Pembrolizumab in patients from China with microsatellite instability-high/mismatch repair deficient tumors: KEYNOTE-158.

Aim: To evaluate pembrolizumab in patients of Chinese descent with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors enrolled in KEYNOTE-158 (Cohort L). Methods: Patients with MSI-H/dMMR advanced tumors received pembrolizumab 200 mg IV Q3W. Primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: 24 patients were enrolled (20 were evaluable for efficacy). With median follow-up of 12.4 months, the ORR was 70%. DOR, PFS and OS were all not reached. A total of 19 (79%) patients had a treatment-related adverse event (AE; grade ≥3 in 4 [17%]), and 8 (33%) had an immune-mediated AE (grade ≥3 in (4 [17%]). Conclusion: Pembrolizumab provided meaningful and durable responses with manageable safety. These results are consistent with those reported for the global trial.

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Efficacy, safety and genomic analysis of SCT200, an anti-EGFR monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type metastatic colorectal cancer: a phase â ¡ study.

BACKGROUND: Limited therapeutic options are available for metastatic colorectal cancer (mCRC) patients after failure of first- and second-line therapies, representing an unmet medical need for novel therapies. METHODS: This is an open-label, single arm, multicenter, phase Ⅱ study aiming to perform the efficacy, safety and genomic analysis of SCT200, a noval fully humanized IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type mCRC. SCT200 (6 mg/kg) was given weekly for the first six weeks, followed by a higher dose of 8 mg/kg every two weeks until disease progression or unacceptable toxicity. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR) and secondary endpoints included ORR in patients with left-sided tumor, disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. FINDINGS: From February 12, 2018 to December 1, 2019, a total of 110 patients aged between 26 and 77 years (median: 55; interquartile range [IQR]: 47-63) with fluorouracil, oxaliplatin, and irinotecan refractory RAS and BRAF wild-type mCRC were enrolled from 22 hospitals in China. As the data cut-off date on May 15, 2020, the IRC-assessed ORR and DCR was 31% (34/110, 95% confidence interval [CI] 22-40%) and 75% (82/110, 95% CI 65-82%), respectively. Thirty one percent (34/110) patients achieved confirmed partial response (PR). The median PFS and median OS were 5.1 months (95% CI 3.4-5.2) and 16.2 months (95% CI 11.1-not available [NA]), respectively. The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hypomagnesemia (17%, 19/110) and acneiform dermatitis (11%, 12/110). No deaths occurred. Genomic analysis suggested positive association between MYC amplification and patients' response (P = 0.0058). RAS/RAF mutation and MET amplification were the most frequently detected resistance mechanisms. Patients with high circulating tumor DNA (ctDNA) at baseline or without ctDNA clearance at the 7th week after the first dose of SCT200 administration before receiving SCT200 had worse PFS and OS. INTERPRETATION: SCT200 exhibited promising clinical efficacy and manageable safety profiles in RAS and BRAF wild-type mCRC patients progressed on fluorouracil, irinotecan and oxaliplatin treatment. The baseline ctDNA and ctDNA clearance status at the 7th week after the first dose of SCT200 administration before receiving SCT200 could be a potential prognostic biomarker for RAS and BRAF wild-type mCRC patients with SCT200 therapy. FUNDING: This study was sponsored by Sinocelltech Ltd., Beijing, China and partly supported by the National Science and Technology Major Project for Key New Drug Development (2019ZX09732001-006, 2017ZX09304015).

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Pucotenlimab in patients with advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A multicenter phase 2 study.

We report a multicenter, phase 2 study evaluating the efficacy of pucotenlimab, an anti-PD-1 antibody, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, and potential biomarkers for response. Overall, 100 patients with previously treated, advanced solid tumors centrally confirmed as dMMR or MSI-H received pucotenlimab at 200 mg every 3 weeks. The most common cancer type is colorectal cancer (n = 71). With a median follow-up of 22.5 months, the objective response rate is 49.0% (95% confidence interval 38.86%-59.20%) as assessed by the independent review committee, while the median progression-free survival and overall survival have not been reached. Grade ≥3 treatment-related adverse events were observed in 18 patients. For the biomarker analysis, responders are enriched in patients with mutations in the KMT2D gene. Pucotenlimab is an effective treatment option for previously treated advanced dMMR/MSI-H solid tumors, and the predictive value of KMT2D mutation warrants further research. This study is registered with ClinicalTrials.gov: NCT03704246.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: PD-1 inhibitors combined with chemotherapy have shown efficacy in gastric or gastro-esophageal junction cancer. We compared the efficacy and safety of pembrolizumab plus chemotherapy with placebo plus chemotherapy in participants with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. METHODS: KEYNOTE-859 is a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial, done at 207 medical centres across 33 countries. Eligible participants were aged 18 years and older with previously untreated histologically or cytologically confirmed locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to receive pembrolizumab or placebo 200 mg, administered intravenously every 3 weeks for up to 35 cycles. All participants received investigator's choice of fluorouracil (intravenous, 800 mg/m2 per day) administered continuously on days 1-5 of each 3-week cycle plus cisplatin (intravenous, 80 mg/m2) administered on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m2) administered twice daily on days 1-14 of each 3-week cycle plus oxaliplatin (intravenous, 130 mg/m2) administered on day 1 of each 3-week cycle. Randomisation was done using a central interactive voice-response system and stratified by geographical region, PD-L1 status, and chemotherapy in permuted block sizes of four. The primary endpoint was overall survival, assessed in the intention-to-treat (ITT) population, and the populations with a PD-L1 combined positive score (CPS) of 1 or higher, and PD-L1 CPS of 10 or higher. Safety was assessed in the as-treated population, which included all randomly assigned participants who received at least one dose of study intervention. Here, we report the results of the interim analysis. This study is registered with ClinicalTrials.gov, NCT03675737, and recruitment is complete. FINDINGS: Between Nov 8, 2018, and June 11, 2021, 1579 (66%) of 2409 screened participants were randomly assigned to receive pembrolizumab plus chemotherapy (pembrolizumab group; n=790) or placebo plus chemotherapy (placebo group; n=789). Most participants were male (527 [67%] of 790 participants in the pembrolizumab plus chemotherapy group; 544 [69%] of 789 participants in the placebo plus chemotherapy group) and White (426 [54%]; 435 [55%]). Median follow-up at the data cutoff was 31·0 months (IQR 23·0-38·3). Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population (12·9 months [95% CI 11·9-14·0] vs 11·5 months [10·6-12·1]; hazard ratio [HR] 0·78 [95% CI 0·70-0·87]; p<0·0001), in participants with a PD-L1 CPS of 1 or higher (13·0 months [11·6-14·2] vs 11·4 months [10·5-12·0]; 0·74 [0·65-0·84]; p<0·0001), and in participants with a PD-L1 CPS of 10 or higher (15·7 months [13·8-19·3] vs 11·8 months [10·3-12·7]; 0·65 [0·53-0·79]; p<0·0001). The most common grade 3-5 adverse events of any cause were anaemia (95 [12%] of 785 participants in the pembrolizumab group vs 76 [10%] of 787 participants in the placebo group) and decreased neutrophil count (77 [10%] vs 64 [8%]). Serious treatment-related adverse events occurred in 184 (23%) participants in the pembrolizumab group and 146 (19%) participants in the placebo group. Treatment-related deaths occurred in eight (1%) participants in the pembrolizumab group and 16 (2%) participants in the placebo group. No new safety signals were identified. INTERPRETATION: Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. FUNDING: Merck Sharp and Dohme.

Comparison of the Novel Digital Multi-dimension Botong Score with the Brief Pain Inventory for Evaluating Cancer-Related Pain: A Randomized Crossover Trial.

INTRODUCTION: Pain is a common symptom in patients with cancer, and comprehensive assessments of pain are crucial for decision-making of treatment regimens. This study aimed to compare the practicality of the novel digital multi-dimension Botong score (BTS) and the brief pain inventory (BPI) for evaluating cancer-related pain. METHODS: This randomized crossover trial enrolled patients with cancer-related pain at the Affiliated Cancer Hospital of Shandong First Medical University between July and December 2022. The participants were randomized 1:1 to BTS evaluation followed by BPI or vice versa. The consistency of BTS and BPI was analyzed, including pain score and the impact of pain on emotions and sleep. The convenience, patient preference, and the filling time of the two tools were compared. The accuracy of BTS in detecting breakthrough pain and neuropathic pain was analyzed. RESULTS: A total of 308 patients with cancer-related pain were screened and 233 were finally included in the analysis. The Pearson correlation coefficients of pain score for BTS and BPI (4 relevant questions) were 0.583 for the worst pain score within 24 h, 0.394 for the mildest pain score within 24 h, 0.551 for the average pain score within 24 h, and 0.511 for the current pain score, respectively (all P < 0.01), indicating a positive correlation between the BTS and BPI pain scores. BTS was superior to BPI for filling time, convenience, and patient preference (191.03 vs. 256.76, 7.70 vs. 6.78, 7.58 vs. 6.70; all P < 0.01). The accuracy of BTS in detecting breakthrough pain and neuropathic pain was 98.28% and 97.42%, respectively. CONCLUSION: Pain scores evaluated by BTS have a positive correlation with those evaluated by BPI. BTS reduces the filling time, is more convenient to use, and is more favored by patients. In addition, BTS could help identify breakthrough pain and neuropathic pain. CLINICAL TRIAL REGISTRATION: Chictr.org.cn, identifier: ChiCTR220062624.

POU2F1/DNMT3a Pathway Participates in Neuropathic Pain by Hypermethylation-Mediated LRFN4 Downregulation Following Oxaliplatin Treatment.

Evidence demonstrates that DNA methylation is associated with the occurrence and development of various neurological diseases. However, the potential target genes undergoing DNA methylation, as well as their involvement in the chemotherapy drug oxaliplatin-induced neuropathic pain, are still unclear. Here, Lrfn4, which showed hypermethylation in the promoter regions, was screened from the SRA methylation database (PRJNA587622) following oxaliplatin treatment. MeDIP and qPCR assays identified that oxaliplatin treatment increased the methylation in Lrfn4 promoter region and decreased the expression of LRFN4 in the spinal dorsal horn. The assays with gain and loss of LRFN4 function demonstrated that LRFN4 downregulation in spinal dorsal horn contributed to the oxaliplatin-induced mechanical allodynia and cold hyperalgesia. Moreover, oxaliplatin treatment increased the DNA methyltransferases DNMT3a expression and the interaction between DNMT3a and Lrfn4 promoter, while inhibition of DNMT3a prevented the downregulation of LRFN4a induced by oxaliplatin. We also observed that the transcriptional factor POU2F1 can bind to the predicted sites in DNMT3a promoter region, oxaliplatin treatment upregulated the expression of transcriptional factor POU2F1 in dorsal horn neurons. Intrathecal injection of POU2F1 siRNA prevented the DNMT3a upregulation and the LRFN4 downregulation induced by oxaliplatin. Additionally, intrathecal injection of DNMT3a siRNA or POU2F1 siRNA alleviated the mechanical allodynia induced by oxaliplatin. These findings suggested that transcription factor POU2F1 upregulated the expression of DNMT3a, which subsequently decreased LRFN4 expression through hypermethylation modification in spinal dorsal horn, thereby mediating neuropathic pain following oxaliplatin treatment.

Human leukocyte antigen-DRB1 gene polymorphism and aplastic anemia: A meta-analysis.

BACKGROUND: The human leukocyte antigen-DRB1 (HLA-DRB1) gene plays key roles in mediating immune response and activating autoreactive T-cells during aplastic anemia (AA) etiology. However, inconsistency appeared in the associations between HLA-DRB1 polymorphism and AA. We aimed to comprehensively clarify their associations in the meta-analysis. METHODS: PubMed, Embase, Web of Science, Science Direct, SinoMed, WanFang Data, China National Knowledge Infrastructure, and Chongqing VIP Chinese Science Database were searched from January 2000 to June 2022. Statistical analysis was performed in STATA 15.0 and Comprehensive Meta-analysis Software 3.0. RESULTS: A total of 16 studies with 4428 patients were eventually analyzed. The results of the meta-analysis suggested that HLA-DRB1*0301 could decrease the risk of AA (odd ratio (OR) = 0.600, 95% CI: 0.427, 0.843). Besides, HLA-DRB1*0901 and HLA-DRB1*1501 were risk factors of AA (OR = 1.591, 95% CI: 1.045, 2.424; OR = 2.145, 95% CI: 1.501, 3.063; respectively). Sensitivity analysis showed heterogeneity among included studies. CONCLUSION: HLA-DRB1 polymorphisms could play roles in the occurrence of AA, however more population-based studies with larger sample sizes are required to certify our findings.

Identification of a potential competing endogenous RNA (ceRNA) network in gastric adenocarcinoma.

Background: Recently, a growing body of evidence has revealed the role of competing endogenous RNA (ceRNA) networks in various human cancers. However, there is still a lack of research on the systemic ceRNA network related to gastric adenocarcinoma. Methods: The intersection of differentially expressed genes (DEGs) was obtained by mining the GSE54129, GSE13861, and GSE118916 datasets from the Gene Expression Omnibus (GEO) website. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for the enrichment analysis. A protein-protein interaction (PPI) network was established with the STRING online database, and hub genes were identified by Cytoscape software. The prediction of key microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) was conducted by miRNet. The prognostic analysis, expression difference, and correlation analysis of messenger RNAs (mRNAs), lncRNAs, and miRNAs were carried out using the Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, and Encyclopedia of RNA Interactomes (ENCORI). Results: We identified180 significant DEGs. Extracellular matrix (ECM) receptor interaction, focal adhesion, ECM tissue, and collagen catabolic processes were the most significant pathways in the functional enrichment analysis. Nineteen upregulated hub genes and one downregulated hub gene were found to be significantly associated with the prognosis of gastric adenocarcinoma. Of the 18 miRNAs targeting 12 key genes, only six were associated with a promising prognosis in gastric adenocarcinoma. By comprehensive differential expression and survival analysis, 40 key lncRNAs were identified. Finally, we constructed a network of 24 ceRNAs associated with gastric adenocarcinoma. Conclusions: Potential mRNA-miRNA-lncRNA subnets were constructed, each RNA of which can be used as a prognostic biomarker for gastric adenocarcinoma.

Long noncoding RNA ZEB1-AS1 attenuates ferroptosis of gastric cancer cells through modulating miR-429/BGN axis.

Gastric cancer (GC) is the fifth utmost common malignant cancer type globally, in which ferroptosis acts a critical function in the progress of GC. Long noncoding RNA ZEB1-AS1 has been recognized in numerous cancers, but the role of ZEB1-AS1 in ferroptosis remains obscure. Hence, we investigated the efficacy of ZEB1-AS1 on ferroptosis of GC cells. The cell growth and viability were analyzed via cell counting kit assay and xenograft tumor model in vivo and in vitro, respectively. The RNA and protein expression were measured by qRT-PCR and western blot analysis assay, respectively. The levels of Fe2+ , malondialdehyde (MDA), and lipid reactive oxygen species (ROS) were tested to determine ferroptosis. The erastin and RSL3 were used to induce ferroptosis. The mechanism was analyzed via luciferase reporter gene and RIP assays. The treatment of ferroptosis inducer Erastin and RSL3 suppressed the viability of GC cells and the ZEB1-AS1 overexpression rescued the phenotype in the cells. The levels of Fe2+ , MDA, and ROS were enhanced through the depletion of ZEB1-AS1 in Erastin/RSL3 treated GC cells. ZEB1-AS1 directly sponged miR-429 in GC cells and miR-429 targeted BGN in GC cells, and the inhibition of miR-429 rescued ZEB1-AS1 depletion-inhibited BGN expression. We validated that miR-429 induced and BGN-repressed ferroptosis in cancer cells. The BGN overexpression and miR-429 suppression could reverse the efficacy of ZEB1-AS1 on proliferation and ferroptosis in cancer cells. The expression of ZEB1-AS1 and BGN was enhanced and miR-429 expression was decreased in clinical GC tissues. ZEB1-AS1 attenuated ferroptosis of cancer cells by modulating miR-429/BGN axis.

Prognostic impact of examined lymph-node count for patients with esophageal cancer: development and validation prediction model.

Esophageal cancer (EC) is a malignant tumor with high mortality. We aimed to find the optimal examined lymph node (ELN) count threshold and develop a model to predict survival of patients after radical esophagectomy. Two cohorts were analyzed: the training cohort which included 734 EC patients from the Chinese registry and the external testing cohort which included 3208 EC patients from the Surveillance, Epidemiology, and End Results (SEER) registry. Cox proportional hazards regression analysis was used to determine the prognostic value of ELNs. The cut-off point of the ELNs count was determined using R-statistical software. The prediction model was developed using random survival forest (RSF) algorithm. Higher ELNs count was significantly associated with better survival in both cohorts (training cohort: HR = 0.98, CI = 0.97-0.99, P < 0.01; testing cohort: HR = 0.98, CI = 0.98-0.99, P < 0.01) and the cut-off point was 18 (training cohort: P < 0.01; testing cohort: P < 0.01). We developed the RSF model with high prediction accuracy (AUC: training cohort: 87.5; testing cohort: 79.3) and low Brier Score (training cohort: 0.122; testing cohort: 0.152). The ELNs count beyond 18 is associated with better overall survival. The RSF model has preferable clinical capability in terms of individual prognosis assessment in patients after radical esophagectomy.

Pharmacokinetic and bioequivalence study of two capecitabine tablets in Chinese patients with breast, colorectal or gastric cancer under fed condition: A multicentric, randomized, open-label, single-dose, two-period, two-way crossover clinical trial.

OBJECTIVE: The aim of this study was to examine the pharmacokinetics, bioequivalence, and safety of two tablet formulations of capecitabine 500 mg in Chinese patients with breast, colorectal or gastric cancer under fed condition. METHODS: A multicentric, randomized, open-label, single-dose, two-period, two-way crossover trial was conducted by randomizing a single oral dose of test (T) or reference (R, Xeloda®) capecitabine (500 mg) to patients of either sex with colon, colorectal or breast cancer under fed condition (high-fat and high-calorie diet). Pharmacokinetic parameters were calculated using non-compartmental methods. Patients were monitored for safety and tolerability throughout the study. RESULTS: 74 subjects were randomly enrolled. The T/R geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for Cmax, AUC0-t and AUC0-∞ of capecitabine were 96.60% (85.87-108.67%), 99.07% (95.40-102.89%), 99.17% (95.29-103.21%), respectively. All 90% CIs fell within the bioequivalence acceptance range of 80.00-125.00%. The common adverse events (AEs) included clinically significant laboratory abnormalities and gastrointestinal diseases. There were no serious adverse events (SAEs) or deaths during the study. No subject withdrew from the study due to AEs. CONCLUSION: Single oral intake of test and the reference capecitabine tablets were bioequivalent under fed condition and had similar favourable safety profiles in Chinese patients with breast, colorectal or gastric cancer. TRIAL REGISTRATION: chinadrugtrials.org.cn (CTR20182110).

PHF5A facilitates the development and progression of gastric cancer through SKP2-mediated stabilization of FOS.

BACKGROUND: Gastric cancer (GC) is the fifth most common cancer and the third most common cause of cancer death worldwide. Plant homeodomain (PHD)-finger domain protein PHF5A has been demonstrated to play a promoting role in a variety of cancers. This study aimed to clarify the role of PHF5A in the progression of GC and its potential mechanism of action. METHODS: Immunohistochemical staining experiments were performed based on tissues from clinical GC patients to reveal PHF5A expression. A series of functional experiments in vitro and in vivo were used to clarify the role of PHF5A in GC. RESULTS: Clinically, PHF5A was abundantly expressed in GC and existed clinical value indicating poor prognosis. In addition, GC cells with knockdown of PHF5A expression showed slowed proliferation, enhanced sensitivity to apoptosis and inhibition of migration. Mechanically, knockdown of PHF5A led to decreased protein stability of FOS, which was mediated ubiquitination of E3 ubiquitin ligase S-phase kinase-associated protein 2 (SKP2). Moreover, downregulation of FOS attenuated the promotion of PHF5A overexpression on GC cells. Consistently, Pladienolide B (PHF5A inhibitor) treatment reversed the induction of PHF5A overexpression on the malignant phenotypes and tumor formation of GC cells. CONCLUSION: Knockdown of PHF5A inhibited the progression of GC through SKP2-mediated ubiquitination of FOS, which may be a promising candidate target with potential therapeutic value.

The reliability and integrity of overall survival data based on follow-up records only and potential solutions to the challenges.

Overall survival (OS) is considered the standard clinical endpoint to support effectiveness claims in new drug applications globally, particularly for lethal conditions such as cancer. However, the source and reliability of OS in the setting of clinical trials have seldom been doubted and discussed. This study first raised the common issue that data integrity and reliability are doubtful when we collect OS information or other time-to-event endpoints based solely on simple follow-up records by investigators without supporting material, especially since the 2019 COVID-19 pandemic. Then, two rounds of discussions with 30 Chinese experts were held and 12 potential source scenarios of three methods for obtaining the time of death of participants, including death certificate, death record and follow-up record, were sorted out and analysed. With a comprehensive assessment of the 12 scenarios by legitimacy, data reliability, data acquisition efficiency, difficulty of data acquisition, and coverage of participants, both short-term and long-term recommended sources, overall strategies and detailed measures for improving the integrity and reliability of death date are presented. In the short term, we suggest integrated sources such as public security systems made available to drug inspection centres appropriately as soon as possible to strengthen supervision. Death certificates provided by participants' family members and detailed standard follow-up records are recommended to investigators as the two channels of mutual compensation, and the acquisition of supporting materials is encouraged as long as it is not prohibited legally. Moreover, we expect that the sharing of electronic medical records and the legal disclosure of death records in established health registries can be realized with the joint efforts of the whole industry in the long-term. The above proposed solutions are mainly based on the context of China and can also provide reference for other countries in the world.

KN026 (anti-HER2 bispecific antibody) in patients with previously treated, advanced HER2-expressing gastric or gastroesophageal junction cancer.

BACKGROUND: KN026 is a novel human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody that binds two distinct domains of HER2. We report the safety and efficacy results of the phase 2 trial in patients with advanced HER2-expressing gastric or gastroesophageal junction cancer who failed from at least one prior line of standard treatment. MATERIAL AND METHODS: In this open-label, multicentre, phase 2 trial, eligible patients were enrolled in the high-level HER2 cohort or low-level HER2 cohort and assigned to receive KN026 10 mg/kg (once a week), 20 mg/kg (once every two weeks) or 30 mg/kg (once every three weeks) intravenously. The primary end-points were the objective response rate (ORR) and duration of response assessed according to Response Evaluation Criteria in Solid Tumours (version 1.1). RESULTS: Between 17th June 2019 and 23rd August 2021, 45 patients were enrolled and received at least one dose of KN026, including 27 patients in the high-level HER2 cohort, 14 patients in the low-level HER2 cohort and four patients who had no HER2 expression. The ORR in the high-level HER2 cohort was 56% (95% confidence interval [CI] 35%-76%), with a durable response duration of 9.7 months (95% CI 4.2-not evaluable); while for the patients with low-level HER2, the ORR was 14% (95% CI 2%-43%). The most frequent ≥ grade 3 treatment-emergent adverse events were gastrointestinal disorders (five patients, 11%). No drug-related deaths were reported. CONCLUSIONS: KN026 showed a favourable safety profile and promising anti-tumour activity. Our results support further studies evaluating KN026 and the combination treatment with other active drugs in patients with advanced gastric or gastroesophageal junction cancer having high-level HER2 expression.

Dynamic peripheral blood immune cell markers for predicting the response of patients with metastatic cancer to immune checkpoint inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICIs) have shown durable responses in various malignancies. However, the response to ICI therapy is unpredictable, and investigation of predictive biomarkers needs to be improved. EXPERIMENTAL DESIGN: In total, 120 patients receiving ICI therapy and 40 patients receiving non-ICI therapy were enrolled. Peripheral blood immune cell markers (PBIMs), as liquid biopsy biomarkers, were analyzed by flow cytometry before ICI therapy, and before the first evaluation. In the ICI cohort, patients were randomly divided into training (n = 91) and validation (n = 29) cohorts. Machine learning algorithms were applied to construct the prognostic and predictive immune-related models. RESULTS: Using the training cohort, a peripheral blood immune cell-based signature (BICS) based on four hub PBIMs was developed. In both the training and the validation cohorts, and the whole cohort, the BICS achieved a high accuracy for predicting overall survival (OS) benefit. The high-BICS group had significantly shorter progression-free survival and OS than the low-BICS group. The BICS demonstrated the predictive ability of patients to achieve durable clinical outcomes. By integrating these PBIMs, we further constructed and validated the support vector machine-recursive and feature elimination classifier model, which robustly predicts patients who will achieve optimal clinical benefit. CONCLUSIONS: Dynamic PBIM-based monitoring as a noninvasive, cost-effective, highly specific and sensitive biomarker has broad potential for prognostic and predictive utility in patients receiving ICI therapy.

A narrative review on the development of the ethical review mode of multicenter clinical trials in China.

Background and Objective: The number of new drug clinical trials in China is surging, and ethics review played an important part in clinical trials. However, there are certain problems of ethical review in China. This review aims to conduct a review to propose recommendations of an ethical review mode for multicenter clinical trials and ultimately contribute to improving the ethics review mechanism and the efficiency. Methods: A literature review, publication research and interpretation of the related governmental policies and requirements in China were conducted to collect available information for analysis of the current situation in terms of the various ethical review modes for multicenter clinical research. The literatures and information were searched and selected from national and international database and related governance website by following some inclusion and exclusion criteria. And a comparation with the relevant practical experience in the USA was conducted to support the proposing of recommendations to China by referring to some successful practice in the USA. Key Content and Findings: China has undergone several stages of development. The most traditional and least efficient model is institutional review boards (IRBs) review, which is most commonly used. After IRB review mode, other modes such as central IRB and single IRB review have emerged, which have improved the efficiency of ethical review. However, multiple challenges exist like, no clear definition of regulatory responsibilities and the consensus is not easy to be made due to the gap of interpretation and the unbalanced development on ethic review system from Chinese hospitals. Conclusions: The multicenter ethical review should adopt the conditional 'approval' mode of the leading site's ethical review decisions, gradually establish a single IRB review and select the best ethics committee. Regional ethics committees can gradually take responsibility for the primary review in the multicenter ethics review model and ultimately contribute to improving the mechanism and efficiency of the ethics review.

A multi-center, single-arm, phase II study of anlotinib plus paclitaxel and cisplatin as the first-line therapy of recurrent/advanced esophageal squamous cell carcinoma.

BACKGROUND: Anlotinib, a tyrosine kinase inhibitor, has shown encouraging anti-tumor activity in esophageal squamous cell carcinoma (ESCC). This study was designed to assess the efficacy and safety of anlotinib plus paclitaxel and cisplatin (TP) as first-line therapy for advanced ESCC. METHODS: In a multi-center, single-arm, phase II clinical trial, patients (aged > 18 years) with ESCC, which was judged to be locally advanced, recurrent, or metastatic, received 10 mg oral anlotinib once daily on days 1-14, 135 mg/m2 intravenous paclitaxel on day 1, and 60-75 mg/m2 intravenous cisplatin on days 1-3 every 3 weeks for a maximum of 4-6 cycles as the initial therapy in five centers in China. Subsequently, patients received anlotinib monotherapy (10 mg) as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-seven patients were enrolled in this study between October 2019 and March 2021. The median follow-up was 14.04 months (IQR, 9.30-19.38). Of 46 with assessable efficacy, the median PFS and median overall survival were 8.38 months (95% CI, 6.59-10.17) and 18.53 months (95% CI, 13.11-23.95), respectively. The objective response rate was 76.1% (95% CI, 61.2-87.4%), with 4 (8.7%) complete responses and 31 (67.4%) partial responses. The disease control rate was 91.3% (95% CI, 79.2-97.6%). The median duration of response was 6.80 months (95% CI, 4.52-9.08), and 1 patient had an ongoing response for 23 months. Subgroup analysis revealed no association between clinical factors and survival or response. Of the 47 patients with assessable safety, the main grade ≥ 3 treatment-emergent adverse events (TEAEs) were neutropenia (17.0%), bone marrow suppression (12.8%), and vomiting (10.6%). No treatment-related deaths or serious TEAEs were observed. Notably, higher c-Kit levels were an independent factor for superior PFS (HR = 0.032; 95% CI, 0.002-0.606; P = 0.022). CONCLUSIONS: The study demonstrated a manageable safety profile and durable clinical response of anlotinib plus TP as first-line therapy in advanced ESCC, which suggested a potential therapeutic option for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04063683. Registered 21 August 2019.

Megestrol acetate dispersible tablets with a 5-HT3 receptor antagonist and dexamethasone vs. 5-HT3 receptor antagonist plus dexamethasone, can better control chemotherapy-induced nausea and vomiting: a randomized controlled study.

Background: A reasonable and effective control of chemotherapy-induced nausea and vomiting (CINV) plays an important role in the comprehensive treatment of cancer. Megestrol belongs to the 17α-hydroxyprogesterone derivative and is a highly effective synthetic progesterone. Recorded in the instructions may improve appetite and cachexia in patients with advanced tumors. In recent years, clinical practice and small sample studies have shown that megestrol combined with chemotherapy can improve CINV. This randomized controlled trial aimed to evaluate the clinical efficacy and safety of megestrol acetate combined with a 5-Hydroxytryptamine (5-HT3) receptor antagonist and dexamethasone in patients with CINV. Methods: Patients with malignant tumors who were treated with cisplatin-containing chemotherapy in our hospital from September 2018 to December 2019 were enrolled. A total of 120 patients were selected and randomly assigned to receive either megestrol acetate dispersible tablets with a 5-HT3 receptor antagonist and dexamethasone (megestrol group) or a 5-HT3 receptor antagonist plus dexamethasone (control group). Megestrol acetate dispersible tablets: 160 mg orally every morning from the day of chemotherapy until it lasts for ten days. Abstract IV of the quality-of-life scale for cancer patients in China was used to assess the quality of life (QOL) of the participants. All adverse reactions during chemotherapy were assessed according to the CTCAE 4.03 evaluation standard issued by the National Cancer Institute and divided into five grades according to severity. Results: For the control of nausea, the rates of complete prevention were significantly higher in the megestrol group than in the control patients during the delayed [53.3% (31/60) vs. 30.0% (18/60), P=0.012] and overall [40.0% (24/60) vs. 15.0% (9/60), P=0.002] observation periods. Moreover, the megestrol combination treatment group also achieved markedly higher rates of complete remission of vomiting than the control group during the delayed observation period [76.7% (46/60) vs. 51.7% (31/60), P=0.001], achieving an overall higher proportion of remission during the study period [68.3% (41/60) vs. 46.6% (28/60), P=0.0016]. Conclusions: The triple antiemetic protocol using megestrol acetate with a 5-HT3 receptor antagonist plus dexamethasone can improve CINV symptoms caused by highly emetogenic chemotherapy (HEC) with cisplatin, with an excellent control effect and few adverse reactions, especially for delayed CINV. Trial Registration: Chinese Clinical Trial Registry ChiCTR1800017953.