efficacy, and excellent safety profile in both cell and animal models. Methods: This is an open label first in human Phase 1 dose escalation study to evaluate the safety and efficacy of IMC002 in advanced solid tumors with CLDN18.2 expression which is defined as CLDN18.2 expression of ≥1+ membrane staining intensity in ≥10% tumor cells. Accelerated titration followed by Bayesian optimal interval design was adopted with a total of 4 dose levels planned at 1, 3, 5 and 7 million (mil) CAR-T cells/kg respectively. All patients (pts) were given a single dose of IMC002 infusion after lymphodepletion chemotherapy. Dose limiting toxicity (DLT) was evaluated during the 28-day period after IMC002 infusion. Safety, anti-tumor activity, pharmacokinetics and pharmacodynamics were explored in this study. Here, we present preliminary safety and efficacy data for the pts dosed with up to 3 mil CAR-T cells/kg. Results: As of January 17, 2024, 3 advanced unresectable gastric cancer pts received IMC002 infusion, 1 patient at 1 mil CAR-T cells/kg and 2 pts at 3 mil CAR-T cells/kg. No DLT or SAE was reported. Manageable CRS (grade 1) was reported in all 3 pts. Other adverse events related to cell therapy included grade 1-2 lipase increase (3/3), diarrhea (1/3), pruritis (1/3) and γ-GGT increase (1/3). All adverse events recovered quickly. Preliminary efficacy data showed that best overall response of the 3 pts was all stable disease as evaluated by RECIST 1.1. The two pts at the dose level of 3 mil CAR-T cells/kg underwent successful radical surgery at week (W) 11 and 44 after IMC002 infusion respectively. Pathological complete response (pCR) was achieved in the patient with surgery at W44. Distinct CAR-T cell expansion in peripheral blood was observed in all 3 pts, with the peak number of CAR+ cells reaching on day 7-11 in the peripheral blood after the infusion. Moreover, CAR-T cell infiltration was detected in the W11 and W44 surgical samples. Significant elevations of serum levels of IFN-γ, IL-10, IP-10, IL-2 and IL-6 were observed in the 3 pts. The trial is ongoing. Conclusions: IMC002 showed a favorable safety profile, encouraging anti-tumor activities with observed pCR and persistent expansion in the tumor tissue at the low dosage levels in pts with advanced CLDN18.2+ gastric cancer. In addition, our trial has successfully provided a surgical treatment opportunity after CAR-T therapy downstaging of unresectable gastric cancers. Clinical trial information: NCT05472857 .
Revolutionizing outcome prediction for immunotherapy with vision transformer-based pathomics signature in esophageal squamous cell cancer.
Authors: Butuo Li, Wenru Qin, Linlin Wang
Journal: Journal of Clinical Oncology (2024)

e16049 Background: Immune checkpoint inhibitors (ICIs) has notably enhanced the survival prospects for patients with esophageal squamous cell carcinoma (ESCC), however the clinical benefit was limited to only a small portion of patients. This study aimed to perform a deep learning signature based on H&amp;E-stained pathological specimens for the purpose of identifying effective markers that can accurately predict the clinical benefit of ICIs among patients with ESCC. Methods: ESCC patients receiving PD-1 inhibitors from Shandong Cancer Hospital were included. Whole slide images (WSIs) of H&amp;E-stained histological specimens of included patients were collected, and subsequently randomly allocated into two sets: a training set comprising 70% of the samples, and a validation set consisting of the remaining 30%. The labels of images were defined by the progression-free survival (PFS) with the interval of 4 months. The pretrained ViT model was used for patch-level model training, and all patches were projected into probabilities after linear classifier. Then the most predictive patches were passed to RNN for final patient-level prediction to construct ESCC-pathomics signature (ESCC-PS). Accuracy rate and survival analysis were performed to evaluate the performance of ViT-RNN survival model in validation cohort. Results: 163 ESCC patients receiving PD-1 inhibitors were included for model training. There were 486,188 patches of 1024*1024 pixels from 324 WSI images of H&amp;E-stained histological specimens after image pre-processing. The training cohort consisted of 120 patients with a total of 227 images, while the validation cohort comprised 43 patients and featured 97 images. Notably, both groups exhibited balanced baseline characteristics between them. The ESCC-PS achieved an accuracy of 84.5% in the validation cohort, and could distinguish patients into three risk groups with the median PFS of 2.7, 4.8 and 16.7 months (P &lt; 0.001). The multivariate cox analysis revealed ESCC-PS could act as an independent predictor of survival from PD-1 inhibitors (P &lt; 0.001). A combined signature incorporating ESCC-PS and expression of PD-L1 shows significantly improved accuracy in outcome prediction of PD-1 inhibitors compared to ESCC-PS and PD-L1 anlone, with the area under curve value of 0.952, 0.924, 0.648 for 6-month PFS and C-index of 0.816, 0.806, 0.66, respectively. Conclusions: The outcome supervised pathomics signature based on deep learning has the potential to enable superior prognostic stratification of ESCC patients receiving PD-1 inhibitors, which convert the images pixels to an effective and labour-saving tool to optimize clinical management of ESCC patients.
Impact of positive tumor-informed margin and <i>TP53</i> mutations on surgical outcomes in esophageal squamous cell carcinoma.
Authors: Di Lu, Yu Tong, Jingwen Liu, Zhiming Chen, Zhizhi Wang, Chunhong He, Shaobin Li, Shijie Mai, Xuguang Rao, Kaican Cai
Journal: Journal of Clinical Oncology (2024)

e16024 Background: The complete removal of esophageal squamous cell carcinoma (ESCC) with clear margins (R0 resection) is pivotal for patient prognosis. However, it is limited by the potential inaccuracies of conventional histopathology. Next-generation sequencing (NGS) for minimal residual disease (MRD) detection might improve the prediction of postoperative outcomes. Methods: The study cohort included a total of 48 operable ESCC patients, from whom resected esophageal tumors, resection margins, and normal tissues were collected and profiled by a 425-gene panel. Comparisons of mutational features were conducted across various tissue types, and their associations with disease-free survival (DFS) were explored. Results: Mutations were detected in 81.8% (27/33) of normal tissues, 95.8% (46/48) of tumors, and 50.0% (24/48) of resection margins. In general, genetic alterations in resection margins closely resembled those in tumor tissues, but were distinct from normal tissues. Both tumor and margin samples showed higher variant allele frequencies (VAFs) and fewer mutations per patient than normal samples ( p &lt; 0.0001). Moreover, eight patients exhibited identical mutations in paired margin and tumor samples. Notably, one patient out of eight with the same TP53 p.T175H mutation across all sample types exhibited the shortest DFS of only two months. Mutations in TP53 and NOTCH1 were the most common, displaying unique mutational patterns among different sample types. While NOTCH1 mutations were detected more frequently in normal tissues ( p = 0.001), TP53 mutations were enriched in tumors ( p = 0.04). Furthermore, normal tissues exhibited a distinct pattern of mutation sites for TP53 and NOTCH1 compared to those observed in tumor or margin tissues. We characterized tumor-informed margin (TiM) by the presence of identical mutations in both tumor and adjacent margins. The positive TiM status was associated with a shorter DFS, particularly when considering TP53 mutations alone ( p = 0.022) or excluding NOTCH1 mutations ( p = 0.031). Conclusions: A positive TiM status with TP53 mutations is a promising biomarker indicating poor surgical outcomes in ESCC. Mutations within NOTCH1 are common but showed no association with DFS. These findings provide novel insights into the feasibility of genetic profiling of resection margins to facilitate optimizing postoperative therapeutic regimens for ESCC.
Gender disparity in enrollment in clinical trials for hairy cell leukemia (HCL) in the last 40 years.
Authors: Oscar Felipe Borja Montes, Tomas Escobar Gil, Narendranath Epperla, Leslie Ann Andritsos
Journal: Journal of Clinical Oncology (2024)

e19024 Background: Hairy Cell Leukemia (HCL) is a B-cell lymphoproliferative disorder characterized by infiltration of the bone marrow, liver, and spleen by malignant B cells with hairy cell cytoplasmic projections(1). There is a significant predominance of HCL in males, with a male-to-female ratio of 4:1, especially in Western countries. Differences have been found in the role of gender influencing the severity of the disease. The latest data had identified better outcomes in females with HCL(2). In the last 40 years of HCL research a distinct gender participation gap has surfaced, favoring males in the enrollment of clinical trials. Our study aims to investigate the contributing factors to this imbalance, such as physio-pathological reasons, socio-demographic characteristics, accessibility barriers, and awareness limitations. Methods: In this descriptive, retrospective study, we searched EMBASE, PUBMED, and ClinicalTrials.gov from January 1983 to December of 2023 for publications on randomized clinical trials (RCT) in Hairy Cell Leukemia. The number of participants in clinical trials, their gender, the country where the trial was conducted, year of publication was recorded and descriptive statistical analysis of all the variables was performed. Results: We identified 57 studies comprising 4595 individuals with different subtypes of HCL. Of the total RCT, 79.10% of the patients were male and 20.89% were female. 49.12% of the studies were performed in the United States, 38.59% in Western Europe, 5.26% in Eastern Europe, and the remaining in Japan, Australia, and Iran. 36.84% of RCT were performed between 2000 and 2010. The male-to-female ratio was 7.92 for RTC performed between 1983 to 1989, 3.81 for RCT performed between 1991 to 1999 and 3.36 for RCT performed between 2000 and 2010. Conclusions: Female patients with HCL were recently shown to have a significantly longer progression free survival than male patients. Our retrospective analysis confirms that there is smaller than expected percentage of female participants enrolled in HCL clinical trials published over the last four decades. When examining the male-to-female ratio over different time periods there was a notable decrease from RCTs performed in the 1980s compared to RTCs performed after 2000. The gender disparity observed in clinical trials where males may be overrepresented could be attributed to the predominantly higher prevalence of both newly diagnosed and relapsed HCL in males, making them more likely to be eligible for the RCT. Bridging this gender gap in trials is crucial to accurately reflect the efficacy of novel therapies in both males and females, enabling improved treatment design and better outcomes for all.
Real-world adherence and healthcare resource utilization of Bruton tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma.
Authors: Bijal D. Shah, Wesley Furnback, Kaitlyn Esselman, Po-Ya Chuang, Mei Xue, Keri Yang
Journal: Journal of Clinical Oncology (2024)

e19048 Background: This study aimed to examine treatment adherence and healthcare resource utilization (HCRU) of BTKi treatment in mantle cell lymphoma (MCL). Methods: The Symphony Integrated Dataverse (IDV) was used to conduct a retrospective observational study. Adult patients with MCL initiating their first BTKi or second BTKi (after ibrutinib) between 01/2020 and 10/2023 were included in the study. The index was defined as the date of BTKi initiation. Patients without 30 days of continuous enrollment pre- and post-index date were excluded. Patients were followed until the end of the study period or lost to follow-up. Adherence was evaluated by compliance and persistence. Compliance was calculated as the proportion of days covered &gt;0.80 using 30-day intervals from initiation to 1 year. Persistence was measured as the proportion of patients who remained in treatment among patients with sufficient follow-up periods. HCRU was measured by all-cause outpatient visits, inpatient services, and other medical/hospital services per-patient-per-month (PPPM) during BTKi treatment. Results: Among 2,122 patients who were first-time BTKi users, there were significant differences for mean age at index (acalabrutinib=70; ibrutinib=68; zanubrutinib=70, P&lt;.0001), commercial insurance (acalabrutinib=34%; ibrutinib=42%; zanubrutinib=47%, P&lt;.0001), and baseline atrial fibrillation (acalabrutinib=1.94%; ibrutinib=1.24%; zanubrutinib=3.47%, P=0.0232). A total of 228 patients switched from ibrutinib to acalabrutinib or zanubrutinib. Adherence results suggested zanubrutinib had numerically better 1-year compliance ( P=0.2176) and treatment persistence at 1 and 2 years ( P=0.2687; P=0.6270) for patients who switched from ibrutinib to zanubrutinib or acalabrutinib (Table). HCRU showed that the mean (SD) outpatient visits (1.12 [1.67] vs 1.62 [3.17]; P=0.1755) and inpatient services (0.22 [0.68] vs 0.68 [3.12]; P=0.1693) were lower in patients switched from ibrutinib to zanubrutinib than acalabrutinib. Conclusions: In this study, zanubrutinib was associated with a trend towards improved compliance, persistence, and HCRU when used as the first BTKi and after prior ibrutinib. [Table: see text]
Survival outcomes with curative intent hyperthermic intraperitoneal chemotherapy (HIPEC) for gastric cancer with peritoneal metastasis.
Authors: Bowon Joung, Dani Ran Castillo, Daniel Park, Farris Al-Manaseer, Won Jin Jeon, Chieh Yang, Linnea Burke, Yanghee Woo
Journal: Journal of Clinical Oncology (2024)

e16070 Background: The prognosis of gastric cancer with peritoneal metastasis (GC-PM) remains dismal. Despite the many studies evaluating hyperthermic intraperitoneal chemotherapy and cytoreductive surgery (HIPEC-CRS) for GC-PM in various treatment settings, its curative role in combination with systemic chemotherapy remains unclear. Methods: To determine the survival benefit of CRS-HIPEC in patients with GC-PM, we conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines on primary studies from January 1, 2010 to December 31, 2023. Inclusion criteria were studies involving adults with GC and histologically proven PM who received curative intent gastrectomy, D2 lymphadenectomy, and systemic chemotherapy. Exclusion criteria were studies involving patients with GC without PM involvement and HIPEC utilized strictly for prophylactic purposes. The primary endpoint was overall survival (OS), with a focus on 1-year, 2-year, and 3-year survival outcomes. We performed a random effects meta-analysis of risk ratios using RevMan and assessed heterogeneity using I 2 . Results: Of 452 studies identified, we included 5 studies and a total of 524 patients with survival outcome of CRS-HIPEC and standard chemotherapy were compared. We observed significantly better OS for patients who received CRS+HIPEC compared to those who received systemic chemotherapy without CRS-HIPEC (odds ratio (OR) 0.50, 95% CI [0.39-0.65], I 2 = 3%, P &lt; 0.00001). Further analysis demonstrated improved 1-year OS (OR 0.53, 95% CI [0.30-0.93], I 2 = 45%, p = 0.03), 2-year OS (OR 0.53, 95% CI [0.35-0.81], I 2 = 0%, p = 0.003), and 3-year OS (0.35, 95% CI [0.14-0.84], I 2 = 21%, p = 0.02). Low heterogeneity (3%) amongst all the groups suggests that variations within the subgroups did not impact the homogeneity of the dataset. Conclusions: Overall, use of CRS and HIPEC in addition to systemic chemotherapy resulted in statistically significant improvement in OS up to year 3 compared to standard palliative chemotherapy alone in patients with GC-PM. Further studies are warranted to evaluate HIPEC in the curative attempt setting, specifically in combination with emerging targeted therapies.