Circumventing drug resistance in gastric cancer: A spatial multi-omics exploration of chemo and immuno-therapeutic response dynamics.

BACKGROUND: Gastric Cancer (GC) characteristically exhibits heterogeneous responses to treatment, particularly in relation to immuno plus chemo therapy, necessitating a precision medicine approach. This study is centered around delineating the cellular and molecular underpinnings of drug resistance in this context. METHODS: We undertook a comprehensive multi-omics exploration of postoperative tissues from GC patients undergoing the chemo and immuno-treatment regimen. Concurrently, an image deep learning model was developed to predict treatment responsiveness. RESULTS: Our initial findings associate apical membrane cells with resistance to fluorouracil and oxaliplatin, critical constituents of the therapy. Further investigation into this cell population shed light on substantial interactions with resident macrophages, underscoring the role of intercellular communication in shaping treatment resistance. Subsequent ligand-receptor analysis unveiled specific molecular dialogues, most notably TGFB1-HSPB1 and LTF-S100A14, offering insights into potential signaling pathways implicated in resistance. Our SVM model, incorporating these multi-omics and spatial data, demonstrated significant predictive power, with AUC values of 0.93 and 0.84 in the exploration and validation cohorts respectively. Hence, our results underscore the utility of multi-omics and spatial data in modeling treatment response. CONCLUSION: Our integrative approach, amalgamating mIHC assays, feature extraction, and machine learning, successfully unraveled the complex cellular interplay underlying drug resistance. This robust predictive model may serve as a valuable tool for personalizing therapeutic strategies and enhancing treatment outcomes in gastric cancer.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Vancomycin in Patients with External Ventricular Drain.

Vancomycin is a commonly used antibacterial agent in patients with primary central nervous system (CNS) infection. This study aims to examine predictors of vancomycin penetration into cerebrospinal fluid (CSF) in patients with external ventricular drainage and the feasibility of CSF sampling from the distal drainage port for therapeutic drug monitoring. Fourteen adult patients (9 with primary CNS infection) were treated with vancomycin intravenously. The vancomycin concentrations in blood and CSF (from proximal [CSF_P] and distal [CSF_D] drainage ports) were evaluated by population pharmacokinetics. Model-based simulations were conducted to compare various infusion modes. A three-compartment model with first-order elimination best described the vancomycin data. Estimated parameters included clearance (CL, 4.53 L/h), central compartment volume (Vc, 24.0 L), apparent CSF compartment volume (VCSF, 0.445 L), and clearance between central and CSF compartments (QCSF, 0.00322 L/h and 0.00135 L/h for patients with and without primary CNS infection, respectively). Creatinine clearance was a significant covariate on vancomycin CL. CSF protein was the primary covariate to explain the variability of QCSF. There was no detectable difference between the data for sampling from the proximal and the distal port. Intermittent infusion and continuous infusion with a loading dose reached the CSF target concentration faster than continuous infusion only. All infusion schedules reached similar CSF trough concentrations. Beyond adjusting doses according to renal function, starting treatment with a loading dose in patients with primary CSF infection is recommended. Occasionally, very high and possibly toxic doses would be required to achieve adequate CSF concentrations, which calls for more investigation of direct intraventricular administration of vancomycin. (This study has been registered at ClinicalTrials.gov under registration no. NCT04426383).

Impact of low serum iron on treatment outcome of PD-1 inhibitors in advanced gastric cancer.

BACKGROUND: The aim of this study was to investigate the influence of serum iron levels in advanced gastric cancer (GC) patients treated with programmed cell death protein-1 (PD-1) inhibitors. METHODS: We retrospectively reviewed 149 GC patients who were treated with PD-1 inhibitors at our center. Clinicopathological characteristics, laboratory data, and clinical outcomes were analyzed. RESULTS: Multivariate analysis showed that Eastern Cooperative Oncology Group performance status (ECOG PS), histological subtype, and baseline serum iron levels were independent prognostic factors for overall survival (OS), while ECOG PS, multiple metastatic sites, and baseline serum iron levels were independent prognostic factors for progression-free survival (PFS). Patients with baseline low serum iron levels (LSI) had a significantly shorter median OS and PFS compared to patients with normal serum iron levels (NSI) (Median OS: 7 vs. 14 months, p = 0.001; median PFS: 3 vs. 5 months, p = 0.005). Patients with baseline LSI had a disease control rate (DCR) of 58.3% at 2 months after PD-1 inhibitor initiation (M2), compared to 81.1% in patients with NSI (p = 0.005). Patients with baseline LSI had a DCR of 43.8% at 4 months, compared to 64.2% in patients with NSI (p = 0.017). CONCLUSIONS: LSI was associated with worse OS, PFS, and DCR in GC patients treated with PD-1 inhibitors and might be a quick and efficient biomarker to predict the efficacy of PD-1 inhibitors.

Integrated multi-omic data and analyses reveal the response pathways of to high-temperature stress.

With the intensification of the greenhouse effect and the continuous rise of global temperature, high temperatures in summer seriously affect the growth of green onion (Allium fistulosum L.var.caespitosum Makino) and reduce its yield and quality. It is important to study the mechanism of heat tolerance in green onion for selecting and breeding new varieties with high-temperature tolerance. In this study, we used the heat-tolerant green onion variety AF60 and heat-sensitive green onion variety AF35 and measured their physiological indexes under different durations of heat stress. The results showed that high-temperature stress adversely affected the water content, protein composition and antioxidant system of green onion. In addition, a comprehensive analysis using transcriptomics and metabolomics showed that heat-tolerant green onions responded positively to heat stress by up-regulating the expression of heat shock proteins, whereas heat-sensitive green onions responded to heat stress by activating the galactose metabolic pathway and maintained normal physiological activities. This study revealed the physiological performance and high-temperature response pathways of different heat-tolerant green onion cultivars under heat stress. The results further deepen the understanding of the molecular mechanism of green onion's heat stress response.

Nano-selenium enhances melon resistance to Podosphaera xanthii by enhancing the antioxidant capacity and promoting alterations in the polyamine, phenylpropanoid and hormone signaling pathways.

Powdery mildew is one of the main problematic diseases in melon production, requiring the use of chemical pesticides with disease-resistant cultivars for control. However, the often rapid acquisition of fungicidal resistance by mildew pathogens makes this practice unsustainable. The identification of crop treatments that can enhance resistance to powdery mildew resistance is therefore important to reduce melon crop attrition. This study indicates that the application of Nano-Se can reduce the powdery mildew disease index by 21-45%. The Nano-Se treatment reduced reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation, with increases in glutathione (GSH), proline and 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH). Increases were also observed in the activities and transcriptional levels of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and peroxidase (POD). Assays with four different cultivars of melon with differing levels of mildew resistance demonstrated that relative to the control, the Nano-Se treatment resulted in larger responses to mildew infection, including increases in the levels of putrescine (PUT; 43-112%) and spermine (SPM; 36-118%), indoleacetic acid (IAA; 43-172%) and salicylic acid (SA; 24-73%), the activities of phenylalanine ammonium lyase (PAL), trans-cinnamate 4-hydroxylase (C4H) and 4-coumarate: Co A ligase (4CL) of the phenylpropanoid pathway (22-38%, 24-126% and 19-64%, respectively). Key genes in the polyamine and phenylpropanoid pathway were also upregulated. These results indicate that the foliar application of Nano-Se improved melon defenses against powdery mildew infection, with a significant reduction in mildew disease development.

Unveiling the mechanisms of peracetic acid activation by iron-rich sludge biochar for sulfamethoxazole degradation with wide adaptability.

Advanced oxidation processes (AOPs) based on peracetic acid (PAA) has been extensively concerned for the degradation of organic pollutants. In this study, metallic iron-modified sludge biochar (Fe-SBC) was employed to activate PAA for the removal of sulfamethoxazole (SMX). The characterization results indicated that FeO and Fe2O3 were successfully loaded on the surface of the sludge biochar (SBC). Fe-SBC/PAA system achieved 92% SMX removal after 30 min. The pseudo-first-order kinetic reaction constant of the Fe-SBC/PAA system was 7.34 × 10-2 min-1, which was 2.4 times higher than the SBC/PAA system. The degradation of SMX was enhanced with increasing the Fe-SBC dosage and PAA concentration. Apart from Cl-, NO3- and SO42- had a negligible influence on the degradation of SMX. Quenching experiments and electron paramagnetic resonance (EPR) techniques identified the existence of reactive species, of which CH3C(O)OO•, 1O2, and O2•- were dominant reactive species in Fe-SBC/PAA system. The effect of different water matrices on the removal of SMX was investigated. The removal of SMX in tap water and lake water were 79% and 69%, respectively. Four possible pathways for the decay of SMX were presented according to the identification of oxidation products. In addition, following the ecological structure-activity relationship model (ECOSAR) procedure and the germination experiments with lettuce seeds to predict the toxicity of the intermediates. The acute and chronic ecotoxicity of SMX solution was dramatically diminished by processing with Fe-SBC/PAA system. In general, this study offered a prospective strategy for the degradation of organic pollutants.

Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients.

BACKGROUND: KEYNOTE-063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second-line therapy in Asian patients with advanced programmed death ligand 1 (PD-L1)-positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer. METHODS: This randomized, open-label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/m2 of paclitaxel intravenously every week. Primary end points were overall survival (OS) and progression-free survival (PFS). Secondary end points were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and safety. RESULTS: Between February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE-061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4-10 months) with pembrolizumab versus 8 months (95% CI, 5-11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63-1.54). Median PFS was 2 months (95% CI, 1-3 months) with pembrolizumab versus 4 months (95% CI, 3-6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04-2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any-grade treatment-related adverse events occurred in 28 pembrolizumab-treated patients (60%) and 42 paclitaxel-treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively. CONCLUSIONS: Definitive conclusions about the efficacy of second-line pembrolizumab in Asian patients with advanced PD-L1-positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE-061 trial.

Comprehensive Analysis of Cellular Senescence-Related Genes in Prognosis, Molecular Characterization and Immunotherapy of Hepatocellular Carcinoma.

BACKGROUND: Cellular senescence is a tumor suppressive response in which the cell cycle is in a state of permanent arrest and can inhibit tumor cell proliferation. In recent years, induction of cellular senescence has been shown to be important for antitumor therapy, and the link between cellular senescence and clinical prognosis and immunotherapy of hepatocellular carcinoma is still unknown. METHODS: We performed enrichment analysis of genes in three cellular senescence gene sets, screened for gene sets significantly enriched in hepatocellular carcinoma and extracted genes from them. Signature were constructed using senescence-related genes, and their expression was verified at the protein and RNA levels. Survival, clinical staging and grading, immune infiltration, immunotherapy, and drug sensitivity were also analyzed between risk groups. RESULTS: The q-PCR and immunohistochemistry results revealed significant differences in the expression of the signature genes between normal and tumor tissues. Significant differences in clinicopathological features, prognosis and immune infiltration were observed between risk groups. In the low-risk group, better OS and lower TMB scores were demonstrated, while the high-risk group had higher immune checkpoint expression, as well as lower risk of immune escape. In addition, we found that the High-risk group was more sensitive to sorafenib. CONCLUSION: In summary, the signature constructed using aging-related genes can reliably predict patient prognosis and immunotherapy efficacy, providing a new idea for immune system therapy of hepatocellular carcinoma.

Mechanistic Study on the Species Differences in Excretion Pathway of HR011303 in Humans and Rats.

Excretion of [14C]HR011303-derived radioactivity showed significant species difference. Urine (81.50% of dose) was the main excretion route in healthy male subjects, whereas feces (87.16% of dose) was the main excretion route in rats. To further elucidate the underlying cause for excretion species differences of HR011303, studies were conducted to uncover its metabolism and excretion mechanism. M5, a glucuronide metabolite of HR011303, is the main metabolite in humans and rats. Results of a rat microsome incubation study suggested that HR011303 was metabolized to M5 in the rat liver. According to previous studies, M5 is produced in both human liver and kidney microsomes. We found that M5 in the human liver can be transported to the blood by multidrug resistance-associated protein (MRP) 3, and then the majority of M5 can be hydrolyzed to HR011303. HR011303 enters the human kidney or liver through passive diffusion, whereas M5 is taken up through organic anion transporter (OAT) 3, organic anion-transporting polypeptide (OATP) 1B1, and OATP1B3. When HR011303 alone is present, it can be metabolized to M5 in both sandwich-cultured rat hepatocytes (SCRH) and sandwich-cultured human hepatocytes (SCHH) and excreted into bile as M5 in SCRH. Using transporter inhibitors in sandwich-cultured model and membrane vesicles expressing MRP2 or Mrp2, we found that M5 was a substance of MRP2/Mrp2, and the bile efflux of M5 was mainly mediated by MRP2/Mrp2. Considering the significant role of MRP3/Mrp3 and MRP2/Mrp2 in the excretion of glucuronides, the competition between them for M5 was possibly the determinant for the different excretion routes in humans and rats. SIGNIFICANCE STATEMENT: Animal experiments are necessary to predict dosage and safety of candidate drugs prior to clinical trials. However, extrapolation results often differ from the actual situation. For HR011303, excretory pathways exhibited a complete reversal, through urine in humans and feces in rats. Such phenomena have been observed in several drugs, but no in-depth studies have been conducted to date. In the present study, the excretion species differences of HR011303 can be explained by the competition for M5 between MRP2/Mrp2 and MRP3/Mrp3.

Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [14C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase.

HR011303, a promising selective urate transporter 1 inhibitor, is currently being studied in a phase III clinical trial in China for the treatment of hyperuricemia and gout. In the current study, the pharmacokinetics, mass balance, and metabolism of HR011303 were examined in six healthy Chinese male subjects who received a single oral dose of 10 mg of [14C]HR011303 (80 µCi). The results showed that HR011303 was rapidly absorbed with a median time to reach C max of 1.50 hours postdose, and the arithmetic mean half-life of total radioactivity was approximately 24.2 hours in plasma. The mean blood-to-plasma radioactivity concentration ratio was 0.66, suggesting the preferential distribution of drug-related components in plasma. At 216 hours postdose, the mean cumulative excreted radioactivity was 91.75% of the dose, including 81.50% in urine and 10.26% in feces. Six metabolites were identified, and the parent drug HR011303 was the most abundant component in plasma and feces, but a minor component in urine. Glucuronidation of the carboxylic acid moiety of HR011303 was the primary metabolic pathway in humans, amounting to 69.63% of the dose (M5, 51.57% of the dose; M5/2, 18.06% of the dose) in the urine; however, it was not detected in plasma. UDP-glucuronosyltransferase (UGT) 2B7 was responsible for the formation of M5. Overall, after a single oral dose of 10 mg of [14C]HR011303 (80 µCi), HR011303 and its main metabolites were eliminated via renal excretion. The major metabolic pathway was carboxylic acid glucuronidation, which was catalyzed predominantly by UGT2B7. SIGNIFICANCE STATEMENT: This study determined the absorption and disposition of HR011303, a selective urate transporter (URAT) 1 inhibitor currently in development for the treatment of hyperuricemia and gout. This work helps to characterize the major metabolic pathways of new URAT inhibitors and identify the absorption and clearance mechanism.

Mechanistic Study on the Effect of Renal Impairment on the Pharmacokinetics of Vildagliptin and its Carboxylic Acid Metabolite.

PURPOSE: To clarify the mechanism of renal impairment leading to different degrees of increased plasma exposure to dipeptidyl peptidase 4 inhibitor vildagliptin and its major metabolite, M20.7. METHODS: The 5/6 nephrectomized (5/6 Nx) rat model, to simulate chronic renal failure (CRF) patients, combined with kidney slices and transporter studies in vitro were used to assess this pharmacokinetic differences. RESULTS: After intragastric administration to 5/6 Nx rats, vildagliptin showed increased plasma levels by 45.8%, and M20.7 by 7.51 times, which was similar to patients with severe renal impairment. The recovery rate of M20.7 in urine and feces increased by less than 20%, showing limited effect of renal impairment on vildagliptin metabolism. In vitro studies found M20.7 to be the substrate for organic anion transporter 3 (OAT3). However, the active uptake of M20.7 in renal slices showed no difference between the 5/6 Nx and normal rats. In OAT3 overexpressed cells, the protein-bound uremic toxins, 3-carboxy-4-methyl-5propyl-2-furanpropionate (CMPF), hippuric acid (HA) and indoxyl sulfate (IS), which accumulate in CRF patients, inhibited M20.7 uptake with IC50 values of 5.75, 29.0 and 69.5 µM respectively, far lower than plasma concentrations in CRF patients, and showed a mixed inhibition type. CONCLUSIONS: The large increase in plasma exposure of M20.7 could be attributed to the accumulation of uremic toxins in CRF patients, which inhibited OAT3 activity and blocked renal excretion of M20.7, while vildagliptin, with high permeability, showed a slight increase in plasma exposure due to reduced glomerular filtration.

Furmonertinib (Alflutinib, AST2818) is a potential positive control drug comparable to rifampin for evaluation of CYP3A4 induction in sandwich-cultured primary human hepatocytes.

Furmonertinib (Alflutinib, AST2818), as a third-generation epidermal growth factor receptor inhibitor with an advanced efficacy and a relatively wide safety window, has been commercially launched in China recently. However, previous clinical studies demonstrated its time- and dose-dependent clearance in a multiple-dose regimen. In vitro drug metabolism and pharmacokinetic studies have suggested that furmonertinib is mainly metabolized by cytochrome P450 3A4 (CYP3A4) and can induce these enzymes via an increased mRNA expression. This study investigated two important evaluation criteria of CYP3A4 induction by furmonertinib through quantitative proteomics and probe metabolite formation: simultaneous (1) protein expression and (2) enzyme activity with sandwich-cultured primary human hepatocytes in the same well of cell culture plates. Results confirmed that furmonertinib was a potent CYP3A4 inducer comparable with rifampin and could be used as a positive model drug in in vitro studies to evaluate the induction potential of other drug candidates in preclinical studies. In addition, inconsistencies were observed between the protein expression and enzyme activities of CYP3A4 in cells induced by rifampin but not in groups treated with furmonertinib. As such, furmonertinib could be an ideal positive control in the evaluation of CYP3A4 induction. The cells treated with 10 µM rifampin expressed 20.16 ± 5.78 pmol/mg total protein, whereas the cells induced with 0.5 µM furmonertinib expressed 4.8 ± 0.66 pmol/mg protein compared with the vehicle (0.1% dimethyl sulfoxide), which contained 0.65 ± 0.45 pmol/mg protein. The fold change in the CYP3A4 enzyme activity in the cells treated with rifampin was 5.22 ± 1.13, which was similar to that of 0.5 µM furmonertinib (3.79 ± 0.52).

Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans.

Furmonertinib was designed for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. In this study, we investigated the metabolic disposition and mass balance in humans and tissue distribution in rats. After a single oral administration of 97.9 µCi/81.5 mg [14C]-furmonertinib mesylate to six healthy male volunteers, the absorption process of furmonertinib was fast with a tmax of total plasma radioactivity at 0.75 h. Afterward, furmonertinib was extensively metabolized, with the parent drug and active metabolite AST5902 accounting for 1.68% and 0.97% of total radioactivity in plasma. The terminal t1/2 of total radioactivity in plasma was as long as 333 h, suggesting that the covalent binding of drug-related substances to plasma proteins was irreversible to a great extent. The most abundant metabolites identified in feces were desmethyl metabolite (AST5902), cysteine conjugate (M19), and parent drug (M0), which accounted for 6.28%, 5.52%, and 1.38% of the dose, respectively. After intragastric administration of 124 µCi/9.93 mg/kg [14C]-furmonertinib to rats, drug-related substances were widely and rapidly distributed in tissues within 4 h. The concentration of total radioactivity in the lung was 100-fold higher than that in rat plasma, which could be beneficial to the treatment of lung cancer. Mass balance in humans was achieved with 77.8% of the administered dose recovered in excretions within 35 days after administration, including 6.63% and 71.2% in urine and feces, respectively. In conclusion, [14C]-furmonertinib is completely absorbed and rapidly distributed into lung tissue, extensively metabolized in humans, presented mostly as covalent conjugates in plasma, and slowly eliminated mostly via fecal route.

Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Camrelizumab plus oxaliplatin-based chemotherapy as first-line therapy for advanced biliary tract cancer: A multicenter, phase 2 trial.

Biliary tract cancer (BTC) is a highly malignant tumor with limited treatment options and poor prognosis. Our study aimed to evaluate camrelizumab plus oxaliplatin-based chemotherapy as first-line therapy for advanced BTC. In this multicenter, open-label, phase 2 trial conducted in China (ClinicalTrials.gov, NCT03092895), untreated patients with advanced BTC were given camrelizumab (3 mg/kg iv drip injection, every 2 weeks) plus typical FOLFOX4 (Cam-FOLFOX4 group; infusional 5-fluorouracil, leucovorin and oxaliplatin) or GEMOX (Cam-GEMOX group; infusional gemcitabine and oxaliplatin). The primary endpoint was objective response rate (ORR). Ninety-two patients were enrolled: 29 received Cam-FOLFOX4 and 63 received Cam-GEMOX. The confirmed ORR and disease control rate were 16.3% (95% confidence interval [CI] = 9.4-25.5) and 75.0% (95% CI = 64.9-83.4), respectively. Median duration of response was 8.7 months (95% CI = 5.1-not reached). Median progression-free survival and overall survival were 5.3 months (95% CI = 3.7-5.7) and 12.4 months (95% CI = 8.9-16.1), respectively. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 82.8% of patients receiving Cam-FOLFOX4 and in 68.3% receiving Cam-GEMOX, with no unexpected effects observed. Six (6.5%) patients discontinued treatment due to TRAE. Camrelizumab plus FOLFOX4 or GEMOX as first-line treatment was effective and tolerable for Chinese patients with advanced BTC, warranting phase 3 trials.

Anlotinib Monotherapy for Refractory Metastatic Colorectal Cancer: A Double-Blinded, Placebo-Controlled, Randomized Phase III Trial (ALTER0703).

BACKGROUND: Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC. MATERIALS AND METHODS: This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1-14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety. RESULTS: A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4-4.5) over placebo group (1.5 months; 95% CI, 1.4-1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27-0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8-9.7 vs. 7.2 months; 95% CI, 6.2-8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%). CONCLUSION: Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients. IMPLICATIONS FOR PRACTICE: In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

A Comparison of the Seventh and Eighth Editions of the AJCC Staging Systems to Predict Recurrence in Papillary Thyroid Microcarcinoma.

BACKGROUND: The incidence of papillary thyroid microcarcinoma has been constantly rising in recent decades. The tumor, node, metastasis staging system is designed to predict prognosis in patients with papillary thyroid carcinoma. Recent studies have shown that the American Joint Committee on Cancer (AJCC) 8th edition is superior to the 7th edition for predicting tumor recurrence in PTC patients. To date, whether the 8th edition is also better able to predict recurrence in papillary thyroid microcarcinoma (PTMC) remains unclear. METHOD: We enrolled 1007 cases from our thyroid cancer database in the First Affiliated Hospital, Zhejiang University School of Medicine, from 1997 to 2011. Univariable and multivariate Cox hazard regression analyses were used to identify the association between variables and recurrence. Disease-free survival was calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 1007 PTMC patients were enrolled, with a median follow-up of 67 months. Of 93 (9.2%) patients downstaged by the changes in versions, 49 (52.7%) were downstaged because the age-at-diagnosis cut-off used for staging increased from 45 to 55 years, while 35 (37.6%) were downstaged due to the weakening of the effects of lymph node metastasis. The recurrence rate of PTMC was 4.17%. Univariate Cox hazards regression analyses showed that TNM stage according to the AJCC 8th edition was significantly associated with recurrence, while the recurrence survival curves showed that TNM stage (stage I vs. stage II-IV) according to the AJCC 8th edition, but not the 7th edition, was significantly associated with disease-free survival (p < 0.05). CONCLUSIONS: The AJCC 8th edition has better ability to predict recurrence in PTMC patients than the 7th edition.

Randomized and dose-escalation trials of recombinant human serum albumin /granulocyte colony-stimulating factor in patients with breast cancer receiving anthracycline-containing chemotherapy.

BACKGROUND: To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents. METHODS: The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 µg, 2100 µg, and 2400 µg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 µg and rhG-CSF 5 µg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 µg, 1500 µg, and continuous rhG-CSF 5 µg/kg. RESULTS: Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 µg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 µg to 2400 µg, while the double delivery of HSA/G-CSF 2400 µg failed to meet the noninferiority in comparison with rhG-CSF. CONCLUSION: The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 µg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).