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Importance: Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options.Objective: To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC.Design, Setting, and Participants: FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017.Interventions: Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal.Main Outcomes and Measures: The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events.Results: Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization.Conclusions and Relevance: Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China.Trial Registration: ClinicalTrials.gov Identifier: NCT02314819. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the fifth leading cause of cancer death and the fifth most commonly diagnosed cancer in China. Approximately, 25% of CRC was in the advanced stage as diagnosed, and 40% of patients with CRC progress to metastatic colorectal cancer (mCRC). RAS mutation status is now routinely used to select their therapy. But it is still a question whether RAS mutation status is a prognostic marker. In our study, we detected RAS mutation, immunoscore (IS), and PD-L1 expression in 60 Chinese mCRC patients who received palliative operation. The Kaplan-Meier survival analysis showed that the overall survival (OS) in patients with RAS wild type was better than those with RAS mutated type. Moreover, in multivariate analysis, RAS mutation and PD-L1 expression were demonstrated to be the independent negative prognostic factors for OS (P=0.044, HR: 0.258, and 95% CI: 0.069–0.967; P=0.048, HR: 0.276, and 95% CI: 0.077–0,988). All results suggested that, combined with IS, PD-L1 expression and RAS status may be the prognostic indicators for mCRC patients with palliative operation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To study the relationship between Helicobacter pylori eradication and the pathological development of the gastric mucosa in H. pylori-related diseases. METHODS: One hundred and ninety-one H. pylori-infected patients were randomly given anti-H. pylori or non-anti-H. pylori medications. Endoscopic examination was carried out 1 year after treatment. Pathological classifications followed the Sydney System. RESULTS: Of the 191 patients, those with chronic inflammation of the gastric mucosa improved (P < 0.05), as did those with atrophy and intestinal metaplasia (P < 0.05). Helicobacter pylori was eradicated in 107 patients, but not in 84 patients. Compared with those patients in whom H. pylori was not eradicated, those with H. pylori eradicated had ameliorated chronic inflammation of the gastric mucosa (P < 0.05) and active inflammation reduced in some cases (P < 0.05). Notwithstanding a stratification of different gastric diseases and different treatments, patients with H. pylori eradicated showed a more marked improvement in mucosal chronic inflammation than did patients in whom H. pylori was not eradicated (P < 0.05). CONCLUSIONS: These results suggest that H. pylori infection is closely related to active inflammation of the gastric mucosa. Helicobacter pylori eradication is beneficial in improving chronic inflammation of the gastric mucosa. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov , NCT03852251 , and closed to new participants; follow-up has been completed. Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3–4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1–17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3–42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0–15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2–40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7–19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7–37·4). Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. Akeso Biopharma. For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

China is experiencing a stage of rapid urban development. The energy consumption and related carbon dioxide emissions of households continue to increase. This paper calculates direct and indirect carbon dioxide emissions of households based on the input–output method in China from 1996 to 2012. The results reveal that there were more total carbon dioxide emissions from urban households than from rural households, far more indirect emissions from urban households than from rural households, slightly more direct emissions from urban households than from rural households, and differences in direct carbon dioxide emissions from various fuels and in indirect emissions from various sectors between urban and rural households. To examine the causal relationship between urbanization and the carbon dioxide emissions of households, cointegration and Granger causality tests are applied. A unidirectional causal relation was found running from urbanization to both direct and indirect household carbon dioxide emissions, and the direct and indirect carbon dioxide emissions of households would increase 2.9% and 1.1%, respectively, for every increase of one percent in urbanization. We discuss the reasons of why the development of urbanization will lead to more household direct and indirect carbon dioxide emissions, and suggest certain policy implications for urbanization and carbon dioxide emissions based on the results of this study. [ABSTRACT FROM AUTHOR]

Combination of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor (VEGF) therapy has increasingly become a promising strategy in various tumors. However, the combination might be associated with increased cardiotoxicities. Myocarditis is a potentially fatal complication in cancer patients treated with ICI. Currently, there are no clear guidelines for the management of this disease nor data characterizing the clinical course of myocarditis patients due to the combination of ICI and anti-VEGF therapy. This study included all patients consecutively admitted to Shanghai Zhongshan Hospital, Fudan University for the diagnosis of ICI-associated myocarditis according to Bonaca's criteria. The clinical presentation and outcome of myocarditis patients were collected receiving ICI and anti-VEGF combined therapy. A total of 48 patients were included (23 received combined treatment of ICI and anti-VEGF while 25 received ICI only). No differences in baseline characteristics, clinical course, and outcomes were observed among patients receiving ICI with or without anti-VEGF treatment. The patients were subdivided into 3 groups including 8 fulminant cases, 25 clinically significant cases, and 15 subclinical cases based on clinical severity. The fulminant group was associated with a higher rate of cardiovascular deaths (CVDs) compared with clinically significant and subclinical groups (87.5% versus 4.0% versus 0.0%, p < 0.01). When stratified by the dose of corticosteroids used, cases with high-dose usage were more likely to have a CVD when compared to low dose or no use and intermediate dose groups (0.0% versus 4.0% versus 57.1%, p < 0.01). No significant differences between myocarditis patients receiving ICI or combined anti-VEGF therapy in terms of clinical presentation and outcome were observed. Treatment strategy for myocarditis in patients using ICI or combined anti-VEGF therapy should be based on clinical severity. Specifically, immunosuppressive therapy besides high-dose corticosteroids is needed for fulminant cases. • Describing the clinical course of ICI combined with anti-VEGF related myocarditis. • Patients who received combined therapy may develop a severe form of myocarditis. • Use of steroids for myocarditis patients should be guided by clinical severity. • Intensified therapy besides high-dose steroids is needed for fulminant cases. [ABSTRACT FROM AUTHOR]

Background: Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs.Methods: SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing.Findings: Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure).Interpretation: Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population.Funding: Hutchison MediPharma. [ABSTRACT FROM AUTHOR]

The XELOX regimen (capecitabine plus oxaliplatin) has been demonstrated as first-line chemotherapy for gastric cancer in China. However, the efficacy of XELOX varies in individuals. Some evidences indicate that the variable efficacy might be related to the distinct immune status not only in the tumor site but also in the systemic immune system, and further investigation is required. In this study, we collected 32 PBMC samples from 16 XELOX-treated patients with gastric cancer and analyzed the patterns of immune cells. At the end point, the proportion of CD24 hi CD27 + CD19 + B cells in patients without progression revealed a significant decrease compared with that in patients with progression, but not other immune cells, such as T cells and NK cells. Furthermore, CD19 + B cells were more sensitive to capecitabine plus oxaliplatin stimulation in vitro than other immune cells, displaying higher frequency of apoptosis in a dose-dependent way. Thus, our results suggested that the outcomes of XELOX chemotherapy were inversely correlated with peripheral B cell subsets, which might provide a more convenient method to predict gastric cancer progression of XELOX-treated patients. [ABSTRACT FROM AUTHOR]

Background: Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens., Methods: In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed., Results: Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 10 9 /L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11., Conclusions: This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding., Plain Language Summary: To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. We aimed to characterise molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours., Methods: Molecular alterations of 48 606 gastrointestinal tumours from Caris Life Sciences (CARIS) identified with next-generation sequencing were compared among MSS-TMB-H, dMMR/MSI-H, and MSS-TMB-low (L) tumours, using χ 2 or Fisher's exact tests. Antitumour immune response within the tumour environment was predicted by analysing the infiltration of immune cells and immune signatures using The Cancer Genome Atlas database. The Kaplan-Meier method and the log-rank test were used to evaluate the impact of gene alterations on the efficacy of immune checkpoint inhibitors in MSS gastrointestinal cancers from the CARIS database, a Memorial Sloan Kettering Cancer Center cohort, and a Peking University Cancer Hospital cohort., Findings: MSS-TMB-H was observed in 1600 (3·29%) of 48 606 tumours, dMMR/MSI-H in 2272 (4·67%), and MSS-TMB-L in 44 734 (92·03%). Gene mutations in SMAD2, MTOR, NFE2L2, RB1, KEAP1, TERT, and RASA1 might impair antitumour immune response despite TMB-H, while mutations in 16 other genes (CDC73, CTNNA1, ERBB4, EZH2, JAK2, MAP2K1, MAP2K4, PIK3R1, POLE, PPP2R1A, PPP2R2A, PTPN11, RAF1, RUNX1, STAG2, and XPO1) were related to TMB-H with enhanced antitumour immune response independent of dMMR/MSI-H, constructing a predictive model (modified TMB [mTMB]) for immune checkpoint inhibitor efficacy. Patients with any mutation in the mTMB gene signature, in comparison with patients with mTMB wildtype tumours, showed a superior survival benefit from immune checkpoint inhibitors in MSS gastrointestinal cancers in the CARIS cohort (n=95, median overall survival 18·77 months [95% CI 17·30-20·23] vs 7·03 months [5·73-8·34]; hazard ratio 0·55 [95% CI 0·31-0·99], p=0·044). In addition, copy number amplification in chromosome 11q13 (eg, CCND1, FGF genes) was more prevalent in MSS-TMB-H tumours than in the dMMR/MSI-H or MSS-TMB-L subgroups., Interpretation: Not all mutations related to TMB-H can enhance antitumour immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs., Funding: US National Cancer Institute, Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong Research Project, Ming Hsieh Research Fund, Shanghai Sailing Program, China National Postdoctoral Program for Innovative Talents, China Postdoctoral Science Foundation, National Natural Science Foundation of China., Competing Interests: Declaration of interests H-JL reports receiving honoraria from serving as a consultant or from advisory board membership for Merck Serono, Bayer, and Genentech. JX, AF, YB, MO, DS, and WMK are employees of Caris Life Sciences. AFS reports funding for research, travel, and speakers bureau participation from Caris Life Sciences. BAW reports receiving honoraria from Bayer, Sirtex, Lilly, Taiho, and HalioDx. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. By multiplexing mass spectrometry fingerprints from two independent nanostructured matrixes through machine learning for highly sensitive detection and high throughput analysis, we report a laser desorption/ionization (LDI) mass spectrometry-based liquid biopsy for pan-cancer screening and classification. The Multiplexed Nanomaterial-Assisted LDI for Cancer Identification (MNALCI) is applied in 1,183 individuals that include 233 healthy controls and 950 patients with liver, lung, pancreatic, colorectal, gastric, thyroid cancers from two independent cohorts. MNALCI demonstrates 93% sensitivity at 91% specificity for distinguishing cancers from healthy controls in the internal validation cohort, and 84% sensitivity at 84% specificity in the external validation cohort, with up to eight metabolite biomarkers identified. In addition, across those six different cancers, the overall accuracy for identifying the tumor tissue of origin is 92% in the internal validation cohort and 85% in the external validation cohort. The excellent accuracy and minimum sample consumption make the high throughput assay a promising solution for non-invasive cancer diagnosis., (© 2022. The Author(s).)

Background: In the global phase 3 RAINBOW study, ramucirumab plus paclitaxel significantly improved overall survival compared with placebo plus paclitaxel in patients with advanced gastric or gastro-oesophageal junction (GEJ) adenocarcinoma. RAINBOW-Asia, a bridging study with similar design to RAINBOW, aimed to evaluate the efficacy and safety of ramucirumab plus paclitaxel for advanced gastric or GEJ adenocarcinoma in Asian, predominantly Chinese, patients., Methods: RAINBOW-Asia was a randomised, double-blind, placebo-controlled, phase 3 trial done at 32 centres in China, Malaysia, the Philippines, and Thailand. Adult patients (≥18 years) with metastatic or locally advanced, unresectable gastric or GEJ adenocarcinoma who previously received fluoropyrimidine-platinum-based chemotherapy were randomly assigned with a centralised interactive web response system in a 2:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15 plus paclitaxel 80 mg/m 2 intravenously on days 1, 8, and 15 of every 28-day cycle. Randomisation was stratified by Eastern Cooperative Oncology Group performance status and presence of peritoneal metastases. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done in the intention-to-treat population, and safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02898077, and has been completed., Findings: Between March 2, 2017, and June 30, 2020, 440 patients were randomly assigned to receive ramucirumab plus paclitaxel (n=294) or placebo plus paclitaxel (n=146). Median progression-free survival was 4·14 months (95% CI 3·71-4·30) in the ramucirumab plus paclitaxel group compared with 3·15 months (2·83-4·14) in the placebo plus paclitaxel group (hazard ratio [HR] 0·765, 95% CI 0·613-0·955, p=0·0184). Median overall survival was 8·71 months (95% CI 7·98-9·49) in the ramucirumab plus paclitaxel group and 7·92 months (6·31-9·10) in the placebo plus paclitaxel group (HR 0·963, 95% CI 0·771-1·203, p=0·7426). The most common grade 3 or worse treatment-emergent adverse events were decreased neutrophil count (159 [54%] of 293 patients in the ramucirumab plus paclitaxel group vs 56 [39%] of 145 in the placebo plus paclitaxel group), decreased white blood cell count (127 [43%] vs 42 [29%]), anaemia (46 [16%] vs 24 [17%]), hypertension (21 [7%] vs nine [6%]), and febrile neutropenia (18 [6%] vs one [<1%])., Interpretation: These findings, along with the results from RAINBOW, support the use of ramucirumab plus paclitaxel as second-line therapy in a predominantly Chinese population with advanced gastric or GEJ adenocarcinoma., Funding: Eli Lilly and Company, USA., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests CZ and WLZ are employees of Eli Lilly and Company. LS has received grants from Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), Beihai Kangcheng (Beijing) Medical Technology, and Jacobio Pharmaceuticals; consulting fees from Merck Sharp & Dohme, Merck, Mingji Biopharmaceutical, Haichuang Pharmaceutical, Herbour Biomed, and Boehringer Ingelheim; payment for speakers bureaus from Hutchison Whampoa, Hengrui, ZaiLab Pharmaceutical (Shanghai), and CSTONE Pharmaceutical; and has participated as an advisory board member for Rongchang Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), CSTONE Pharmaceutical, and Bristol Myers Squibb. All other authors declared no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: In FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese patients with metastatic colorectal cancer (mCRC). However, its safety profile, including adverse events of special interest (AESIs) and treatment-emergent adverse events (TEAEs) by age, sex, and body mass index (BMI), is not well known. The present analysis evaluated the safety profile and AESIs for fruquintinib in the FRESCO trial., Methods: In FRESCO, eligible Chinese patients were randomized (2:1) to receive fruquintinib (5 mg once daily for 3 weeks, followed by 1 week off in 28-day cycles) or placebo plus best supportive care. Treatment-related AESIs and time to first occurrence of AESIs were summarized. Treatment-related TEAEs by age, sex, and BMI were also summarized., Results: A total of 266 patients (95.7%) in the fruquintinib group and 97 (70.8%) in the placebo group had at least one treatment-related TEAE; the mean relative dose intensity was 92% and 98%, respectively. In the fruquintinib group, the most common (in > 40% of patients) treatment-related AESIs were hypertension (55.4%), palmar-plantar erythrodysesthesia syndrome [known as hand-foot skin reaction (HFSR)] (49.3%), and proteinuria (42.1%). The most common treatment-related grade ≥ 3 AESIs (≥ 3% of patients) were hypertension (21.2%), HFSR (10.8%), and proteinuria (3.2%); the median time to onset of these events was 10, 21, and 20 days, respectively. Subgroup analysis by age, sex, and BMI revealed that the frequencies of treatment-related TEAEs were similar across all subgroups, and were consistent with the overall safety profile of fruquintinib., Conclusions: The most common treatment-related grade ≥ 3 AEs were hypertension, HFSR, and proteinuria. The treatment-related TEAE profile of fruquintinib in Chinese patents with mCRC was comparable among different subgroups and consistent with that reported in the overall population., Trial Registration: Clinical Trials identifier NCT02314819.

Background: The aim of this study was to explore the utility of circulating free DNA (cfDNA) in the evaluation of clinical tumor burden and survival in Chinese patients with metastatic colorectal cancer (mCRC) and to preliminarily summarize some metastatic characteristics associated with mutational status., Methods: A panel covering a total of 197 hotspot mutations of KRAS, NRAS, BRAF and PIK3CA was used to evaluate the mutational status in plasma by next-generation sequencing (NGS) technology in 126 patients with mCRC. An amplification-refractory mutation system (ARMS) was used to analyze genomic DNA from matched tissue samples. Clinical markers including carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) in serum and the sum of all tumor diameters on CT or PET/CT were collected to indicate clinical tumor burden. The correlations between cfDNA and clinical tumor burden were analyzed using Pearson correlation and linear regression models. The median progression-free survival (PFS) and 1-year overall survival (OS) rates were calculated by Kaplan-Meier (K-M) survival analysis., Results: Of the 126 enrolled patients, patients who were tested positive for mutations in plasma accounted for 45.2% (57/126). Mutations in KRAS, NRAS, BRAF and PIK3CA were detected in 37.3% (47/126), 1.6% (2/126), 3.2% (4/126) and 13.5% (17/126) of patients, respectively. The overall concordance rate of mutational status between plasma and matched tissues was 78.6% (99/126). Sixteen patients had mutations in plasma that were not detected in tissue, including some rare hotspot mutations. The cfDNA concentration was significantly correlated with the levels of clinical markers, especially CEA (P < 0.0001, Pearson r = 0.81), LDH (P < 0.0001, Pearson r = 0.84) and the sum of tumor diameters (P < 0.0001, Pearson r = 0.80). Patients with a high cfDNA concentration (> 17.91 ng/ml) had shorter median progression-free survival (6.6 versus 11.7 months, P < 0.0001) and lower 1-year overall survival rate (56% versus 94%, P < 0.0001) than those with a low cfDNA concentration (≤17.91 ng/ml). The most common metastatic site was the liver (77.8%), followed by the lymph nodes (62.7%), lung (40.5%), peritoneum (14.3%) and bone (10.3%), in all patients. There was no significant difference in metastasis between different mutational statuses., Conclusion: Analyzing mutations in plasma could provide a more comprehensive overview of the mutational landscape than analyzing mutations in tissue. The cfDNA concentration could be a quantitative biomarker of tumor burden and could predict survival in Chinese patients with mCRC.

Background: Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients., Methods: ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m 2 every 3 weeks) or irinotecan (180 mg/m 2 every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov, NCT03099382, and is closed to new participants., Findings: From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1-12·8) in the camrelizumab group and 6·2 months (3·6-10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8-9·7) in the camrelizumab group and 6·2 months (5·7-6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57-0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [<1%]), and diarrhoea (three [1%] vs nine [4%]). Serious treatment-related adverse events occurred in 37 (16%) of 228 patients in the camrelizumab group, and in 32 (15%) of 220 patients in the chemotherapy group. Ten treatment-related deaths occurred, seven (3%) in the camrelizumab group (three deaths from unknown causes, one enterocolitis, one hepatic function abnormal, one pneumonitis, and one myocarditis) and three (1%) in the chemotherapy group (two deaths from unknown causes, and one gastrointestinal haemorrhage)., Interpretation: Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China., Funding: Jiangsu Hengrui Medicine., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Tislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy., Methods: The purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1., Results: As of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2-21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types., Conclusions: Tislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors., Trial Registration Number: CTR20160872., Competing Interests: Competing interests: LS, JG, QZ, HP, YY, YB, TL, QZ, JZ, YS, XH, SW, JW, AZ, DY, TS, and Y-LW have nothing to declare. YG, SY, ZW, and JL are employees of BeiGene., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Evaluating the tumor RAS/BRAF status is important for treatment selection and prognosis assessment in metastatic colorectal cancer (mCRC) patients. Correction of artifacts from library preparation and sequencing is essential for accurately analyzing circulating tumor DNA (ctDNA) mutations. Here, we assessed the analytical and clinical performance of a novel amplicon-based next-generation sequencing (NGS) assay, Firefly™, which employs a concatemer-based error correction strategy. Methods Firefly assay targeting KRAS/NRAS/BRAF/PIK3CA was evaluated using cell-free DNA (cfDNA) reference standards and cfDNA samples from 184 mCRC patients. Plasma results were compared to the mutation status determined by ARMS-based PCR from matched tissue. Samples with a mutation abundance below the limit of detection (LOD) were retested again by droplet digital polymerase chain reaction (ddPCR) or NGS. Results The Firefly assay demonstrated superior sensitivity and specificity with a 98.89% detection rate at an allele frequency (AF) of 0.2% for 20 ng cfDNA. Generally, 40.76% and 48.37% of the patients were reported to be positive by NGS of plasma cfDNA and ARMS of FFPE tissue, respectively. The concordance rate between the two platforms was 80.11%. In the pre-treatment cohort, the concordance rate between plasma and tissue was 93.33%, based on the 17 common exons that Firefly™ and ARMS genotyped, and the positive percent agreement (PPA) and negative percent agreement (NPA) for KRAS/NRAS/BRAF/PIK3CA were 100% and 99.60%, respectively. Conclusions Total plasma cfDNA detected by Firefly offers a viable complement for mutation profiling in CRC patients, given the high agreement with matched tumor samples. Together, these data demonstrate that Firefly could be routinely applied for clinical applications in mCRC patients.

Background: The JACOB trial (NCT01774786) was a double-blinded, placebo-controlled, randomized, multicenter, international, phase III trial evaluating the efficacy and safety of adding pertuzumab to trastuzumab and chemotherapy in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer/gastroesophageal junction cancer (GEJC). The aim of this analysis was to investigate efficacy and safety outcomes in the Chinese subpopulation from the JACOB trial., Methods: This post hoc subpopulation analysis included all patients recruited in mainland China (n = 163; 20.9%) between June 2013 and January 2016. The patients were randomly assigned in a 1:1 ratio to receive pertuzumab plus trastuzumab and chemotherapy (pertuzumab group; n = 82) or placebo plus trastuzumab and chemotherapy (control group; n = 81). Intravenous pertuzumab (840 mg) and trastuzumab (8 mg/kg loading and 6 mg/kg maintenance doses) were given every 3 weeks until disease progression or unacceptable toxicity. Chemotherapy was given as per standard regimens/doses of capecitabine or 5-fluorouracil plus cisplatin. The primary endpoint was overall survival (OS); secondary efficacy endpoints included progression-free survival (PFS), and overall objective response rate (ORR)., Results: The median OS was 18.7 months in the pertuzumab group and 16.1 months in the control group (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.49 to 1.14). The median PFS was 10.5 and 8.6 months in the pertuzumab and control groups, respectively (HR 0.85; 95% CI 0.60 to 1.21), and the median ORRs were 68.9% and 55.7%, respectively. The treatment effect in this Chinese subpopulation showed consistency with that in the global ITT population with numerically lower HR for OS and PFS compared with the control group. The safety profiles of the pertuzumab and control groups in this Chinese subpopulation analysis were generally comparable. The most common grade 3-5 adverse events were neutropenia, anemia, and leukopenia. However, due to the nature of being a post hoc subgroup analysis, the results presented here are descriptive only and need to be interpreted with caution., Conclusions: OS and PFS were numerically improved by adding pertuzumab to trastuzumab and chemotherapy as first-line treatment in Chinese HER2-positive gastric cancer/GEJC patients, and this regimen demonstrated an acceptable safety profile. Trial registration ClinicalTrials.gov. NCT01774786. Registered on 24 January 2013, https://clinicaltrials.gov/ct2/show/NCT01774786.

Purpose: To investigate the prevalence of normal-tension glaucoma (NTG) in the Chinese population through systematic review and meta-analysis., Design: Systematic review and meta-analysis., Methods: All Chinese population-based studies that reported the prevalence of NTG were identified. We searched PubMed and Chinese databases including Wanfang, China National Knowledge Infrastructure, and VIP for studies published before December 31, 2017. Random effects meta-analysis was conducted to estimate the pooled prevalence of NTG., Results: Twelve studies were included in this review and meta-analysis, including 9 population-based studies and 3 studies from glaucoma clinics and managed care networks. The 9 population-based studies included a total of 30,892 subjects with 498 patients with primary open-angle glaucoma (POAG) and 354 patients with NTG. The prevalence of estimated NTG ranged from 0.36% to 1.98% and the percentage of NTG among POAG ranged from 51.43% to 83.58%. In the glaucoma clinic and managed care network studies, NTG prevalence was much lower. The overall pooled proportion of NTG among POAG in the Chinese population was 70.0% (95% confidence interval [CI] 62.0-77.0%). The overall pooled prevalence of POAG and NTG was 2.0% (95% CI 1.0-2.0%) and 1.0% (95% CI 1.0-1.0%), respectively. For the meta-regression of the NTG/POAG proportion, we found that age, gender, intraocular pressure, and China versus not China were not significantly associated with NTG/POAG prevalence, although the proportional prevalence decreased with increasing age category., Conclusions: In this systematic review, we found that NTG is common among patients with POAG in the Chinese population. Our findings can help guide future glaucoma studies and public health guidelines in the Chinese population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts' clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

Purpose: Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC); however, the efficacy of cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) has never before been proven in a controlled and randomized phase III trial. To our knowledge, the TAILOR trial ( ClinicalTrials.gov identifier: NCT01228734) is the first randomized, multicenter, phase III study of the addition of cetuximab to first-line FOLFOX prospectively choosing a RAS wt population and thus providing confirmative data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone., Patients and Methods: TAILOR is an open-label, randomized (1:1), multicenter, phase III trial in patients from China comparing FOLFOX-4 with or without cetuximab in RAS wt ( KRAS / NRAS , exons 2 to 4) mCRC. The primary end point of TAILOR was progression-free survival time; secondary end points included overall survival time, overall response rate, and safety and tolerability., Results: In the modified intent-to-treat population of 393 patients with RAS wt mCRC, adding cetuximab to FOLFOX-4 significantly improved the primary end point of progression-free survival time compared with FOLFOX-4 alone (hazard ratio, 0.69; 95% CI, 0.54 to 0.89; P = .004; median, 9.2 v 7.4 months, respectively), as well as the secondary end points of overall survival time (current assessment after 300 events: hazard ratio, 0.76; 95% CI, 0.61 to 0.96; P = .02; median, 20.7 v 17.8 months, respectively) and overall response rate (odds ratio, 2.41; 95% CI, 1.61 to 3.61; P < .001; 61.1% v 39.5%, respectively). Treatment was well tolerated, and there were no new or unexpected safety findings., Conclusion: The TAILOR study met all of its objectives and relevant clinical end points, confirming cetuximab in combination with FOLFOX as an effective standard-of-care first-line treatment regimen for patients with RAS wt mCRC.