bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracranial outcomes of 1L selpercatinib in advanced RET fusion-positive NSCLC: LIBRETTO-431 study.
Authors: Uh Minji , Perol Maurice , Goto Koichi , Solomon Benjamin J. , Park Keunchil , Nadal Ernest , Bria Emilio , Martin Claudio , Bar Jair , Williams Justin , Puri Tarun , Li Jian , Lin Boris K. , Zhou Caicun 
Published: August 2024

199 Background: Selpercatinib is a highly selective and potent CNS active RET inhibitor approved for treatment of advanced RET fusion-positive ( RET+) NSCLC. Treatment or prevention of CNS disease is critical in RET+ NSCLC patients (pts), who have nearly a 50% lifetime prevalence of brain metastases (mets) (Drilon et al. JTO 2018). LIBRETTO-431 is the first study to compare intracranial (IC) efficacy of a targeted therapy to chemo/IO in pts with oncogene driven NSCLC. Methods: LIBRETTO-431 (NCT04194944) is a randomized, open-label, phase 3 trial comparing 1L selpercatinib vs chemotherapy (cisplatin/carboplatin + pemetrexed) +/- pembrolizumab. As previously reported, the study met its primary endpoint of PFS by blinded independent central review (BICR) at the pre-planned interim analysis. IC analyses included CNS and non-CNS PD, IC PFS and IC responses by BICR per RECIST 1.1 in all pts who had a baseline and one or more post-baseline CNS scans (CNS-evaluable) and were designated to receive pembrolizumab if randomized to the control arm (CNS-pembro population). Adverse events were evaluated in the CNS safety population. Results: A total of 192 of 261 pts enrolled were CNS-evaluable (selpercatinib: 120, control: 72). Baseline characteristics were generally balanced with the selpercatinib arm having a slightly lower proportion of pts with BICR-assessed baseline brain mets (21% vs 25%) and prior CNS radiotherapy (RT; 6% vs 10%) compared to the control arm. Selpercatinib delayed CNS PD as evidenced by a lower 12 mo cumulative incidence rate (CIR) for CNS PD, as well as delaying non-CNS PD compared to control in pts with and without brain mets (Table). In pts with measurable brain mets at baseline (n=29), median time to IC response per RECIST 1.1 was similar between selpercatinib and control (1.4 mo [range: 1.2-2.9] vs 1.6 mo [range: 1.2-2.9]); however, as previously reported the IC response rates were higher (82% vs 58%) and more durable (12 mo DOR rate 76% vs 63%) with selpercatinib vs control (Zhou et al. NEJM 2023). IC responses to selpercatinib were more common in pts without prior CNS RT (14/15, 93%) than with prior CNS RT (3/6, 50%). Conclusions: Selpercatinib delayed IC progression in advanced RET+ NSCLC pts with or without baseline brain mets and achieved higher IC response rates compared to chemotherapy + pembrolizumab. LIBRETTO-431 is the first study to demonstrate IC efficacy improvement of a targeted therapy vs chemo/IO in a biomarker selected NSCLC population. These data further support selpercatinib as the preferred 1L regimen in pts with advanced RET+ NSCLC. Clinical trial information: NCT04194944 . [Table: see text]
Updated efficacy of anti-TROP2 ADC ESG401 for first-line metastatic TNBC in phase 1b study.
Authors: Ma Fei , Qiu Fuming , Tong Zhongsheng , Shi Yehui , Yu Guohua , Wu Xinhong , Wang Hong , Wang Jiani , Yang Hua , Liu Anwen , Zhang Yan , Zheng Hongmei , Lan Qiongyu , Zhang Yongqiang , Cheng Ying , Zhou Qing , Xing Xiaoyan , Chen Xiaomei 
Published: August 2024

2 Background: ESG401, a novel ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to SN-38, with a Drug-Antibody Ratio of 8 and a stable cleavable linker, demonstrated preliminary efficacy and tolerability in the Phase Ia trial (Ma, ASCO 2023). This report presents updated results from the first-line mTNBC cohort of the Phase Ib trial and results from patients with brain metastases. Methods: Patients (pts) aged ≥18 years with confirmed local advanced/unresectable or metastatic TNBC, without prior metastatic treatment, received ESG401 (16 mg/kg IV on Day 1,8, and 15, with a 28-day cycle) until unacceptable toxicity, progressive disease, or consent withdrawal. Results: As of the cutoff date (Apr 7th, 2024), 24 pts in the cohort received ≥1 dose of ESG401. Median age was 53 years (range: 33-73), 33.3% were ECOG 0, 25.0% were de novo stage IV, 70.8% had visceral disease (8.3% brain, 33.3% liver, 50.0% lung). Updated efficacy results are shown in the Table. Thirteen pts (68.4% of 19 efficacy evaluable pts) remained on treatment, with the longest on-treatment duration being 10.3 mons. Median PFS has not been reached. Two pts in this cohort had brain metastases, with one achieving a complete intracranial response and an overall response of PR, and the other demonstrating overall PR with a -13.8% reduction in brain lesion size. Totally 16 pts with brain metastases were enrolled in the entire Phase Ia/1b trials, for these pts, the best overall intracranial response rate was 31%, with an intracranial disease control rate of 75%, while the corresponding overall response rate and disease control rate were 50% and 69%, respectively. The response of intracranial lesions to the treatment is consistent with that of extracranial lesions. The safety profile of ESG401 remained consistent with previous reports, showing no new or unexpected safety signals. Conclusions: ESG401 monotherapy demonstrates promising antitumor activity in 1L mTNBC pts, characterized by a high response rate and durable response. The ORR numerically exceeded that reported in the BEGONIA Study arm 7 in which pts with the same indication were treated with TROP-2 ADC and PD-L1 combination therapy. Additionally, ESG401 shows clear potential for treating HER2-negative breast cancer with brain metastases, including mTNBC and HR+/HER2- BC. These results support further clinical investigation of ESG401. Clinical trial information: NCT04892342 . [Table: see text]
Outcomes of EGFR, ALK, ROS1, BRAF, MET, and RET mutated non-small cell lung cancer with brain metastases (NSCLC BM).
Authors: Li Xiaoyan , Shi Weiwei 
Published: August 2024

201 Background: Non-small cell lung cancer (NSCLC) is a leading cause of brain metastases. Advances in gene-directed therapies have shifted the focus away from traditional platinum-based chemotherapies. Key targeted mutations in NSCLC include EGFR, ALK, BRAF, MET exon skipping, RET fusions, and ROS1 rearrangements. This retrospective study aims to explore overall survival (OS) and progression-free survival (PFS) in NSCLC BM patients with these gene mutations. Methods: In this retrospective study, conducted by the Department of Medical Oncology at Beijing Tiantan Hospital and the First Medical Center, PLA General Hospital, we reviewed 1526 patients with NSCLC brain metastasis from 2010 to 2022. Data collected included molecular marker status, systemic therapies, and dates of progression. The analysis focused on determining OS and PFS from the time of brain metastasis diagnosis to the last follow-up or death. Statistical analysis used the Cox proportional hazards model. Results: The study reviewed 1526 patients, identifying the following mutation distribution: EGFR mutations in 628 patients, ALK rearrangements in 207 patients, ROS1 rearrangements in 64 patients, BRAF mutations in 31 patients, MET exon skipping in 55 patients, and RET fusions in 42 patients. Significant variations in median OS (mOS) and median PFS (mPFS) were observed across these mutation groups. Patients with EGFR and ALK mutations demonstrated longer mOS and mPFS. Patients with RET and ROS1 mutations also showed better outcomes compared to those with BRAF and MET mutations. Conclusions: This study highlights the importance of molecular mutations in NSCLC BM as prognostic indicators and therapeutic targets. EGFR and ALK mutations were associated with more favorable outcomes, emphasizing the need for personalized medicine in managing NSCLC BM. The study suggests further research focused on specific mutation types is crucial to refine treatment strategies and improve patient care.
Differential expression in potential therapeutic target protein by treatment in small cell lung cancer with and without transformation.
Authors: Murata Saori , Horinouchi Hidehito , Yatabe Yasushi , Kashima Jumpei , Masuda Ken , Shinno Yuki , Okuma Yusuke , Yoshida Tatsuya , Goto Yasushi , Yamamoto Noboru , Watanabe Shun-ichi , Matsumoto Yuji , Okuma Kae , Ohe Yuichiro 
Published: August 2024

202 Background: Small cell lung cancer (SCLC) is a disease with a poor prognosis. Besides combination strategy with immune checkpoint inhibitors (ICIs) and cytotoxic agents, antibody-drug conjugates (ADCs) and bispecific T-cell engagers (BiTE) are being developed. These drugs target tumor-associated surface protein. Whether prior treatment affect the transition of protein expression has not been fully investigated especially in the era of ICIs. The purpose of this study is to evaluate changes in protein expression in SCLC tissues before and after treatment. Methods: We included patients diagnosed with SCLC by surgery or biopsy and underwent re-biopsy after treatment (non-transformed group) at the National Cancer Center Hospital between 2014 and 2023. Patients who were initially diagnosed with non-small cell lung cancer and underwent transformation to SCLC (transformed group) were also included. Tissues were obtained by surgery, bronchoscopy, or CT-guided biopsy with an interval of at least 100 days. We investigated clinicopathological features in paired specimens focusing on DLL3, ASCL1, NEUROD1, POU2F3, and YAP1, which have been reported to be expressed in SCLC, as well as tumor-associated surface proteins potentially related to novel drug development. Results: Fourteen non-transformed group cases and 9 transformed group cases were included. Of these, pathology specimens were evaluable in a total of 15 cases: 9 for the non-transformed group and 6 for the transformed group. The median age was 68 years, 11 (73%) were male, 11 (73%) were smokers, 8 (53%) were in clinical stages I-IIIA, 1 (7%) in stages IIIB and 6 (40%) in stage IV. Among the transformed group, 4 of them were treated by Osimertinib before transformation. Progression free survival from first-line therapy was 298 days (255-446) vs. 314 days (245-NA) and overall survival was 1239 days (567-NA) vs. NA days (517-NA), respectively for non-transformed group and transformed group. For both these group of cases, we have evaluated several protein expressions as described above. The transition of these proteins within each group is presented in the conference. Conclusions: In this study, we focused not only on proteins already reported to be expressed in SCLC, but also on proteins that are potential new therapeutic targets and evaluated changes in protein expression. [Table: see text]
Feasibility of pretreatment FDG PET radiomics in predicting circumferential margin involvement for esophageal cancer after neoadjuvant concurrent chemoradiotherapy.
Authors: Shen Wei-Chih , Chou Ying-Hsiang , Chung Meng-Wei , Wang Guo-Zhi , Lee Jang-Ming , Liao Yi-Han 
Published: August 2024

203 Background: Involvement of circumferential resection margin (CRM) proves to be a valuable factor in predicting prognosis for patients with esophageal cancer. This study aimed to explore the feasibility of using pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in predicting CRM involvement for patient received neoadjuvant concurrent chemoradiotherapy (CCRT). Methods: We retrospectively enrolled patients with esophageal cancer who received neoadjuvant CCRT followed by radical surgery between October 2013 and July 2023. All patients received FDG PET/CT examinations before CCRT. The maximum standardized uptake value (SUVmax) within a tumor was identified, and the metabolic tumor volume (MTV) was calculated by using a fixed SUV threshold method (50 % of SUVmax). Descriptive features and five groups of radiomic features (Gray Level Co-occurrence Matrix [GLCM], Gray Level Dependence Matrix [GLDM], Gray Level Run Length Matrix [GLRLM], Gray Level Size Zone Matrix [GLSZM], and Neighboring Gray Tone Difference Matrix [NGTDM]) were further calculated to describe the heterogeneity of the FDG uptakes within MTV. The CRM involvement status was defined by the Royal College of Pathologists (RCP). Tumor presence at or within 1 mm of the cut margin was considered CRM positive. Finally, we used the area under the receiver operating characteristic curve (AUC) to evaluate the predictive performance of radiomic features for CRM. The significance level was set to 0.05. Results: A total of 71 cases of esophageal tumors, encompassing data from 70 patients were included. Of the 70 patients, 94% were male with a mean age 58 years across the entire cohort. Sixteen tumors were proved as CRM positive (16/71, 22.5%). Finally, 2 descriptive features and 10 radiomic features were selected that can effectively predict CRM status. These ten radiomic features exhibit robust predictive power for CRM status, demonstrating significance across various discretization bin number. The best performing feature is Skewness (AUC=0.716, p-value<0.0001). Conclusions: This preliminary result revealed that CRM involvement for esophageal cancer tumors could be predicted by using radiomic features. Future studies are warranted for clinical application. [Table: see text]
Efficacy and safety analysis on the combination of camrelizumab with nab-paclitaxel and cisplatin-based chemotherapy in first-line treatment of advanced or metastatic esophageal squamous cell carcinoma.
Authors: Cong Xiaofeng , Xu Zijun , Liu Ziling 
Published: August 2024

205 Background: Nab-paclitaxel has indicated good efficacy during the multi-line esophageal squamous cell carcinoma (ESCC) treatment. Our study summarized the efficacy and safety of the first-line combination treatment of camrelizumab with nab-paclitaxel and platinum in advanced or metastatic ESCC patients. This could provide evidence of the positive effects of using nab-paclitaxel. Methods: We included patients with advanced or metastatic ESCC who received camrelizumab in association with nab-paclitaxel and cisplatin for 3-6 cycles as first-line therapy. The patients were recruited from the First Hospital of Jilin University between August 2021 and December 2023. The primary endpoint was the objective response rate (ORR), while the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), PFS, and OS rates at 12, 18, and 24 months, including safety. Results: 43 patients were included in this study, they were assessed based on the therapeutic effect, with 72.1% [95% CI,58.1%-86.1%]ORR and 100% DCR. The median PFS was 25.5 months, and the median OS was not achieved. The OS rates were 96.8%, 86.4%, and 78.6% at 12 months, 18 months, and 24 months, respectively. In contrast, the PFS rates were 90.1%, 75.8%, and 68.3%, respectively. Grade 3 or above treatment-related adverse reactions (TRAEs) occurred in nine patients (20.9%). No patient developed severe grade 5 TRAEs. Conclusions: During the first-line treatment of advanced or metastatic ESCC, applying nab-paclitaxel in associated with camrelizumab and cisplatin -based therapy showed a positive effect. Therefore, the results exhibit an extension of OS and PFS with manageable safety and no new TRAEs.
Programmed cell death ligand 1 (PD-L1) inhibitors versus programmed cell death 1 (PD-1) inhibitors for the first-line therapy of extensive-stage small cell lung cancer: A propensity score-matched study.
Authors: Tian Yaru , Lu Shuangqing , Sun Yulan , Tang Xiaoyong , Sun Zhuoran , Zhao Ke , Du Guochang , Li Wanjing , Zhu Hui 
Published: August 2024

206 Background: Addition of programmed cell death ligand 1 (PD-L1) inhibitors or programmed cell death 1 (PD-1) inhibitors to etoposide‐platinum (EP) chemotherapy has become the standard first-line regimen for ES-SCLC. The clinical efficacy and safety between the two types of immune checkpoint inhibitors (ICIs) remain controversial. We conduct the retrospective study and propensity score-matched analysis to explore the potential differences between them. Methods: Patients diagnosed with ES-SCLC and treated by EP plus PD-L1 or PD-1 inhibitors at Shandong Cancer Hospital between March 2019 and November 2022 were reviewed retrospectively. According to PD-L1 or PD-1 inhibitors, they were divided into two groups. Propensity score matching (1:1) was performed to balance the baseline characteristics of the two groups. The baseline characteristics and adverse events between the two groups were compared using the chi-squared test. The survival curves of overall survival (OS) and progression-free survival (PFS) were plotted by the Kaplan-Meier method and differences were analyzed by the log-rank test.The primary endpoints were OS and PFS. Results: As a result, 448 patients were analyzed in this study. 264 patients received PD-L1 inhibitors plus EP and 184 received PD-1 inhibitors plus EP. The median follow-up was 17.6 months. The median OS and PFS was 20.4 months and 7.8 months in the overall population. Before propensity score matching, the median OS was 20.1 months in PD-L1 inhibitor plus EP group and 20.7 months in PD-1 inhibitor plus EP group, respectively (HR 1.043, 95%CI 0.776-1.401; p= 0.781). The median PFS was 7.6 months in the PD-L1 inhibitor plus EP group and 8.5 months in PD-1 inhibitor plus EP group (HR 1.099, 95%CI 0.886-1.364; p= 0.390). After propensity score matching, the median OS and PFS were 20.4 months and 7.8months in PD-L1 inhibitor plus EP group, and those were 20.1 months and 8.6 months in PD-1 inhibitor plus EP group. There was no significant difference in OS and PFS between PD-L1 inhibitors plus EP and PD-1 inhibitors plus EP in the matched population (HR 1.104; p= 0.578 and HR 1.072; p= 0.602, respectively). The overall adverse events were comparable in the two groups. Only ≥3 grade neutropenia was more frequent in the PD-L1 inhibitors plus EP group (77.7% vs 69.0%, p= 0.040). Conclusions: In conclusion, the overall efficacy and safety profile was similar between PD-L1 inhibitors and PD-1 inhibitors for the first-line treatment of ES-SCLC.
A comprehensive meta-analysis of tissue resident memory T cell shaping non-small-cell lung cancer immune microenvironment and patient prognosis.
Authors: Shen Aidan , Garrett Aliesha , Chao Cheng-chi , Liu Dongliang , Zhu Yangzhi , Mai Junhua , Jiang Chongming 
Published: August 2024

210 Background: Tissue-resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of TRM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Methods: Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we inferred the abundance of TRM in NSCLC. A machine learning model was developed to prognosticate survival, tested in multiple independent NSCLC cohorts. Model performance was corroborated through Kaplan-Meier survival plots, receiver operating characteristic (ROC) curves, principal component analysis, and t-SNE analyses. Results: We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, TRM signatures are strongly associated with immune checkpoint genes and the prognosis of NSCLC patients. A TRM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the TCGA dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the TRM signature revealed low TRM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Conclusions: Altogether, this study provides valuable insights into the complex interactions between TRM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification. Keywords: Tissue resident memory T cell, non-small-cell lung cancer, prognosis, tumor immune microenvironment, machine learning.
Predictive and pharmacodynamic biomarkers for combination therapy in stage III-IV melanoma: A Simon phase II trial (NCT03999749).
Authors: Mizutani Teruyuki , Muramatsu Tomoaki , Handzlik Joanna , Kimono Diana , Mitra Ankita , Yang Eddy , Kirchhoff Tomas , Puranik Amrutesh , Weber Jeffrey S. 
Published: August 2024

222 Background: The evaluation of biomarkers that predict response and immune-related adverse events (irAEs) is crucial for optimizing melanoma treatment with Immune checkpoint inhibitors (ICIs). We report predictive and pharmacodynamic biomarkers for response and irAEs using high-dimensional flow cytometry in a phase II trial combining nivolumab (3 mg/kg), ipilimumab (1 mg/ml), and the IL-6 receptor inhibitor tocilizumab (4 mg/kg) in unresectable/advanced melanoma patients. Methods: We analyzed serum and blood from melanoma patients at baseline, weeks 7 and 37, categorized them by irAE severity and clinical response. Patients were categorized based on the severity of irAEs (grades 3-5) (TOX), the absence of toxicity or grades 1-2 irAE (NT), clinical benefit (CB), and non-clinical benefit (NCB). Immune monitoring regimen included ELISA for IL-6, gp130, IL-23, osteopontin, and Luminex oncological panel (LXSAHM-22). We employed multi-parametric flow cytometry panels to examine myeloid cells, cytotoxic T cells, and checkpoint protein expression on immune cells. We processed ~1 million PBMCs per sample using various antibodies, with data acquisition performed via Sony’s ID7000 cytometer. The data underwent quality control, normalization PBMCs per patient, concatenation, dimensionality reduction, and clustering in FlowJo. Results: Among the 70 patients administered treatment, we observed a best overall response rate of 57%. Grade 3-5 irAEs occurred in 22% of patients by week 24. Patients manifesting irAEs exhibited notably higher baseline Th17 cell counts (NT=181±18 vs. Tox=311±49, p<0.01) and CD26+ Naive CD4 T-cell populations (NT=5838±801 vs. Tox=9632±1343, p<0.04), suggesting their potential role as predictive markers for toxicity. Additionally, in vitro investigations led us to identify CD26 co-stimulation as a preliminary step in TH17 cell differentiation. Key pharmacodynamic markers included a significant elevation in Treg cells (NCB=1286±71 vs. CB=1492±95, p=0.02) and reduction in serum gp130 levels (NCB=104±5 vs. CB=83±5 ng/ml, p<0.01) at week 7 in addition to IL-6 (NCB=7.5±1.5 vs. CB=4.6±1.1 pg/ml, p<0.01) and osteopontin (NCB=95±15 vs. CB=25±3 ng/ml, p<0.01) by week 37 when compared to baseline. Conclusions: Our findings suggest that Th17 cells can serve as a toxicity biomarker for combination therapy with ipilimumab, nivolumab and tocilizumab. Circulating Treg cells and serum osteopontin have emerged as promising pharmacodynamic biomarkers. Clinical trial information: NCT03999749 .