bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the integration of refugee health data into national health information systems in Jordan, Lebanon, and Uganda
Authors: Bou-Karroum Lama , Daher Najla , Jabbour Mathilda , Akhu-Zaheya Laila , Khater Wejdan , Alloubani Aladeen , Orach Christopher Garimoi , Komakech Henry , Bennett Sara , El-Jardali Fadi
Published: August 2024

Background

With the increasing number of protracted refugee crises globally, it is essential to ensure strong national health information systems (HIS) in displacement settings that include refugee-sensitive data and disaggregation by refugee status. This multi-country study aims to assess the degree of integration of refugee health data into national HIS in Jordan, Lebanon, and Uganda and identify the strengths and weaknesses of their national HIS in terms of collecting and reporting on refugee-related health indicators.

Methods

The study employs a comparative country analysis approach using a three-phase framework. The first phase involved reviewing 4120 indicators compiled from global health organizations, followed by a multi-stage refinement process, resulting in 45 indicators distributed across five themes. The second phase consisted of selecting relevant criteria from the literature, including data sources, annual reporting, disaggregation by refugee status, refugee population adjustments, accuracy, and consistency. The third phase involved assessing data availability and quality of the selected indicators against these criteria.

Results

Our analysis uncovered significant challenges in assessing the health status of refugees in Jordan, Lebanon, and Uganda, primarily stemming from limitations in the available health data and indicators. Specifically, we identified significant issues including incomplete local data collection with reliance on international data sources, fragmented data collection from various entities leading to discrepancies, and a lack of distinction between refugees and host populations in most indicators. These limitations hinder accurate comparisons and analyses. In light of these findings, a set of actionable recommendations was proposed to guide policymakers in the three countries to improve the integration of refugee health data into their national HIS ultimately enhancing refugees’ well-being and access to healthcare services.

Conclusion

The current status of refugee-related health data in Jordan, Lebanon, and Uganda indicates the need for improved data collection and reporting practices, disaggregation by refugee status and better integration of refugee health data into national HIS to capture the health status and needs of refugees in host countries. Key improvement strategies include establishing a centralized authority for consistent and efficient data management, fostering transparent and inclusive data governance, and strengthening workforce capacity to manage refugee health data effectively.
Role of CDK4 as prognostic biomarker in Soft Tissue Sarcoma and synergistic effect of its inhibition in dedifferentiated liposarcoma sequential treatment
Authors: Vanni Silvia , Miserocchi Giacomo , Gallo Graziana , Fausti Valentina , Gabellone Sofia , Liverani Chiara , Spadazzi Chiara , Cocchi Claudia , Calabrese Chiara , De Luca Giovanni , Bassi Massimo , Gessaroli Manlio , Tomasetti Nicola , Campobassi Angelo , Pieri Federica , Ercolani Giorgio , Cavaliere Davide , Gurrieri Lorena , Riva Nada , Recine Federica , Ibrahim Toni , Mercatali Laura , Jones Robin , De Vita Alessandro
Published: August 2024

Soft tissue sarcomas represent an heterogeneous group of rare mesenchymal tumors comprising 1% of all solid malignancies. Among them, liposarcoma is one of the most common histotypes with atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma (ALT/WDLPS and DDLPS) as the major sub-entities. The unavailability of predictive, prognostic and druggable biomarkers makes the management of these lesions challenging. In recent years CDK4 and its inhibitors have emerged as potential agents for these lesions especially for ALT/WDLPS and DDLPS but the results are not conclusive and need to be elucidated. This study involved 21 ALT/WDLPS and DDLPS patients. Histological analyses of MDM2 and CDK4 were carried out. Moreover, a DDLPS patient-derived cancer model was established in vitro and in vivo assessing the efficacy of palbociclib in combination and sequential treatment. Finally, in silico analyses on CDK4 expression were carried out. The results showed a higher expression of CDK4 and MDM2 in DDLPS compared to ALT/WDLPS. Moreover, no correlation between MDM2 expression and CDK4 was observed. Next, in vitro analysis of CDK4 inhibitor palbociclib showed an antagonistic effect when combined to other chemotherapeutics, while it exhibited a significant synergy when administered in sequential schedule with lenvatinib. Next, in vivo analysis on DDLPS xenotransplanted embryos assessing the efficacy and safety profile of the in vitro tested schedules confirmed the observed data. This proof-of-concept study sheds light on the natural history of ALT/WDLPS and DDLPS and provides the rationale for the clinical applicability of sequential treatment with palbociclib in the management of DDLPS.
The next frontier in immunotherapy: potential and challenges of CAR-macrophages
Authors: Li Jing , Chen Ping , Ma Wenxue
Published: August 2024

Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages’ phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options.
Pharmacokinetic/Pharmacodynamic modelling of Saxagliptin and its active metabolite, 5-hydroxy Saxagliptin in rats with Type 2 Diabetes Mellitus
Authors: Wang Tianyan , Tao Ting , Liu Yi , Dong Jie , Ni Shanhong , Liu Yun , Li Yanli , Xu Ning , Sun Zengxian
Published: August 2024

Background and purposes

It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect.

Methods

First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX.

Results

A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5−OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature.

Conclusions

The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.
Pooled analysis on characteristics of nausea and vomiting in patients receiving trastuzumab deruxtecan (T-DXd) in clinical studies.
Authors: Park Yeon Hee , Cortés Javier , Modi Shanu , Hurvitz Sara A. , Bianchini Giampaolo , Iwata Hiroji , Shitara Kohei , Siena Salvatore , Goto Yasushi , Ku Geoffrey Yuyat , Charles Powell Andrew , Swain Sandra M. , Arunachalam Meena , Janek Martin , Cheng Yingkai , Chu Changan , Verma Purnima , Mathias Elton , Karnoub Maha , Rugo Hope S.
Published: August 2024

12118

Background: The efficacy and safety profile of T-DXd has been established in patients (pts) with various tumor types, and nausea and vomiting are the most common treatment-emergent adverse events (TEAEs). T-DXd study protocols were refined over time to recommend prophylaxis (eg, neurokinin or serotonin receptor antagonists and/or steroids) before T-DXd treatment, in line with antiemetic and institutional guidelines. We conducted a pooled, post hoc analysis capturing safety information across tumor types; we report results on nausea and vomiting. While this analysis was not designed to assess antiemetic effectiveness, it reveals the incidence of nausea and vomiting in clinical trials of T-DXd 5.4 mg/kg in more detail across a large dataset. Methods: 1449 pts treated with ≥1 dose of 5.4 mg/kg T-DXd (every 3 wks) were included from 7 phase 1-3 clinical trials in metastatic HER2+ and HER2-low breast cancer, HER2+ gastric cancer, and HER2-mutant non–small cell lung cancer (DESTINY-Breast01, -Breast02, -Breast03, -Breast04, -Lung01, -Lung02, and the first-in-human phase 1 study J101 in multiple tumor types; study enrollment starting 2015-2021). Regardless of antiemetic use (including prophylaxis), the incidence, severity, time to onset, and duration of nausea and vomiting TEAEs were assessed along with event outcomes. Results: Of 1449 pts receiving T-DXd 5.4 mg/kg (median [range] number of 3-wk treatment cycles: 13 [1-60]), 74.6% (n=1081) experienced nausea, and 41.6% (n=603) reported vomiting. Most pts had grade 1/2 nausea (41.2%/27.6%) and/or vomiting (26.2%/12.8%). Grade 3 TEAEs of nausea were reported in 5.8% of pts, with grade ≥3 TEAEs of vomiting observed in 2.6% of pts. By the data cutoff for each trial, 66.9% of pts with nausea and 87.6% with vomiting had their symptoms resolve. Most pts who experienced nausea and vomiting did so during the initial 21 days (cycle 1; n=879 [81.3%] and 336 [55.7%], respectively; 35.8% of all pts received antiemetic prophylaxis at cycle 1); both TEAEs declined notably in subsequent cycles. Rates of drug discontinuation, dose reduction, and drug interruption due to nausea and vomiting were generally low (Table). Conclusions: Most nausea and vomiting events were reported during the first 3 wks of treatment and resolved. Appropriate prophylaxis of nausea and vomiting is a key management strategy and allows pts to benefit from longer treatment durations with T-DXd. Ongoing studies are exploring the implementation and impact of prophylaxis for T-DXd–related emesis. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 , NCT03734029 , NCT03505710 , NCT04644237 , NCT02564900 . [Table: see text]
Acute care and overall survival results of a randomized trial of a virtual health intervention during routine cancer treatment.
Authors: Daly Robert Michael , Bryl Karolina , Baser Raymond E , Green Angela , Hung Tony , Gillespie Erin F. , Panageas Katherine , Postow Michael A. , Mao Jun J.
Published: August 2024

1503

Background: Despite rapid development of virtual health interventions, little is known of their impact on acute healthcare utilization and survival outcomes. This study aimed to evaluate the effectiveness of Integrative Medicine at Home (IM@Home), a virtual mind-body fitness program, on unplanned hospital admission and overall survival among patients undergoing systemic cancer treatment. Methods: We conducted a randomized clinical trial of IM@Home (choice of 23 weekly virtual live mind-body and fitness classes) compared with an enhanced usual care (EUC) control intervention consisting of asynchronous recordings (standard of care plus access to 17 pre-recorded online meditation resources) for patients with melanoma, thoracic, gynecological, or head/neck cancers on systemic treatment who reported moderate or greater fatigue. The study intervention lasted up to 12 weeks, and patients were followed thereafter for clinical events. Admission to a hospital over the study period was collected from patient-reported-outcomes and the electronic medical records and compared between arms. Overall survival was estimated using the Kaplan-Meier method. Results: Between October 2021 and March 2023,128 patients were randomized: (mean age 64 years) 109 (85.2%) were female, 106 (82.8 %) white, 10 (7.8%) Black, 7 (5.5%) Asian, and 118 (92.2%) non-Hispanic. 49 (38.3%) patients had thoracic, 44 (34.4%) gynecological, 25 (19.5%) head/neck, and 10 (7.8%) melanoma cancer. 58 (45.3%) were receiving chemotherapy, 45 (35.2%) immunotherapies, and 29 (22.7%) targeted therapies. Compared to EUC, patients in the IM@Home group were less likely to be hospitalized (4/64 [6.3%] vs. 12/63 [19.1%], p=0.038) and spent fewer days in the hospital (4.3 vs. 10.5 mean days per patient, p<0.001) during the 12-week study period. Overall survival results were assessed in Feb 2024 after a median follow up of 20.3 months. Median overall survival was 24.3 months in the EUC arm and was not reached in the IM@Home intervention arm (p=0.06). Conclusions: Participation in the virtual IM@Home program reduced unplanned hospitalizations and number of hospitalization days among patients with cancer receiving systemic treatment. Larger studies with longer follow-up are needed to confirm the effect of virtual supportive care on improving overall survival and reducing acute healthcare utilization. Clinical trial information: NCT05053230 .
Efficacy and safety of LM-108, an anti-CCR8 monoclonal antibody, in combination with an anti-PD-1 antibody in patients with gastric cancer: Results from phase 1/2 studies.
Authors: Gong Jifang , Liu Chang , Yao Jun , Xue Junli , Dai Jing , Ji Yinghua , Markman Ben , Hiong Alison , Yang Xiuli , Zhao Rusen , Zheng Yi , Li Qingshan , Wu Jun , Barve Minal A. , Ariyapperuma Mihitha Hashara , Richardson Gary Edward , Qin Xia , Qin Crystal Ying , Shen Lin
Published: August 2024

2504

Background: Targeting tumor-infiltrating regulatory T cells (Tregs) is a potential approach to overcome immunotherapy resistance in the treatment of cancers. LM-108 is a novel Fc-optimized, anti-CCR8 monoclonal antibody that selectively depletes tumor-infiltrating Tregs. Here we report a pooled analysis of results from 3 phase 1/2 studies (NCT05199753; NCT05255484; NCT05518045) to evaluate the efficacy and safety of LM-108 in combination with anti-PD-1 therapy in patients with gastric cancer. Methods: Eligible patients with gastric cancer treated with LM-108 in combination with an anti-PD-1 antibody were included in the analysis. Patients received intravenous LM-108 at dose levels of 3 mg/kg Q2W, 6 mg/kg Q3W, or 10 mg/kg Q3W plus an anti-PD-1 antibody (intravenous pembrolizumab 200 mg Q3W or 400 mg Q6W or toripalimab 240 mg Q3W). The primary endpoint was investigator-assessed ORR per RECIST v1.1. The secondary endpoints included safety, other efficacy outcomes, and biomarkers analysis. Data cutoff date for the pooled analysis was December 25, 2023. Results: Forty-eight patients with gastric cancer (median age: 60.5 years; male: 72.9%) from China, USA, and Australia were treated ≥ 1 dose of LM-108 in combination with pembrolizumab or toripalimab. Most (n = 47, 97.9%) patients had received at least 1 prior anticancer treatment, and 43 (89.6%) had received prior anti-PD-1 therapy. Treatment-related adverse events (TRAEs) occurred in 39 (81.3%) patients, in which the most common events (≥15%) were alanine transaminase increased (25.0%), aspartate transaminase increased (22.9%), white blood cell decreased (22.9%), anemia (16.7%). Grade ≥ 3 TRAEs occurred in 18 (37.5%) patients, the most common events (≥ 4%) were anemia (8.3%), lipase increased (4.2%), rash (4.2%), and lymphocyte count decreased (4.2%). Among 36 efficacy-evaluable patients across all regimens, ORR was 36.1% (95% CI 20.8%–53.8%) and DCR was 72.2% (95% CI 54.8%–85.8%). The median PFS was 6.53 months (95% CI 2.96–NA). Among 11 patients whose disease had progressed on first-line treatment, ORR was 63.6% (95% CI 30.8%–89.1%) and DCR was 81.8% (95% CI 48.2%–97.7%). Of the 11 patients who progressed on first-line treatment, 8 had high CCR8 expression. Among these 8 patients, ORR was 87.5% and DCR was 100%, with 1 CR, 6 PR, and 1 SD observed. Conclusions: LM-108 in combination with an anti-PD-1 antibody showed promising antitumor activity in patients with gastric cancer that was resistance to anti-PD-1 therapy. The combination therapy was well tolerated. These results support further evaluation of LM-108 in CCR8 positive gastric cancer. Clinical trial information: NCT05199753 ; NCT05255484 ; NCT05518045 .
Early clues in the battle against advanced gastric cancer: How plasma ctDNA signals the effectiveness of PD-1 inhibitors with chemotherapy.
Authors: Jiang Rongqi , Wu Hao , Meng Enqing , Li Ping , Cheng Xu
Published: August 2024

3042

Background: Combination therapy with Programmed Death 1 (PD-1) inhibitors and chemotherapy has shown efficacy in improving survival in advanced gastric cancer, but not all patients derive benefit. We aimed to explore whether early dynamic changes in circulating tumor DNA (ctDNA) can serve as predictors of treatment response and long-term survival in patients receiving first-line PD-1 inhibitors combined with chemotherapy. Methods: This is a prospective, single-center trial in which all patients are adults with advanced or metastatic GC/GEJC confirmed by pathology or imaging. 30 eligible patients will receive PD-1 mab (sintilimab/nivolumab (NIVO) Q3W) and chemotherapy (SOX/XELOX Q3W) regardless of programmed death ligand-1 status. Blood samples were collected before treatment and after two treatment cycles for ctDNA analysis. Plasma ctDNA was isolated for evaluating variant allele frequencies (VAF) of somatic mutations in 47 cancer-related genes using next-generation sequencing (NGS), ctDNA response was defined as clearance of maximum VAF (maxVAF) compared to baseline. CT scans were performed after every two cycles and will be categorized as responding (complete response plus partial response) or non-responding (progress disease plus stable disease) according to RECIST v1.1. Overall survival was calculated from the date of first PD-1 mab infusion to the time of death or censored at most recent follow-up; progression‐free survival was calculated from the date of first PD-1 mab infusion to the time of death or first documented progression, whichever came first, or censored at most recent follow-up. Results: In thirty advanced gastric cancer patients, the dynamic changes in maxVAF demonstrated a significant association with patients attaining either complete response (CR) or partial response (PR) to treatment (P=0.0021), but showed no correlation with stable disease (SD) or progress disease (PD). A substantial agreement was observed between ctDNA response and the best tumor shrinkage rate (Cohen's kappa=0.69). The objective response rate (ORR) among ctDNA responders was 85%, markedly higher compared to the 22% observed in non-responders (P=0.0073). Additionally, patients with ctDNA response had a significantly longer progression‐free survival (PFS) compared to patients without ctDNA response (median PFS 15.6 months vs 6.0 months; HR, 0.18; 95% CI, 0.06 to 0.61; p=0.003), overall survival (OS) was also significantly longer among ctDNA responders (median OS not reach[NR] vs 9.0 months; HR, 0.10; 95% CI, 0.01 to 0.88; p=0.011). Conclusions: ctDNA response serves as a potential biomarker for assessing treatment efficacy and long-term outcomes in advanced gastric cancer patients treated with first-line PD-1 inhibitors and chemotherapy. Clinical trial information: ChiCTR2200065366.
Efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in metastatic colorectal cancer: Updated results of a multicenter, single-arm, phase 2 trial.
Authors: Zhao Wensi , Li Jun , Li Liping , Huang Junping , Gong Wei , Yu Xiongjie , Le Kefa , He Linli , Han Qi , Wang Songlin , Tang Ze , Li Wenbin , Hua Xianliang , Chen Yongshun
Published: August 2024

3571

Background: Fruquintinib, a potent and highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor, combined with investigator’s choice of chemotherapy as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC) showed promising efficacy in preliminary analysis (2023 ASCO Poster-3582) of the prospective, open-label, multicenter, single-arm phase 2 trial (ChiCTR2200059280). Here we reported the updated efficacy data. Methods: Pts with mCRC progressed after first-line prior systemic treatment were administered fruquintinib (5~3 mg, d1-21, q4w) and investigator’s choice of chemotherapy (fluorouracil ± irinotecan ± oxaliplatin, d1, q3w) for up to 8 cycles. Patients without disease progression (PD) were followed by fruquintinib maintenance until PD or unacceptable toxicities. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS) and safety. Results: From November 2021 to November 2023, 100 pts were enrolled. Median age was 63 years (IQR, 56.5-71) and 61.0% were male. The left colon cancer involved in 77.0% pts. All pts had MSS/pMMR phenotype and 37.0% had RAS/BRAF-mutated tumors. 9.0% received prior anti-EGFR and 55.0% received anti-VEGF therapy. Most common sites of metastatic disease were liver (57.0%) and lung (41.0%). As of January 20, 2024, with a median follow-up of 9.3 mo, the median PFS was 6.9 mo (95%CI, 5.2-8.6), median OS was 20.1 mo (95%CI, 13.7-26.3). ORR was 26.0% (95%CI, 17.9-36.2), DoR was 11.3 mo (95%CI, 8.6-14.0), and DCR was 83.3% (95%CI, 74.0-89.9) in 96 efficacy-evaluable pts. The incidence of adverse events was comparable to the known toxicities associated with fruquintinib and chemotherapy. No treatment-related deaths occurred. Grade 3/4 adverse effects occurred in 33 pts (33.0%), and most commonly were neutropenia (21.0%), leukopenia (14.0%), thrombocytopenia (6.0%), proteinuria (5.0%), hypothyroidism (3.0%), diarrhea (2.0%), hand-foot syndrome (2.0%) and hypertension (1.0%). Conclusions: Fruquintinib combined with investigator’s chemotherapy followed by fruquintinib maintenance as second-line therapy showed satisfactory anti-tumor activity, prolonged PFS and OS, and manageable safety profiles in pts with mCRC. Further analysis of all pts with long-term follow-up will be presented in the future. Clinical trial information: ChiCTR2200059280.
Characteristics of patients (pts) with disease relapse despite absence of molecular residual disease (MRD) after resection of colorectal oligometastases (CRM): Implications from PRECISION study.
Authors: Kobayashi Shin , Takamoto Takeshi , Shiomi Akio , Takahashi Amane , Shiozawa Manabu , Shimizu Yasuhiro , Kagawa Yoshinori , Nobuoka Daisuke , Yamauchi Junichiro , Kato Takeshi , Oki Eiji , Taketomi Akinobu , Takahahshi Yu , Natsume Soichiro , Niguma Takefumi , Kani Satoru , Nakamura Yoshiaki
Published: August 2024

3602

Background: Detection of MRD after curative-intent resection of CRM is prognostic for disease relapse and may guide decisions regarding adjuvant chemotherapy (ACT). However, some pts without MRD detected immediately after resection may also experience disease relapse. We explored the features of pts enrolled in a prospective multicenter study with disease relapse who did and did not have post-resection MRD. Methods: Pts with previously untreated resectable CRM scheduled for surgery were prospectively enrolled between March 2021 and October 2022. Pretreatment genomic alterations were assessed in circulating tumor DNA (ctDNA) by Guardant360, while MRD was assessed 4 weeks after resection with a methylation-based ctDNA MRD assay (Guardant Reveal). Characteristics of pts who were MRD negative but relapsed later were analyzed. Results: Of 118 eligible pts enrolled, pretreatment ctDNA was detected in 99 (84%), 62 (53%) of whom had poor genomic profile, defined as a mutation in BRAF, RAS, PIK3CA, and/or SMAD4. Of 110 pts who underwent surgery, postoperative MRD was detected in 35 (32%). With a median follow-up time of 11.0 months (m), 37 pts recurred, of whom 14 were MRD negative and 23 MRD positive. MRD negative pts were more likely to develop lung metastases (64.3% vs. 30.4%, p=0.09) but less likely to have liver metastases (21.4% vs. 60.9%, p=0.03). Median recurrence-free survival (RFS) of MRD-negative relapsed pts was longer than that of MRD positive pts (8.6 m vs. 3.5 m; hazard ratio [HR], 0.28 [95% CI, 0.13-0.58]). Among MRD-negative pts with recurrence, risk factors most associated with recurrence were a history of lymph node metastases (LNM) (odds ratio [OR], 6.20 [95% CI, 1.28-30.1]) and poor pre-operative genomic profile (OR, 3.85 [95% CI, 1.08-13.70]). Among all resected pts, LNM (HR, 2.55 [95% CI, 1.10–5.89]), poor genomic profile (HR, 2.97 [95% CI, 1.29–6.85]), and MRD positivity (HR, 6.36 [95% CI, 2.96–13.64]) were significantly associated with shorter RFS in multivariate analyses. Conclusions: Pts with a history of LNM or poor pre-operative genomic profile were at risk of recurrence despite the absence of MRD after curative-intent resection of CRM. Clinical trial information: UMIN000042490.
Efficacy of EpCAM CAR-T IMC001 in advanced gastric cancers.
Authors: Luo Tianhang , Fang Weijia , Lu Zhengmao , Tong Chuchu , Zhang Hangyu , Ai Guoqiang , Wang Suqiong , Hao Ruidong , Sun Minmin
Published: August 2024

4043

Background: EpCAM is highly expressed in various cancer types of the GI system and serves as a promising prognostic/predictive marker and therapeutic target. IMC001 is an autologous EpCAM-targeting CAR-T cell exhibited promising anti-tumor activity in preclinical studies. The specificity of the extracellular humanized scFv of IMC001 was confirmed by membrane proteome array. Patient derived organoids study and murine GLP study indicated a favorable safety profile of IMC001. Previous IIT data showed promising safety and efficacy. Here we present updated clinical data with longer follow up and more pts treated in the expansion recommended dose of 1 million (M) CAR-T cells/kg. Methods: This first-in-human, open-label trial followed a 3+3 design with IMC001 monotherapy dose escalation of 0.3 (n=3), 1 (n=3) or 3 (n=3) M/kg after lymphodepletion chemotherapy, 2 additional pts had been enrolled at dose-expansion (1M/kg). Eligible patients were those with EpCAM-positive (expression ≥1+ staining intensity in ≥10% tumor cells) advanced gastric cancers who had failed or not tolerated at least 2 lines of chemotherapy and were ECOG 0 or 1. The objective was to assess the safety, PK/PD profile and preliminary efficacy of IMC001. Results: As of Dec 30, 2023, 11 pts were infused with IMC001, 10 with evaluable efficacy are included in the efficacy analysis. The median time from diagnosis to enroll was 17.0 months (range 6.9-31.2). All pts were in stage IV, with more than 2 lines previous chemotherapy (1 pt failed 1st line and refused a 2nd line treatment), all had metastasis and 72.7% (8/11) had 2 or more metastasis organs. CAR T-cell expansion was observed in most pts; the median Cmax was 547, 500 and 9540 copies/μg gDNA in the 0.3, 1, and 3M/kg dose groups respectively, median Tmax was 7 days (7-28), with a persistence of IMC001 range from 4 to 12 weeks. Significant elevations of serum levels of cytokines were observed in most patients. Three out of 10 evaluable pts achieved PR response and 6 remained SD, with a DCR of 90%. For the recommended dose of 1M/kg, 2 out of 5 pts had PR (ORR 40%), including 1 pt underwent successful radical gastrectomy around W27 after IMC001 infusion and remained survival for more than 81 wks. The other PR pt had a tumor reduction of 48% at W16. The other 2 SD pts had an OS of 55 wks and 43 wks. Patients were well tolerated with no unexpected safety signals were observed at the recommended dose. Conclusions: This phase I study in advanced gastric cancer resulted in durable response with a favorable safety and efficacy profile especially for the recommended dose of 1M/kg, demonstrate a promising of EpCAM CAR-T therapy in advanced GC pts. Further expanding of this dose with larger patient population and longer follow-up shall bring the hope to this unmet medical need. Clinical trial information: ChiCTR2100047129.
Tislelizumab plus intensity modulated radiotherapy in resectable hepatocellular carcinoma with macrovascular invasion: A prospective, single-arm, phase II trial.
Authors: Pan Hongyu , Zhou Liuyu , Cheng Zhuo , Yang Cheng , Zhang Jin , Shen Ningjia , Ma Hongbin , Li Yao , Jin Riming , Zhou Weiping , Wu Dong , Sun Wen , Wang Ruoyu
Published: August 2024

4118

Background: Hepatocellular carcinoma (HCC) patients (pts) with macrovascular invasion (MVI) have dismal prognosis, and limited evidence for perioperative therapies is available. This study aims to explore the safety and feasibility of perioperative tislelizumab (a PD-1 monoclonal antibody) plus intensity modulated radiotherapy (IMRT) for resectable HCC with MVI. Methods: This single-arm phase II trial enrolled resectable HCC pts with MVI, as assessed by the investigators before surgery. Pts were treatment-naïve, with ECOG of 0-1, and had adequate organ and bone marrow function. Eligible pts received 3 cycles of tislelizumab (200mg, d1, Q3W) and concurrent IMRT (45 Gray in 15 fractions). After surgical feasibility assessment, HCC resection is scheduled after IMRT, followed by adjuvant tislelizumab up to one year. The primary endpoints include overall response rate (ORR) and overall survival (OS). Secondary endpoints are significant pathological response (viable tumor cells <10%), recurrence-free survival (RFS) and safety. Results: From Oct 21, 2020 to Feb 15, 2023, 30 pts were enrolled, with most pts 26 (86.7%) were males and 29 pts (96.7%) had HBV infection. 28 pts (93.3%) had Child-Pugh grade A and 29 pts (96.7%) had ECOG PS 0. The types of vascular invasion were main portal vein (n=9), branched portal vein (n=15), major hepatic vein (n=2), or both portal and hepatic vein (n=4). In 30 pts, ORR was 30.0% (RECIST1.1), DCR was 36.6% and the median OS was 18.7 months. 15 (50%) underwent radical surgical resection followed by adjuvant tislelizumab, 10 (66.7%) achieved a significant pathological response. By Sep 30, 2023, median RFS was not reached with a median follow-up of 21.77 months (95% CI 12.50-31.03) post-surgery. Of the pts who underwent surgery, 7 (46.7%) pts experienced tumor relapse with 1-year RFS rate was 60%. The most common events of any grade were increased thyroid stimulating hormone (TSH) (83.3%), leukopenia (60.0%) and anemia (53.3%). 4 (13.3%) pts experienced grade 3 TRAEs (leukopenia, increased TSH and increased alkaline phosphatase).An exploratory analysis suggests that pts who underwent surgery have longer median OS (not reached versus 7.0 months, p=0.025). AFP reduction after perioperative therapy was found to be prognostic of RFS. Conclusions: The effectiveness and tolerability of tislelizumab plus radiotherapy as perioperative therapy for resectable HCC with MVI is worth further exploration. Clinical trial information: ChiCTR2000036385.
Efficacy and safety of anlotinib combined with sintilizumab in locally advanced or metastatic anaplastic thyroid carcinoma.
Authors: Zhu Haohua , Liu Shaoyan , Shi Yuankai , Gui Lin
Published: August 2024

6103

Background: Anaplastic thyroid carcinoma (ATC) is rare aggressive and fatal malignancy with poor prognosis. Antiangiogenic and multikinase inhibitors and programmed cell death protein-1 (PD-1) antibodies have conferred benefits for ATC. We aimed to assess the efficacy and safety of anlotinib plus sintilizumab in patients with locally advanced or advanced ATC. Methods: In this prospective study, patients with histologically confirmed locally advanced or metastatic ATC, received a combination therapy of anlotinib and sintilizumab. Anlotinib was started at 12 mg once daily for 14 days and combined with sintilizumab at a fixed dose of 200 mg every three weeks. The primary end point was objective response rate (ORR), assessed in patients who received at least one dose of treatment. Tumor samples were characterized by next-generation sequencing in 12 patients and PD-L1 expression levels in 14 patients. Results: Between June 1st, 2022 and August 21st, 2023, 18 patients with locally advanced or metastatic ATC were enrolled and received combination treatment. Best overall response (BOR) within all patients was 5.6% (1/18) complete remission, 38.9% partial remission (7/18), 33.3% stable disease (6/18), and 22.2% progressive disease (4/18). ORR was 44.4% for all patients and 80.0% for 5 patients with BRAF V600E mutation. The only one patient with PD-L1 negative also reached PR. Median follow up time was 14.6 months for all patients and 16.1 months for patients with BRAF V600E mutation. The median progression-free survival was 7.5 months (0.5 to 56.3 months) for all patients and 5.7 months (1.0 to 13.1 months) for patients with BRAF V600E mutation. Duration of treatment was 5.9 months (0.5 to 38.2 months), and 8 of 18 ATC patients are still on therapy. Grade III/IV toxicities were observed in 4 of 18 patients, necessitating dose reduction/discontinuation of anlotinib. The 1-year overall survival (OS) rate was 61.1% and median OS was 12.9 months (0.6 to 56.3 months), with 8 ATC patients being still alive without progression. Conclusions: The combination of anlotinib and sintilizumab demonstrated promising activity and manageable toxicity in patients with locally advanced or metastatic ATC, suggesting its potential as a viable therapeutic option for this patient population. Clinical trial information: ChiCTR2200067045. [Table: see text]
Dalpiciclib and chidamide in patients with HR+/HER2- advanced breast cancer and resistance to CDK4/6 inhibitors: A phase Ib trial.
Authors: Wang Tao
Published: August 2024

e13072

Background: The combination of CDK4/6 inhibitors and endocrine therapy (ET) as first or second-line therapy could improve PFS and OS for patients with HR-positive/HER2-negative breast cancer. However, the standard treatment for patients who have failed CDK4/6 inhibitors has not been established. Histone deacetylase inhibitors (HDACi) inhibit the proliferation of tumor cells through a variety of ways, such as improving the expression level of p21 and other genes. In China, dalpiciclib (a CDK4/6 inhibitor) in combination with ET has been approved for patients with metastatic HR-positive/HER2-negative breast cancer. Chidamide (an HDAC inhibitor) has been approved for the treatment of metastatic HR-positive/HER2-negative breast cancer. The investigator's previous retrospective study has shown that chidamide combined with ET may be an optional sequential strategy for patients who have progressed on CDK4/6 Inhibitor. The aim of this study was to explore the efficacy and safety of dalpiciclib in combination with chidamide in locally advanced or metastatic HR+/HER2- breast cancer patients who have failed CDK4/6 inhibitors (NCT 05586841). Methods: This study is a single-arm, open-label, prospective, phase Ib, dose escalation clinical trial. Before entering this trial, all patients with HR-positive/HER2-negative locally recurrent or metastatic breast cancer (MBC) must have received ≤1 previous line of chemotherapy for MBC, and have failed CDK4/6 inhibitor therapy. The primary endpoint is maximum tolerated dose (MTD) of dalpiciclib in combination with chidamide. Patients were assigned to four groups to receive dalpiciclib and chidamide (Group A: dalpiciclib 125mg/d and chidamide 25mg/BIW; Group B: dalpiciclib 125mg/d and chidamide 20mg/BIW; Group C: dalpiciclib 100 mg/d and chidamide 25mg/BIW; Group D: dalpiciclib 100 mg/d and chidamide 20mg/BIW). Results: Fourteen patients were enrolled between 19/1/2023 and 30/1/2024 (Group A, N=4; Group B, N=3; Group C, N=4; Group D, N=3). All the patients were received ≥ 1 line CDK4/6 inhibitors and 11 patients (78.6%) received chemotherapy in advanced breast cancer. Two patients experienced dose-limiting toxicities (DLT, Group A, n=1; Group B, n=1). The incidence of adverse events of any grade was 100%. The most frequent grade 3-4 adverse events were neutropenia (100%) and thrombocytopenia (35.7%). The median follow-up was 251 days (range, 188.486-313.514), and median PFS was 201 days (95%CI: 158.49-243.51). 2 of 14 patients achieved partial response (PR; Group C, n=2), 10 of 14 patients achieved stable disease (SD) and 2 of 14 had progressive disease (PD; Group A, n=2). In this study, dose group C was identified as recommended phase II dose (RP2D). Conclusions: The combination of dalpiciclib and tucidinostat is an alternative treatment strategy in patients who have failed CDK4/6 inhibitors. Clinical trial information: NCT05586841 .
Neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin for locally advanced resectable esophageal squamous cell carcinoma: A prospective phase 2 study.
Authors: Jiang Haiping , Ye Peng , Li Ning , Wu Hui , Ding Yongfeng , Xu Xin , Ma Ying , Teng Xiao-Dong , Ji Songxiao , Li Jingjie
Published: August 2024

e16097

Background: Whether combined immunotherapy on the basis of neoadjuvant chemotherapy is beneficial for locally advanced esophageal squamous cell carcinoma (ESCC) remain to be inconclusive. This phase 2 study (ChineseClinical Trial Registry: ChiCTR2000041081) evaluate the efficacy and safety of neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin in locally advanced ESCC. Methods: Patients with locally advanced ESCC (T2N+M0, T3N0-2M0, T4aN0-2M0, or no distant metastases, or viable or potentially viable) were enrolled and received 3 cycles of neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin. Surgery was scheduled within four to six weeks of completing the neoadjuvant treatment. Three additional cycles of adjuvant sintilimab monotherapy or sintilimab plus chemotherapy were scheduled after a multidisciplinary discussion. The primary endpoint was the MPR rate. Results: From November 2020 to November 2021, twenty-four patients (median age: 64.5 years, men: 21/24,lower segment tumor location12/24,stage IV disease 15/24) were included in this study. All patients completed three cycles of neoadjuvant treatment and surgery. The median dose intensities for sintilimab, carboplatin and albumin-bound paclitaxel were 100% (range, 66.7–105.0%), 98.4% (range, 64.1–104.0%), and 100% (range, 38.1–105.8%), respectively. The R0 resection rate was 100%. The pCR rate and MPR rate was 33.3% and 41.7%. Among the 10 patients with PD-L1 CPS of ≥1, the pCR and MPR rates were 40% and 50%. 20 (83.1%) had TNM downstaging. The median DFS and median OS had not been reached yet, 500 days DFS and OS rate was 85.3% (95%CI 85.4%-97.2%) and 94.1% (95%CI 94.8%-100.0%). PD-L1 protein expression showed a higher life expectancy trend in the post-neoadjuvant therapy esophageal tissue samples than in the pre-therapy samples. The most common grade 3-4 treatment-related adverse events were anemia (29.2%), increased gamma-glutamyl transferase level (4.2%) and hyponatremia (4.2%). Emergency reoperation and intensive care were not required, and there were no postoperative mortalities. Conclusions: Neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin preliminarily demonstrate encouraging clinical benefits and acceptable safety. Preoperative immunotherapy combined with chemotherapy alters the immune microenvironment of locally advanced resectable ESCC. Clinical trial information: ChiCTR2000041081.
Effect of perioperative medical therapy on prognosis in recurrent nasopharyngeal carcinoma: A comparative effectiveness research.
Authors: Song Xiaole , Yu Hongmeng , Yan Li , Wang Xiaoshen , Zhang Huankang
Published: August 2024

e18051

Background: Transnasal endoscopic (TEN) surgery has evolved to be an important treatment for rNPC.The role of perioperative chemotherapy or immunotherapy has not been determined yet. Methods: Three single arm, prospective researches were pooled to analyze the comparative effectivenessof neoadjuvant, adjuvant therapy and surgery only in rNPC patients undergoing TEN surgery through 2019 to 2023. Data was collected including sex, age, TNM staging, treatment modality and internal carotid artery (ICA) management in three investigator initial trials (NCT05011227, ChiCTR1900026341, NCT05350891). The primary and secondary outcomes were overall survival (OS) and local recurrence free survival (LRFS). Statistical analysis was performed using SPSS 29.0 (IBM).Variables with two-sided P-values <0.05 in log-rank tests were identified as significant. Multivariable Cox regression analysis was conducted to reveal the prognostic value of treatment modality. Results: Overall, 233 eligible participants were divided into three treatment groups (neoadjuvant, adjuvant, and surgery only group). The clinicopathological characteristics were balanced (Table). In a mean follow-up period of 605 days, the 1-year, 2-year OS rate were 91.9%, 83.3% respectively. According to Kaplan Merier survival analysis, immunotherapy± chemotherapy after surgery significantly improved OS compared with surgery only (P<0.001). Although no significance (P=0.176) was noted in neoadjuvant compared with surgery only group, partially because of the small sample size, the 1-,3-year OS rate was much higher. When blended together, neoadjuvant+adjuvant group also won over surgery only group regarding OS (P<0.001) and LRFS (P=0.002). Subgroup analysis also indicated that age≥52 (P=0.002), higher T staging (P<0.001), and embolization of ICA (P<0.001) were associated with worse prognosis. Sex showed no significant effect on survival (P=0.533). The above four factors were adopted for multivariate COX analysis, elucidating that age (P=0.005), T staging (P=0.024) and treatment modality (P=0.007) were independent predictor for OS, however, embolization of ICA (P=0.097) was not. Conclusions: Adjuvant therapy, as an independent predictor of OS, improved the overall survival in rNPC patients underwent TEN surgery. The efficacy of neoadjuvant therapy demanded solid evidence from larger sample size cohort. Clinical trial information: NCT05011227 , NCT05350891 , ChiCTR1900026341. [Table: see text]
Efficacy and safety of chidamide in combination with serplulimab and standard third-line treatments in advanced colorectal cancer: A single arm, exploratory phase 2 trial.
Authors: Li Wei , Xu Mengdan , Xu Caihua , Wu Mengyao , Chen Kai
Published: August 2024

TPS3637

Background: The efficacy of third line and subsequent treatments for advanced colorectal cancer (mCRC) is suboptimal, and the available drug options are limited. Approximately 95% of mCRC patients belong to the type of satellite stability (MSS), which often shows poor response to single immunotherapy. Previous clinical trials have preliminarily demonstrated that the potential application of combining anti-angiogenesis drugs with immune checkpoint inhibitors (ICIs) in mCRC. Chidamide is an isoform selective inhibitor of histone deacetylase (HDAC). Studies have shown its synergistic effect with PD-1 monoclonal antibody in anti-tumor activity. Therefore, we aim to conduct further investigations centered on the combination of Chidamide+Serplulimab+standard third-line treatments in mCRC. Methods: This prospective, open-label, single-arm, exploratory multi-center clinical trial has been planned to enroll 30 patients with advanced CRC who have progressed after two lines of standard therapies. The key inclusion criteria are: pathologically confirmed colorectal malignancy; age ≥18 years, regardless of gender; estimated survival ≥3 months; ECOG score 0-1; at least one measurable lesion according to iRECIST criteria; requiring third-line or beyond treatment and no prior treatment with PD1 monoclonal antibody, regorafenib/fruquintinib or TAS-102±bevacizumab; adequate major organ function; and signed informed consent and good compliance, agreeing to cooperate with survival follow-up. Enrolled patients receive Chidamide (20mg twice a week), Serplulimab (3mg/kg on day 1 every two weeks), and standard third-line treatments (TAS-102 35mg/m² twice daily on days 1-5 and 8-12 of a 28-day cycle ± bevacizumab 5mg/kg on day 1 every two weeks or regorafenib 120mg daily or fruquintinib 5mg daily for three weeks followed by one week off ).The primary endpoints are safety and objective response rate (ORR) determined by investigators. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate(DCR), PFS rate at 6 months and 12 months, OS rate at 6 months and 12 months, DCR, quality of life score(QoL), and nutritional score PG-SGA. As of February 2024, eight patients have been enrolled in the study. Trial registration number: ChiCTR2300077213. Clinical trial information: ChiCTR2300077213.