Therapy In Chinese Patients Research Articles

Combined carbapenem resulted in a 4.48-fold increase in valproic acid clearance: a population pharmacokinetic model in Chinese children and adults with epilepsy or after neurosurgery

Our study aims to explore the pharmacokinetics of valproic acid (VPA) in Chinese patients with epilepsy or after neurosurgery and establish a robust population pharmacokinetics (PPK) model. The PPK model was developed using nonlinear mixed-effects modeling, incorporating a total of 615 VPA plasma concentration data points from 443 Chinese epilepsy or after neurosurgery patients. A one-compartment model with an additive residual model was established. Forward addition and backward elimination strategies were used to assess the impact of covariates on the model parameters. Goodness-of-fit plots, bootstrap, visual predict check and normalized prediction distribution errors were used for model validation. In the final model, the apparent clearance (CL) was estimated using the following formula: CL L/h=0.430×BW/600.787×Cr/50.3−0.253×ALB/39−0.873×egender×eCBP×eIND2 ×eηCL (gender = 0.121 when is female, otherwise = 0; CBP = 1.50 when combined with carbapenems, otherwise = 0; IND2 = 0.15 when combined with oxcarbazepine, carbamazepine, phenobarbital, or phenytoin, otherwise = 0). The volume of distribution (Vd) was estimated using the formula: Vd L=8.66×BW/600.751. Comedication with carbapenems could increase VPA clearance by 4.48 times, and comedication with oxcarbazepine could enhance VPA clearance by 116%. Besides, creatinine and albumin could affect VPA clearance. Goodness-of-fit plots, bootstrap, visual predict check and normalized prediction distribution showed acceptable data fit, stability, and predictability of the model. In our study, a PPK model was utilized to attain a more comprehensive insight into these variables, improving the accuracy and individualization of VPA therapy in Chinese patients with epilepsy or after neurosurgery.

Longitudinal associations of dietary fiber and its source with 48-week weight loss maintenance, cardiometabolic risk factors and glycemic status under metformin or acarbose treatment: a secondary analysis of the March randomized trial

AimsTo examine longitudinal and dose-d ependent associations between dietary fiber intake and various clinical outcomes over 48 weeks of pharmacological treatment in T2DM patients.MethodsIn this secondary analysis, we used data from the MARCH trial, which was designed to compare the efficacy of acarbose or metformin monotherapy as the initial therapy in Chinese patients newly diagnosed with T2DM. Dietary data were obtained using a 24-h dietary recall method to evaluate the intakes of dietary fiber from different sources as well as the carbohydrate-to-fiber ratio.ResultsA total of 551 newly-diagnosed patients with T2DM complete dietary records (286 in the acarbose group and 265 in the metformin group) were included. Higher intake of total fiber and whole grain fiber was positively associated with better β‐cell function, insulin sensitivity and postprandial glycemic control under acarbose treatment. Higher intake of legume fiber was associated with better glycemic control under both acarbose and metformin treatment but with better weight loss only under metformin treatment. A high-carbohydrate–low-fiber diet was associated with worse glycemic control and lower HDL-C under acarbose treatment but with higher insulin sensitivity and better weight loss under metformin treatment.ConclusionsThe notable effects of various dietary fibers when combined with different oral glucose-lowering medications should be considered to maximize therapeutic benefit.

First real-world study on the effectiveness and tolerability of rimegepant for acute migraine therapy in Chinese patients

BackgroundRimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for acute and preventive migraine treatment in the United States and other countries. However, there is a lack of prospective real-world evidence for the use of rimegepant in Chinese migraine patients.MethodsThis was a single-arm, prospective, real-world study. While taking rimegepant to treat migraine attacks as needed, eligible participants were asked to record their pain intensity, functional ability, and accompanying symptoms for a single attack at predose and 0.5, 1, 2, 24, and 48 h postdose via a digital platform. Adverse events (AEs) during the rimegepant treatment period were recorded and analysed. The percentages of participants who experienced moderate to severe pain at predose and 0.5, 1, 2, 24, and 48 h postdose were assessed. Additionally, the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose were analysed. In addition, the total cohort (full population, FP) was stratified into a prior nonresponder (PNR) group to observe the effectiveness and safety of rimegepant for relatively refractory migraine and a rimegepant and eptinezumab (RE) group to observe the effectiveness and safety of the combination of these drugs.ResultsBy November 24th, 2023, 133 participants (FP, n = 133; PNR group, n = 40; RE group, n = 28) were enrolled, and 99 participants (FP, n = 99; PNR group, n = 30; RE group, n = 23) were included in the analysis. Rimegepant was effective in treating migraine in the FP and both subgroups, with a significant decreasing trend in the percentages of participants experiencing moderate to severe pain postdose (p < 0.05) and a marked increase in the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose compared with predose. AEs were reported by 6% of participants in the FP, and all AEs were mild.ConclusionsIn the real world, rimegepant is effective in the acute treatment of migraine patients in China. The low incidence rate of AEs highlighted the favourable tolerability profile of rimegepant.Trial registrationClinicaltrials.gov NCT05709106. Retrospectively registered on 2023-02-01.Graphical

Effectiveness and safety of glucose-lowering drugs as an adjunct to insulin therapy in Chinese patients with type 1 diabetes: a retrospective, observational study.

To assess the real-world impact of glucose-lowering drugs (GLDs) as an adjunct to insulin in Chinese patients with type 1 diabetes (T1DM). This dual-center, observational, retrospective study included 121 T1DM patients receiving GLDs as adjuncts and 56 participants with insulin-only drugs as comparators. Glycated hemoglobin A1c (HbA1c), daily insulin dosage, fasting blood glucose (FBG), postprandial blood glucose (PBG), nocturnal blood glucose (NBG) and the difference in trough and peak blood glucose levels on the same day (Δ TP) were assessed at baseline and at the end of the study. In total, HbA1c decreased by 1.14% in the GLD+insulin group (p < 0.0001) and 0.36% in the insulin-only group (p = 0.0423, mean adjusted difference, -0.09% [95% CI, -0.55 to 0.37]). The total daily insulin concentration was reduced by 7.34 U per day in the GLD+insulin group vs. 5.55 U per day in the insulin-only group (mean adjusted difference, -2.32 U [95% CI, -4.97 to 0.33]). In particular, among patients with fasting C-peptide levels < 17 pmol/L, the total daily insulin concentration was significantly reduced by 9.22 U vs. 5.09 U per day (mean adjusted difference, -3.84 [95% CI, -6.85-0.84]; p = 0.0129). There were no notable differences in the other glycemic indices between the two groups. A gradual downward trend in changes in glycemic outcomes was observed among patients treated with various combinations of metformin, acarbose, and dipeptidyl peptidase 4 inhibitor (DPP-4i). Similar reductions in the daily insulin dose were also detected in most of the GLD+insulin group in addition to the DPP-4i-only group. No severe hypoglycemia was induced by additional GLDs. The use of additional GLDs tends to improve glycemic outcomes and reduce insulin requirements in patients with T1DM. These results indicate that the use of GLDs as an adjunctive therapy may have been an effective treatment strategy among adults with T1DM in China.

Comparison of the population covered by the 2024 version of the WHO's hepatitis B prevention and treatment guidelines and the Chinese antiviral treatment guidelines

Objective: This study aims to compare the antiviral treatment similarities and differences in the population covered by the 2024 version of the World Health Organization's (WHO) hepatitis B prevention and treatment guidelines and the current Chinese hepatitis B prevention and treatment guidelines, so as to explore their impact on the indications for antiviral therapy in Chinese patients with chronic hepatitis B (CHB). Methods: The information of patients with chronic hepatitis B virus infection who did not receive antiviral treatment was collected through the registration database of the China Clinical Research Platform for Hepatitis B Elimination. Descriptive statistics were conducted on the demographic, blood, biochemical, and virological levels of patients according to the treatment recommendations of the two versions of the guidelines. The Mann-Whitney U test and χ2 test were used to compare the differences and proportional distribution of the treatment populations covered by the two guidelines. The χ2 test was used to analyze the coverage rate of different antiviral treatment indications. Results: A total of 21,134 CHB patients without antiviral treatment were enrolled. 69.4% of patients met the 2024 versions of the WHO guidelines' recommendations. 85.0% of patients met the current Chinese hepatitis B prevention and treatment guidelines. The WHO guidelines for antiviral therapy indications were met in younger patients with higher levels of ALT, AST, and APRI scores, as well as greater proportion of patients with higher viral loads (P<0.001). The WHO guidelines recommended a cut-off value of APRI>0.5, which raised the proportion of patients on antiviral therapy from 6.6% to 30.9%. 45.7% of patients met the antiviral indications for HBV DNA >2000 IU/ml with abnormal transaminase (ALT>30 U/L for males and ALT>19 U/L for females). The reduced APRI diagnostic cut-off value and ALT treatment threshold had further increased the treatment coverage rate by 91.6% in patients with chronic HBV infection in line with the 2024 versions of WHO guidelines. Conclusion: The reduction of the APRI diagnostic cut-off value and the ALT treatment threshold, based on the current hepatitis B guidelines of China, will further improve the treatment coverage of CHB patients.

Effectiveness of PD-1 inhibitor-based first-line therapy in Chinese patients with metastatic gastric cancer: a retrospective real-world study.

Programmed cell death protein-1 (PD-1) inhibitor-based therapy has demonstrated promising results in metastatic gastric cancer (MGC). However, the previous researches are mostly clinical trials and have reached various conclusions. Our objective is to investigate the efficacy of PD-1 inhibitor-based treatment as first-line therapy for MGC, utilizing real-world data from China, and further analyze predictive biomarkers for efficacy. This retrospective study comprised 105 patients diagnosed with MGC who underwent various PD-1 inhibitor-based treatments as first-line therapy at West China Hospital of Sichuan University from January 2018 to December 2022. Patient characteristics, treatment regimens, and tumor responses were extracted. We also conducted univariate and multivariate analyses to assess the relationship between clinical features and treatment outcomes. Additionally, we evaluated the predictive efficacy of several commonly used biomarkers for PD-1 inhibitor treatments. Overall, after 28.0 months of follow-up among the 105 patients included in our study, the objective response rate (ORR) was 30.5%, and the disease control rate (DCR) was 89.5% post-treatment, with two individuals (1.9%) achieving complete response (CR). The median progression-free survival (mPFS) was 9.0 months, and the median overall survival (mOS) was 22.0 months. According to both univariate and multivariate analyses, favorable OS was associated with patients having Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. Additionally, normal baseline levels of carcinoembryonic antigen (CEA), as well as the combination of PD-1 inhibitors with chemotherapy and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive MGC, independently predicted longer PFS and OS. However, microsatellite instability/mismatch repair (MSI/MMR) status and Epstein-Barr virus (EBV) infection status were not significantly correlated with PFS or OS extension. As the first-line treatment, PD-1 inhibitors, either as monotherapy or in combination therapy, are promising to prolong survival for patients with metastatic gastric cancer. Additionally, baseline level of CEA is a potential predictive biomarker for identifying patients mostly responsive to PD-1 inhibitors.

Efficacy and Safety of Ongericimab in Chinese Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia.

A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add-on treatment to optimized lipid-lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia. A total of 806 patients who were receiving stable and optimized lipid-lowering therapy but did not achieve their low-density lipoprotein cholesterol (LDL-C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL-C from baseline to week 24. Our findings demonstrated that the least-squares mean difference of percentage change in LDL-C from baseline to week 24 was -67.7% (95% CI, -72.5% to -63.0%; P<0.0001) in the ongericimab 150 mg every 2 weeks group compared with the placebo every 2 weeks group, and -61.2% (95% CI, -67.1% to -55.2%; P<0.0001) in the ongericimab 300 mg every 4 weeks group compared with the placebo every 4 weeks group. These reductions were sustained up to week 52. Furthermore, treatment with ongericimab favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups. Ongericimab, as an add-on treatment to optimized lipid-lowering therapy, significantly reduced LDL-C and was well-tolerated in Chinese patients with primary hyperlipidemia and mixed dyslipidemia who did not achieve their LDL-C targets. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04781114.

Comparative efficacy of six programmed cell death protein-1 inhibitors in first-line treatment for advanced non-small cell lung cancer: A retrospective cohort study.

e14702 Background: All six programmed cell death-1 (PD-1) inhibitors (nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and camrelizumab) have been used as first-line therapy in Chinese patients with advanced non-small cell lung cancer (NSCLC), but the comparative efficacy of these different drugs remains unclear. Methods: Retrospective collection of patient data from the First, Third, and Fifth Medical Centers of the Chinese PLA General Hospital who received PD-1 inhibitors (monotherapy or combination therapy) from June 2015 to April 2023. Analysis of patient clinical characteristics, treatment response, and survival outcomes was conducted, with the primary endpoints being overall survival (OS) and progression-free survival (PFS). Secondary endpoints include objective response rate (ORR) and disease control rate (DCR). Results: 913 patients were included and divided into 6 groups: nivolumab (123, 13.5%), pembrolizumab (421, 46.1%), sintilimab (239, 26.1%), tislelizumab (64, 7.0%), toripalimab (39, 4.3%), and camrelizumab (27, 3.0%). Median PFS was 16.0, 16.1, 18.4, 16.9, 23.7, and 12.8 months, and median OS was 33.7, 36.1, 32.5, not reached, 30.9, and 46.0 months for the nivolumab, sintilimab, pembrolizumab, tislelizumab, toripalimab, and camrelizumab groups, respectively. PFS and OS did not differ among the different PD-1 inhibitor groups (all P&gt;0.05). There were differences in ORR among the different PD-1 inhibitors (P&lt;0.05), but no differences in DCR (P&gt;0.05). Conclusions: Nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and camrelizumab exhibit similar efficacy in first-line treatment for patients with advanced NSCLC.

Homologous recombination deficiency score for predicting efficacy of platinum-based chemotherapy and PARPi maintenance therapy in ovarian cancer.

e17543 Background: Currently, homologous recombination deficiency (HRD) has been confirmed to be a predictive biomarker for poly-ADP-ribose-polymerase inhibitors (PARPi) in ovarian cancer, while its effects on the clinical outcomes of platinum-based chemotherapy and PARPi maintenance therapy are not assessed rigorously in ovarian cancer. We developed an HRD assay to evaluate the effect of HRD scores on the platinum-based chemotherapy and PARPi maintenance therapy in Chinese patients with ovarian cancer. Methods: HRD testing was performed on the samples obtained at primary cytoreductive surgery. The progression-free survival (PFS) was observed among the BRCA-mutated/HRD-positive and BRCA wild-type/HRD-negative patients. Univariate and multivariate COX analyses were performed to test the association of PFS with different variables, and hazards ratios (HR) and 95% confidence interval (CI) were calculated. The two-tailed p value less than 0.05 was considered statistically significant. Results: Totally 74 patients who received platinum-based chemotherapy were eligible for the study, among whom 81.1% responded to the initial platinum-based chemotherapy, 33.8% harbored BRCA1/2 mutations and 74.3% were HRD-positive. The median HRD score of platinum-sensitive patients (n=60) was 48.5, significantly higher than the 31 of platinum-resistant patients (n=14, p=0.0035). Analysis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) between platinum-sensitive and platinum-resistant patients showed significant differences in TAI ( p=0.0012) and LST ( p=0.004). Compared with HRD-negative patients, HRD-positive patients had a significantly longer median PFS (10 vs. 15 months, p=0.017), and multivariate analysis further indicated that HRD-positive status (HR, 0.423, 95%CI: 0.191-0.939, p=0.035) was a significant predictor for the improvement of PFS. Conclusions: The HRD assay developed in our study can accurately predict the response to platinum-based chemotherapy and PARPi efficacy in patients with ovarian cancer, providing powerful evidence for implementation of genetic testing and guidance of clinical treatment in ovarian cancer.

A random forest model to predict the efficacy of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma based on the data from the KL167-II-05-CTP study.

e18012 Background: KL-A167 is a fully humanized monoclonal antibody targeting programmed cell death-ligand 1. KL167-Ⅱ-05-CTP study had evaluated the efficacy and safety of KL-A167 in Chinese patients with previously treated recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The results of KL167-Ⅱ-05-CTP study showed that not all patients with R/M NPC could benefit from KL-A167 therapy, and an effective model to predict the efficacy of KL-A167 is necessary. Methods: The baseline data of clinical characteristics, laboratory examination and imaging of patients with R/M NPC in KL167-Ⅱ-05-CTP study were collected, who received KL-A167 therapy. The progression-free survival (PFS) was selected as the predicted variable. Patients were randomly divided into training cohort (70%) and test cohort (30%). In the training cohort, uni-Cox regression was used to estimate the value in predicting PFS, and least absolute shrinkage and selection operator (LASSO)-Cox regression was performed to screen clinical, laboratory and imaging indexes to build random forest model. The accuracy of this random forest model was validated in the test cohort. Results: In this study, 137 patients with R/M NPC were enrolled, and the median PFS of them was 2.689 (95% confidence interval [ CI]: 1.475-4.098) months. A total of 14 indexes with P &lt; 0.05 were selected to perform LASSO-Cox regression, and 10 indexes (blood lactate dehydrogenase, blood creatinine, left ventricular ejection fraction, body temperature, weight, blood lymphocyte count, blood chloride ion concentration, Eastern Cooperative Oncology Group performance status, blood triglyceride and blood alanine aminotransferase) were used to build prediction model. The C-index of risk score from this model was 0.820 and 0.790 in the training and test cohort, respectively. Patients were divided into the high and low risk groups according to the median risk score, and the median PFS of the high risk group was shorter than that of the low risk group (training cohort: 1.377 vs. 4.197 months, P &lt; 0.001, hazard ratio [ HR] = 1.142, 95% CI: 1.111-1.175; test cohort: 3.475 vs. 10.984 months, P &lt; 0.001, HR = 1.100, 95% CI: 1.060-1.142). Conclusions: In this study, a random forest model based on 10 clinical, laboratory and imaging indexes was constructed and showed a potential value in predicting the PFS of KL-A167 therapy in Chinese patients with previously treated R/M NPC, which could help to guide clinical trials and practices.

Abstract PO2-16-06: Treatment Patterns of Neoadjuvant Therapy in Chinese Patients with HR-Positive/HER2-Positive Early or Locally Advanced Breast Cancer: A Real-World Study Using NCID Data in 2019-2022

Abstract Background: With the approval of pertuzumab (P) in China in 2019, P plus trastuzumab (T) and chemotherapy has become a standard of care in the neoadjuvant setting for patients with HER2-positive (HER2+) early or locally advanced breast cancer (BC). As a unique subtype, HR-positive (HR+)/HER2+ BC is less responsive to neoadjuvant chemotherapy plus HER2 targeted therapy with lower pathologic complete response (pCR) rates compared with the HR−/HER2+ subgroup. In China, the treatment pattern of HR+/HER2+ BC patients is unclear. In this real-world study, we summarized the current treatment patterns of Chinese patients diagnosed with HR+/HER2+ BC at an early or locally advanced stage based on national-level data to drive clinical decision support. Methods: A representative sample of 51 hospitals (31 cancer centers and 20 general hospitals) covering 29 provinces from NCID (National Cancer Information Database) were generated. Anonymous individual patient data from electronic medical records (EMR) were retrieved to extract information on therapy modalities. Early or locally advanced HR+/HER2+ BC patients who were initially diagnosed between January 1, 2019 and May 31, 2022 were included. Data were analyzed both by year and in the aggregate to ensure accuracy and stability. Results: The types of hospitals and study period reflected the current treatment landscape of HR+/HER2+ early or locally advanced BC in Chinese clinical practice. From 2019 to 2022, the results were consistent by year. In the aggregate, a total of 290,626 patients were initially diagnosed with BC during the study period. 84% (243,528/290,626) were at an early or locally advanced stage, of which 50% (121,548/243,528) had a pathologic diagnosis, 24% (29,390/121,548) were identified as HER2+, 69% (20,370/29,390) were both HR+ and HER2+, and 87% (17,630/20,370) underwent surgery. After excluding those without post-operative pathologic reports or with other primary cancers, 15,368 patients were analyzed regarding treatment patterns. 30% (4,598/15,368) received neoadjuvant therapy but 69% (10,677/15,368) had no neoadjuvant therapy. Among 4,598 patients, 31% (1,434/4,598) received T as single anti-HER2 targeted therapy, 36% (1,649/4,598) received dual HER2 blockade (1,522 T plus P, 127 T plus a TKI [tyrosine kinase inhibitor]), and the rest (1,515) received treatment that not contain a targeted agent. For patients treated with T plus P, 1,465 received concurrent chemotherapy (410 anthracyclines-based, 828 platinum-based); for patients treated with T plus TKI, 123 received concurrent chemotherapy (15 anthracyclines-based, 79 platinum-based). The most frequently prescribed chemotherapies were platinum-based regimens (57% for T plus P plus chemotherapy and 64% for T plus TKI plus chemotherapy). Conclusions: Based on the largest nationwide database, strong representativeness and stability of our data sources, our findings are of great significance to clinical decision-making. The proportion of patients who underwent neoadjuvant therapy of HR+HER2+ BC is much lower than in many other countries, with T plus P in combination with chemotherapy appearing to be the most commonly used targeted regimen. We also found some distinctions between neoadjuvant patterns of early-stage BC in the real world of China and guidelines, which would be further explored in subsequent research. Citation Format: Zhenzhen Liu, Jiujun Zhu, Chengzheng Wang, Zhenduo Lu, Xiuchun Chen, Lianfang Li, Xianfu Sun, Chongjian Zhang, Jianghua Qiao, Min Yan. Treatment Patterns of Neoadjuvant Therapy in Chinese Patients with HR-Positive/HER2-Positive Early or Locally Advanced Breast Cancer: A Real-World Study Using NCID Data in 2019-2022 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-06.

Antibiotics influence the risk of anti-drug antibody formation during anti-TNF therapy in Chinese inflammatory bowel disease patients.

Aims: The formation of anti-drug antibodies (ADAs) during anti-tumor necrosis factor (anti-TNF) therapy is reported to lead to reducing serum drug levels, which may bring about a loss of response to treatment. Previous research has suggested an association between specific antibiotic classes and ADA formation during anti-TNF therapy. However, there are few studies specifically examining this association in Chinese inflammatory bowel disease (IBD) patients. Therefore, our study aimed to evaluate the possible effect of antibiotic use on ADA formation to anti-TNF therapy in Chinese patients with IBD. Methods: A total of 166 patients with IBD, including 149 with Crohn's disease (CD) and 17 with ulcerative colitis (UC), were included in this retrospective analysis. These patients were initially treated with anti-TNF therapy (infliximab or adalimumab) after January 2018 and reviewed with available ADA levels before October 2023. After univariable analysis of all the variables, a multivariate Cox proportional hazards model was used to assess the association between antibiotic use and ADA development. Results: Among 166 IBD patients treated with infliximab (108/166, 65.1%) or adalimumab (58/166, 34.9%), 31 patients (18.7%) were measured as positive ADA levels. Cox proportional hazard model demonstrated an increased risk of ADA formation in IBD patients who used β-lactam-β-lactamase inhibitor combinations (BL-BLIs) (HR = 5.143, 95%CI 1.136-23.270, p = 0.033), or nitroimidazoles (HR = 4.635, 95%CI 1.641-13.089, p = 0.004) during 12months before the ADA test. On the contrary, a reduced risk was noted in patients treated with fluoroquinolones (HR = 0.258, 95% CI 0.072-0.924, p = 0.037). Moreover, the median serum infliximab or adalimumab concentration in patients with positive ADA levels was significantly lower than that in patients with negative ADA levels (infliximab: 0.30 vs. 1.85μg/mL, p < 0.0001; adalimumab: 0.45 vs. 7.55μg/mL, p = 0.0121). Conclusion: ADA development is associated with various antibiotic classes. BL-BLIs and nitroimidazoles might increase the risk of ADA formation during anti-TNF therapy in Chinese IBD patients, while the treatment with fluoroquinolones could probably reduce such risk. There were certain limitations in the retrospective analysis of the study, therefore, the results are just for reference, and other studies are needed to further confirm our findings.

A pivotal bridging study of lurbinectedin as second-line therapy in Chinese patients with small cell lung cancer

This single-arm, multi-center clinical trial aimed to evaluate the safety, tolerability, DLT, recommended dose (RD), preliminary efficacy, and pharmacokinetics (PK) characteristics of lurbinectedin, a selective inhibitor of oncogenic transcription, in Chinese patients with advanced solid tumors, including relapsed SCLC. Patients with advanced solid tumors were recruited in the dose-escalation stage and received lurbinectedin in a 3 + 3 design (two cohorts: 2.5 mg/m2 and 3.2 mg/m2, IV, q3wk). The RD was expanded in the following dose-expansion stage, including relapsed SCLC patients after first-line platinum-based chemotherapy. The primary endpoints included safety profile, tolerability, DLT, RD, and preliminary efficacy profile, while the secondary endpoints included PK characteristics. In the dose-escalation stage, ten patients were included, while one patient had DLT in the 3.2 mg/m2 cohort, which was also the RD for the dose-expansion stage. At cutoff (May 31, 2022), 22 SCLC patients were treated in the ongoing dose-expansion stage, and the median follow-up was 8.1 months (range 3.0–11.7). The most common grade ≥ 3 treatment-related adverse events (TRAEs) included neutropenia (77.3%), leukopenia (63.6%), thrombocytopenia (40.9%), anemia (18.2%), and ALT increased (18.2%). The most common severe adverse events (SAEs) included neutropenia (27.3%), leukopenia (22.7%), thrombocytopenia (18.2%), and vomiting (9.1%). No treatment-related deaths occurred. The Independent Review Committee (IRC)-assessed ORR was 45.5% (95% CI 26.9–65.3). Lurbinectedin at the RD (3.2 mg/m2) showed manageable safety and acceptable tolerability in Chinese patients with advanced solid tumors, and demonstrates promising efficacy in Chinese patients with SCLC as second-line therapy.Trial registration: This study was registered with ClinicalTrials.gov NCT04638491, 20/11/2020.

Efficacy and safety of anti-programmed death-1 antibody-based combination therapy in advanced or metastatic gastric or gastroesophageal junction cancer in Chinese patients: A real-world study.

Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting. In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety profile were measured and analyzed. In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia. Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.

First-line bevacizumab plus chemotherapy in Chinese patients with stage III/IV epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer: a phase III randomized controlled trial.

First-line bevacizumab plus carboplatin and paclitaxel (CP) is approved for stage III/IV ovarian cancer treatment following initial surgical resection, based on global phase III GOG-0218 and ICON7 trials. This study evaluated the efficacy and safety of bevacizumab + CP as first-line ovarian cancer therapy in Chinese patients. Patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer post-primary surgery were randomized 1:1 to receive 6 cycles of CP with bevacizumab/placebo, followed by bevacizumab/placebo maintenance until unacceptable toxicity or disease progression. Primary endpoint was investigator-assessed progression-free survival (PFS). Stratification factors were FIGO stage and debulking status (stage III optimally debulked vs stage III suboptimally debulked vs stage IV) and Eastern Cooperative Oncology Group performance status (0 vs 1 or 2). Of randomized patients, 51 received bevacizumab + CP and 49 received placebo + CP. Median PFS was 22.6 months with bevacizumab + CP (95% confidence interval [CI]=18.6, not estimable) and 12.3 months (95% CI=9.5, 15.0) with placebo + CP (stratified hazard ratio=0.30; 95% CI=0.17, 0.53). Treatment-related grade 3/4 adverse events occurred in 46 of 49 (94%) patients receiving bevacizumab + CP, and 34 of 50 (68%) receiving placebo + CP. Bevacizumab + CP showed clinically meaningful improvement in PFS vs placebo + CP, consistent with GOG-0218 results. Safety data were aligned with the known bevacizumab safety profile. These results support first-line bevacizumab + CP therapy in Chinese patients with ovarian cancer. ClinicalTrials.gov Identifier: NCT03635489.

Ixazomib Maintenance Therapy in Chinese Patients with Newly Diagnosed Multiple Myeloma Not Treated with Stem Cell Transplantation: A Single-Arm, Open-Label Study

Introduction: Multiple myeloma (MM) is a life-threatening cancer of plasma cells in the bone marrow. It often leads to bone marrow failure and bone destruction. Lenalidomide is the only drug approved by Food and Drug Administration (FDA) and European Medical Association (EMA) as maintenance therapy for MM post stem cell transplantation (SCT), however it is not approved as maintenance for patients who are ineligible for high-dose therapy followed by SCT and is also not suitable for all patients due to toxicity and new primary malignancy (NPM) concerns. Hence, new maintenance agents are needed to offer patients continuous disease control while maintaining their health-related quality of life (HRQoL). Ixazomib, an oral protease inhibitor, was approved by FDA for MM patients with at least one prior therapy. The present study assessed the long-term safety, tolerability and efficacy of ixazomib maintenance therapy in Chinese newly diagnosed MM (NDMM) patients who had not undergone SCT. Methods: The C16021 CCS (NCT03748953) was a single arm, open-label extension of the TOURMALINE-MM4 (NCT02312258) phase 3 clinical trial, and was conducted from June 2018 to October 2022. It included Chinese patients aged ≥18 years with a confirmed diagnosis of symptomatic NDMM who had achieved a major response [complete response (CR), very good partial response (VGPR), or partial response (PR)] with initial MM therapy. Patients received oral ixazomib capsules at days 1, 8, and 15 of every 28-day cycle. The dose of ixazomib was escalated from 3 mg to 4 mg if it was tolerated during the first 4 cycles. The duration of treatment was approximately 24 months or until patients experienced progressive disease (PD) or unacceptable toxicity, whichever occurred first. The primary objective was to assess long-term safety and tolerability of ixazomib. The secondary endpoints included progression free survival (PFS), overall survival (OS), time to progression (TTP), time to next line therapy (TTNT), incidence of new primary malignancy (NPM) and HRQoL. Results: A total of 37 patients were included in the study from 7 study centers in China. Of these 37 patients, 35 patients were included in the safety analysis. The dose was escalated to 4 mg at day 1 of cycle 5 in 77% of patients. A total of 34 patients (97%) experienced at least 1 treatment emergent adverse events (TEAE) with 30 patients (86%) experiencing a treatment-related TEAE and 16 patients (46%) experienced a Grade ≥3 TEAE. The most common Grade ≥3 TEAEs reported were thrombocytopenia (2 patients, 6%) and pneumonia (2 patients, 6%). No NPMs were reported. SAEs were reported in 7 patients (20%) and 2 patients (6%) had their study drug discontinued permanently due to a TEAE. Three patients (9%) experienced TEAEs of peripheral neuropathy (PN, all grade 1 or 2) and all 3 patients had resolution and improvement of PN events during the treatment period. The median time to resolution of PN events was 24.0 days and median time to improvement of PN events was 8.0 days. Overall, 33 patients were included in the efficacy analysis. The median age was 68.3 years, male 64% and female 36%, ISS stage at initial diagnosis was 21%, 30% and 48% for stage I, II and III, respectively. The median time from initiation of induction therapy to first dose of study drug was 8.9 months. With a median follow-up of 15.9 months, median PFS and TTNT were 21.3 months and 24.7 months, respectively. If counting from induction therapy, median PFS was 30.0 months. All patients were still alive at date of last contact. Three patients (9%) demonstrated deepening of response during treatment. Of note, since only 9 patients (27%) had VGPR or PR at study entry, the potential for assessing deepening of response in this study was limited to these 9 patients. Ixazomib maintenance treatment showed no negative impact on HRQoL, as measured by the EORTC QLQ-C30, EORTC QLQ-MY20, EQ-5D-5L, and EQ VAS. Conclusion: Ixazomib maintenance therapy showed a tolerable safety profile with prolonged PFS in Chinese patients and the response was maintained thus providing a valuable treatment option in NDMM patients who have not undergone SCT. The results of this study were consistent with TOURMALINE-MM4 global study.

Selinexor, Daratumumab and Dexamethasone for Patients with Multiple Myeloma Previously Treated with Lenalidomide at First Relapse: A Real-World Study

CONCLUSIONS As lenalidomide becomes increasingly established standard of care for patients with newly diagnosed multiple myeloma (NDMM), a significant number of patients may develop resistance to lenalidomide in their treatment, representing a clinically important population in need of effective therapies. Lenalidomide-refractory patients, who relapse quickly and have very poor outcomes, constitute a population with unmet medical needs. Selinexor is a selective inhibitor of exportin-1, leading to the accumulation of tumor suppressor proteins and growth regulator proteins in the nucleus. This results in reduced expression of several oncoproteins, leading to cell cycle arrest and apoptosis of cancer cells. Previous data indicate that the biology associated with resistance to the monoclonal antibody daratumumab is linked to sensitivity to selinexor (ASH 2021), and selinexor conbombined with daratumumab and dexamethasone (SDd) is a well-tolerated and effective option for patients with relapsed/refractory multiple myeloma (RRMM) (Gasparetto C, 2020). Here, we present the safety and preliminary efficacy findings from the first study of SDd combination therapy in Chinese patients with multiple myeloma who refractory to lenalidomide at first relapse (NCT05559788). This study is a single-arm, prospective, non-interventional, real-world study that enrolled pts who had previously received one-line anti-myeloma treatment. Subjects were treated with selinexor (60 mg QW) in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) in 28-day cycles until PD, death or patients' withdrawal. Data collected included treatment response, patient characteristics such as age, sex, multiple myeloma features (cytogenetics by fluorescence in situ hybridization, type, stage, anti-myeloma treatment, and stem cell transplantation [SCT] status), and patients' survival. Between Feb 1, 2023, and May 30, 2023, a total of 8 RRMM pts were enrolled and received treatment at The First Affiliated Hospital of Soochow University. The median age was 63 years (range 44-78), with all pts (100%) had R-ISS stage II/III disease. Among them, 6 (75%) pts were classified as high risk or above by mSMART risk stratification, and 4 (50%) pts had extramedullary disease (EMD). All 8 (100%) pts were refractory to lenalidomide, and 7（87.5%）have received autologous stem cell transplantation (ASCT) (Table 1). At the end of one course, 6 patients (75%) achieved remission (3 very good partial responses [VGPR] and 3 partial responses [PR]). Among the 4 pts with EMD, 1 pt showed progressive disease (PD) after two courses, 1 pt showed stable disease (SD), and 2 pt achieved PR and VGPR but progressed after four and two courses, respectively. The data suggests that SDd combination therapy brings about rapid remission in EMD patients, while the duration of response may be shorter. Therefore, for these patients, it is crucial to closely monitor and plan for the next steps of treatment after achieving rapid remission. All four remaining non-EMD pts achieved remission, three of whom are continuing treatment (one died of COVID-19). Four patients were infected with COVID-19 during the treatment process. One pt was asymptomatic and detected positive with virus infection by antigen test screening. Among the three pts with symptoms, one had fever, cough, and pneumonia, and one had multiple organ failure (MOF). Three pts received antiviral medication (two with Paxlovid and one with Molnupiravir), and three recovered, but the one with MOF died. The SDd treatment was interrupted in all four pts, with a median time of 18 days (range: 12 to 21 days), until COVID-19 turned negative. The most common grade 3 adverse events (AEs) were thrombocytopenia (25%), anemia (13%), and neutropenia (13%). Non-hematological AEs were mainly grade 1-2. Three patients had dose reductions due to myelosuppression. This real-world study demonstrates that SDd combination therapy led to early, deep responses in lenalidomide-refractory multiple myeloma patients at their first relapse. Considering that patients with extramedullary disease had limited benefit from SDd treatment, future study designs may restrict the recruitment of such patients.

Real-world Efficacy and Safety of Naltrexone-bupropion Therapy in Chinese Patients with Obesity: A Single-centre Experience

Real-world Efficacy and Safety of Naltrexone-bupropion Therapy in Chinese Patients with Obesity: A Single-centre Experience

Efficacy and safety of perampanel as early add-on therapy in Chinese patients with focal-onset seizures: a multicenter, open-label, single-arm study.

No interventional study has been conducted in China to assess efficacy and safety of perampanel in treating Chinese patients with epilepsy, nor has there been any study on perampanel early add-on therapy in China. This interventional study aimed to assess efficacy and safety of perampanel as an early add-on treatment of focal-onset seizures (FOS) with or without focal-to-bilateral tonic-clonic seizures (FBTCS) in Chinese patients. In this multicenter, open-label, single-arm, phase 4 interventional study, Chinese patients ≥ 12 years old with FOS with or without FBTCS who failed anti-seizure medication (ASM) monotherapy from 15 hospitals in China were enrolled and treated with perampanel add-on therapy (8-week titration followed by 24-week maintenance). The primary endpoint was 50% responder rate. Secondary endpoints included seizure-freedom rate and changes in seizure frequency from baseline. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were recorded. The full analysis set included 150 patients. The mean maintenance perampanel dose was 5.9 ± 1.5 mg/day and the 8-month retention rate was 72%. The 50% responder rate and seizure-freedom rate for all patients during maintenance were 67.9 and 30.5%, respectively. Patients with FBTCS had higher 50% responder rate (96.0%) and seizure-freedom rate (76.0%) during maintenance. Patients on concomitant sodium valproate had a significantly higher seizure-freedom rate than those on concomitant oxcarbazepine. Eight-six (55.1%) patients experienced treatment-related TEAEs, and the most common TEAEs were dizziness (36.5%), hypersomnia (11.5%), headache (3.9%), somnolence (3.2%), and irritability (3.2%). Withdrawal due to TEAEs occurred to 14.7% of the patients. Perampanel early add-on was effective and safe in treating Chinese patients≥12 years old with FOS with or without FBTCS.Clinical trial registrationwww.chictr.org.cn, Identifier ChiCTR2000039510.

Real-world efficacy and safety data of anti-PD-1 plus anti-CTLA-4 combination therapy in Chinese patients with advanced melanoma.

e21530 Background: Combination of anti-PD-1 plus anti-CTLA-4 has shown superior efficacy over monotherapy in advanced melanoma among Caucasian populations. However, it has not been evaluated in Chinese patients, and data on acral and mucosal melanoma are limited. We aimed to assess the efficacy and safety of anti-PD-1 antibody plus ipilimumab therapy in Chinese patients with advanced melanoma in clinical practice. Methods: Advanced melanoma patients treated with anti-PD-1 antibody combined with ipilimumab in Sun-Yat sen University Cancer Center from May 2015 to October 2022 were retrospectively assessed. Patient baseline characteristics, tumor responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Toxicity was assessed to estimate safety. Results: Altogether, 86 patients were included. The primary site was cutaneous, acral, mucosal, uveal and central nervous system (CNS) in 34, 21, 20, six and five patients, respectively. Among them, 21 patients were treatment-naive, 65 patients were previously treated, and 54 patients progressed of front-line ani-PD-1 therapy. 12 patients received ipilimumab 3mg/kg combined with low dose anti-PD-1 (Nivolumab 80mg or Pembrolizumab 1mg/kg) Q3w for four doses, and the other 74 patients received standard dose of anti-PD-1 plus ipilimumab 1mg/kg Q3w therapy. There were 25(29%) patients with liver metastasis and 26(30.2%) patients with CNS metastasis at baseline. The overall response rate (ORR) was 15.1% in the whole cohort, with complete response observed in six (6%) patients, partial response in 7 (8.1%), stable disease in 28 (32.6%). The response rate in the treatment-naive and prior systemic therapy group was 23.8% and 12.3%, respectively. For those treated with anti-PD-1 followed by the anti-PD-1+ ipilimumab as subsequent therapy after disease progression, the ORR was 11.1%. The response rate for cutaneous melanoma was 23.5%, and 37.5% in the naïve group. Response rates for acral, uveal, CNS and mucosal melanoma were 19.0%, 16.7%,0% and 0% respectively. The median progression-free survival (PFS) and overall survival (OS) in all patients was 4.5 (3.6-5.4) months and 22.0 (12.4-31.6) months, respectively. The 3-year OS were 100% in patients who achieved ORR. There were no significant differences in PFS or OS for patients with cutaneous or acral melanoma. mucosal primary tumor type, liver metastasis and elevated LDH were predictive of shorter PFS and OS. CNS metastasis, previous treatment, BRAF/NRAS mutation status and sex were not found to be related to survival. Adverse events occurred in 71% of patients and 13% were grade 3 or worse. Conclusions: The efficacy of anti-PD-1+ ipilimumab combination therapy in Chinese patients tended to be inferior compared to global studies but was well tolerated. OS were good in cases with CR or PR.