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Purpose:We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC).Patients and Methods:This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight Results:Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred.Conclusions:Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients.See related commentary by Pinato et al., p. 908

Supplementary Figures and Tables

Supplementary Methods, Supplementary Figure S1-4, Supplementary Table S1-8

Background Pancreatic cancer is generally characterized with high levels of malignancy and poor prognosis. In addition, there are currently no effective therapeutic agents against the disease. However, apatinib which is a small molecular agent targeting the vascular endothelial growth factor receptor 2 (VEGFR-2), has been shown to generate favorable outcomes in gastric cancer. Therefore, the present study explored the effects of apatinib on pancreatic cancer. Methods The activity of the ASPC-1 or PANC-1 cells was examined through colony formation assays, wound healing experiments as well as the Transwell and Western blot (WB) analyses. Additionally, a xenograft model was established by subcutaneously injecting the ASPC-1 cells into nude mice. Microvessel density (MVD) and Ki-67 expression were examined through immunohistochemistry (IHC) and WB analyses. Results The findings showed that treatment with either 10 or 20 µM of apatinib led to a decrease in the proliferation, migration and invasion of ASPC-1 and PANC-1 cells. Additionally, apatinib significantly hindered xenograft growth. Moreover, there was a decrease in Ki-67 expression and MVD, 21 days after treatment with apatinib. The results also showed that apatinib had no effect on the levels of the VEGFR-2, ERK1/2 and AKT proteins although there was a significant decrease in the expression of phosphate VEGFR2 (p-VEGFR2), phosphate AKT (p-AKT) and phosphate ERK1/2 (p-ERK1/2). Conclusions Apatinib inhibits the proliferation and migration of pancreatic cancer cells, blocking growth and angiogenesis in transplanted tumors. In addition, the underlying mechanism may involve phosphorylation of the PI3K/AKT and ERK1/2/MAPKs signaling pathways.

Background: MET gene amplification is associated with poor prognosis in gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ). Savolitinib is a potent and highly selective oral MET tyrosine-kinase inhibitor. Here we reported the preliminary efficacy and safety from a phase 2 trial of savolitinib monotherapy in patients (pts) with MET-amplified advanced or metastatic GC/GEJ. (NCT04923932). Methods: Eligible pts had 2L+ GEJ or GC, with MET amplification and measurable lesions. Pts received savolitinib at 600 mg QD for body weight (BW) ≥50 kg, while 400 mg QD for BW Results: As of IA, 20 pts were enrolled for QD regimen. Demographics and clinical outcomes are shown in table 1. The mean relative dose intensity of 93.07%. Median duration of exposure was 2.09 months. Confirmed ORR by IRC was 45%, and reached 50% in 16 patients with MET GCN (high) while only 1 PR was observed in 4 patients with MET GCN (low). Duration of response rate at 4-month was 85.7% with median follow up time of 5.5 months. The most common Gr≥3 TRAE (≥5%) were platelet count decreased, hypersensitivity, anemia, neutropenia and hepatic function abnormal. In all pts, only 1 patient discontinued treatment due to grade 4 liver function abnormal (TRAE) and no patient died due to TRAE. Conclusion: Savolitinib monotherapy had manageable safety and showed promising efficacy in pts with MET-amplified GEJ or GC, particularly in pts with MET high GCN. BID regimen is being investigated to further evaluate the efficacy and safety of savolitinib in pts with MET high GCN. Table 1. Pts baseline characteristics and clinical efficacy Baseline Characteristics ITT in IA (n=20) Median age (min, max), yearsSex (male/female), nECOG (0/1/2)Median BMI (min, max), (kg/m2)Primary location of tumor (GC/GEJ)Tumor stage (IV)Prior line of therapy (1/2/≥3)MET GCN (high/low) 57.00 (39.5, 76.8)17/33/15/220.8 (14.9, 25.8)16/4205/10/516/4 Clinical Efficacy By IRC By Investigator Confirmed objective response rateDisease control rate4m-DoR rate,% (95% CI) 45%65%85.7 (33.4, 97.9) 40%55%71.4 (25.8, 92.0) Citation Format: Zhi Peng, Hua Wang, Baorui Liu, Huiting Xu, Zhenyang Liu, Tianshu Liu, Jun Zhang, Yuxian Bai, Ying Yuan, Tao Wu, Feng Ye, Qinghua Pan, Jufeng Wang, Enxiao Li, Diansheng Zhong, Yueyin Pan, Yanru Qin, Yan Yang, Yusheng Wang, Aiping Zhou, Yongshun Chen, Dianbao Zhang, Hongli Liu, Xiujuan Qu, Shubin Wang, Ning Liu, Jinsheng Wu, Wei Li, Kejun Nan, Hongming Pan, Jianming Xu, Chunmei Bai, Heling Liu, Jia Wei, Runzhi Chen, Rongrong Li, Wei Li, Jinghong Zhou, Hongyan Yin, Qian Xu, Songhua Fan, Yongxin Ren, Weiguo Su, Lin Shen. A multicenter Phase II study of savolitinib in patients with MET-amplified gastroesophogeal junction adenocarcinomas or gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT152.

Purpose: We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods: This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight Results: Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred. Conclusions: Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients. See related commentary by Pinato et al., p. 908

Summary 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 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.

Purpose: This phase II study (NCT03469557) assessed safety/tolerability and antitumor activity of first-line tislelizumab, a monoclonal antibody against programmed cell death-1, plus chemotherapy in patients with locally advanced/metastatic esophageal squamous cell carcinoma (ESCC) or gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Patients and Methods: Patients with ESCC received tislelizumab [200 mg i.v. every 3 weeks (Q3W)] plus cisplatin (80 mg/m² i.v. Q3W for ≤6 cycles) and fluorouracil (800 mg/m²/day i.v., Days 1–5 Q3W for ≤6 cycles); patients with G/GEJ adenocarcinoma received tislelizumab (200 mg i.v. Q3W) plus oxaliplatin (130 mg/m² i.v. Q3W for up to six cycles) and oral capecitabine (1,000 mg/m² twice daily, Days 1–14 Q3W). The safety/tolerability profile of combination therapy was the primary endpoint; secondary endpoints included objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and progression-free survival per RECIST v1.1. Exploratory endpoints included overall survival and potential predictive biomarkers. Results: As of March 31, 2019, 30 patients (n = 15 per cohort) were enrolled. Most common adverse events considered related to tislelizumab and/or chemotherapy were anemia (n = 18), decreased appetite (n = 17), nausea (n = 16), and asthenia (n = 15). One patient experienced fatal hepatic dysfunction, confounded by progressive disease and underlying hepatitis, attributed to treatment by the investigator. Confirmed ORRs and DCRs were 46.7% and 80%, respectively, for both ESCC and G/GEJ adenocarcinoma. In ESCC, median DoR was 12.8 months (95% confidence interval, 3.5–12.8); DoR was not yet mature for the G/GEJ cohort. Conclusions: Tislelizumab plus chemotherapy demonstrated durable responses with manageable tolerability in patients with advanced ESCC or G/GEJ adenocarcinoma.

Chemotherapy resistance represents a major obstacle for the treatment of patients with breast cancer (BC) and greatly restricts the therapeutic effect of the first-line chemotherapeutic agent doxorubicin (DOX). The present study aimed to investigate the feasibility of the recombinant dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor in reversing the DOX resistance of BC. Both DOX-resistant human breast carcinoma cell lines exhibited a multidrug resistance (MDR) phenotype. The ability of the dual-target MDM2/MDMX inhibitor in reversing doxorubicin resistance was subsequently verified, (9.15 and 13.92 - fold reversal indexes) respectively. We observed that the MDM2/MDMX inhibitor in combination with DOX could suppress proliferation, promote cell cycle arrest and induce apoptosis. In addition, it was capable of reducing rhodamine123 efflux in DOX-resistance BC cell lines and further played a key role in BC nude mice model. The groups that were treated with the combination of the drugs had decreased P-glycoprotein/multidrug resistance-associated protein/cdc 2/Bcl-2 expression and increased CyclinB1/Bax expression. These effects were caused due to activation of the transforming growth factor β-activated kinase 1 (TAK1)-binding protein 1 (TAB1)/TAK1/p38 mitogen-activated protein kinase (MAPK) signaling pathway, as shown by small interfering RNA (siRNA) silencing and immumohistochemical staining of BC tissue sections. Furthermore, high MDM2/MDMX expression was positively associated with weak TAB1 expression in BC patients. Therefore, the recombinant dual-target MDM2/MDMX inhibitor could reverse doxorubicin resistance via the activation of the TAB1/TAK1/p38 MAPK pathway in wild-type p53 multidrug-resistant BC.

Objective: Glucagonoma is an extremely rare neuroendocrine tumor that arises from pancreatic islet alpha cells. Although glucagonoma is usually accompanied by a variety of characteristic clinical symptoms, early diagnosis is still difficult due to the scarcity of the disease. Methods: In this study, we present the cumulative experiences, clinical characteristics and treatments of seven patients diagnosed with glucagonoma during the past 10 years at the First Affiliated Hospital of Xi’an Jiaotong University. Results: The seven patients in our cohort consisted of six females and one male with an average diagnosis age of 40.1 years (range 23-51). The average time from onset of symptoms to diagnosis of glucagonoma was 14 months (range 2-36 months). All the patients visited dermatology firstly for necrolytic migratory erythema (NME) 7/7 (100%), other presenting symptoms included: diabetes mellitus (DM) 4/7 (57%), stomatitis 2/7 (28%), weight loss 4/7 (57%), anemia 4/7 (57%), diarrhea 1/7 (14%), DVT1/7 (14%). Plasma glucagon levels were increased in all patients (range 216.92–3155 pg/mL), and declined after surgery. Imaging studies revealed that four of seven patients had liver metastasis. Six of seven patients received surgical resection, and all of them received somatostatin analogue therapy. Symptoms improved significantly in 6 out of 7 patients. Three of seven patients died of this disease by the time of follow-up. Conclusion: Our data suggest that if persistent NME is associated with DM and high glucagon levels, timely abdominal imaging should be performed to confirm glucagonoma. Once diagnosed, surgery and somatostatin analogues are effective for symptom relief and tumor control.

799 Background: Pucotenlimab is a humanized IgG4 anti-PD-1 monoclonal antibody with an engineered Fc domain. We aim to assess the efficacy and safety of pucotenlimab, and potential predictive biomarkers of response in patients with previously treated advanced microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors. Methods: In this single-arm, multi-center, phase 2 study, eligible patients had locally advanced or metastatic, centrally confirmed MSI-H or dMMR solid tumors treated with at least one prior systemic therapy. Patients received pucotenlimab 200mg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) assessed by the independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Besides, patients’ PD-L1 expression, blood neutrophil to lymphocyte ratio (NLR), germline HLA-I genotyping, loss of heterozygosity (LOH) of HLA-I genes, tumor mutational burden (TMB), and genetic alterations in the tumor revealed by next-generation sequencing were investigated to identify potential predictors of efficacy. Results: 100 patients with MSI-H or dMMR solid tumors were enrolled. Colorectal cancer (n=71) and gastric cancer (n=10) were the most common cancer types. The median follow-up duration was 22.5 months (range: 0.3-37.4) at data cutoff (December 4, 2021). The ORR was 49.0% (95% CI 38.86%-59.20%), and the 12-month progression-free survival (PFS) rate was 56.1% (95% CI 45.63%-65.24%) based on IRC’s assessment. Both the median PFS and median duration of response were not reached. Pucotenlimab was well tolerated. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 18 patients, most commonly anemia, leukocytopenia, and hypertension. For the biomarker analysis, patients with NLR

Background: Chemotherapy combined with antivascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor monoclonal antibodies is the most promising approach to prolong survival and improve the quality of life of patients with unresectable metastatic colorectal cancer (mCRC). Anlotinib is an oral antiangiogenic tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, fibroblast growth factor receptors 1-4, and platelet-derived growth factor receptors a/β. Since anlotinib combined with oxaliplatin and capecitabine (CAPEOX) as a first-line treatment was previously shown to be effective and safe for patients with RAS/BRAF wild-type (WT) mCRC, we designed this randomized, open-label, parallel-group, non-inferiority, phase III study to evaluate the efficacy and safety of anlotinib plus CAPEOX versus bevacizumab plus CAPEOX in patients with RAS/BRAF WT mCRC. Methods/design: The primary inclusion criteria are Eastern Cooperative Oncology Group performance status 0/1, confirmed RAS/BRAF WT colorectal adenocarcinoma, and unresectable metastases assessed by a multidisciplinary team. The main exclusion criteria are as follows: high microsatellite instability or deficient mismatch repair status, resectable or potentially resectable metastases, and previous systemic therapy for mCRC. A total of 698 patients will be randomized into the anlotinib and bevacizumab groups in a 1:1 ratio. Patients will receive 4 to 8 cycles of induction therapy (CAPEOX plus anlotinib or bevacizumab), followed by maintenance treatment (capecitabine plus anlotinib or bevacizumab) until disease progression or unacceptable toxicity. Progression-free survival (PFS) assessed by an independent review committee is the primary endpoint, whereas investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, resection rate of liver metastases, quality of life, and safety are the secondary endpoints. Enrollment commenced in May 2021. Discussion: A prospective, randomized, phase III trial will provide a meaningful comparison of the efficacy and safety of anlotinib plus CAPEOX with standard treatment for patients with unresectable RAS/BRAF WT mCRC.

To investigate the health-related quality of life (HRQoL) of patients who had neuroendocrine tumors (NETs) from SANET trials.Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo. HRQoL questionnaires, including the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-G.I.NET21, were collected. The prespecified HRQoL outcome was the mean change of scores from baseline to the last available visit for each domain. Time until definitive deterioration (TUDD) was defined as the time from randomization to deterioration of ≥10 points from baseline in domain score, disease progression, or death.370 patients were enrolled and randomly assigned to surufatinib (n = 242) or placebo (n = 128). No significant difference in mean scores change from baseline to the last available visit was observed for QLQ-C30 and QLQ- G.I.NET21 domains, with the exception of diarrhea. The mean score of diarrhea increased 11.7 points from baseline in the surufatinib arm and decreased 1.2 points in the placebo arm, and the between-group difference was 12.9 points. Compared with placebo, surufatinib treated patients had a significantly longer TUDD for dyspnea (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.39-0.86; P = 0.0058) and a significantly shorter TUDD for diarrhea (HR 2.91; 95% CI, 1.66-5.10; P 0.0001). There were no significant differences in TUDD for the remaining domains of QLQ-C30 and G.I.NET-21.HRQoL was similar in patients treated with surufatinib and placebo except for diarrhea. The preservation of HRQoL supports surufatinib as a treatment option for NETs.ClinicalTrials.gov: NCT02589821, NCT02588170.

Ras protein activator like 2 (RASAL2) has a cancer-related function, but plays inconsistent roles in different malignancies. This project was designed to determine the role of RASAL2 in carcinogenesis in gastric cancer. The Cancer Genome Atlas data revealed high levels of RASAL2 in gastric cancer tissue, which was confirmed in clinical specimens of gastric cancer via real-time quantitative PCR and western blotting assays. High RASAL2 was correlated with a reduced survival rate in gastric cancer patients. In gastric cancer cell lines, the silencing of RASAL2 restrained cellular proliferation, invasion and epithelial-to-mesenchymal transition, while enhancing chemosensitivity to cisplatin. Mechanistically, the silencing of RASAL2 was found to inhibit the activation of Yes-associated protein 1 (YAP1), a pro-oncogenic protein in gastric cancer, and decrease the expression of YAP1 target genes. The re-expression of constitutively active YAP1 substantially reversed RASAL2-silencing-produced antitumor effects. Moreover, treatment with YAP1 inhibitors could diminish RASAL2-overexpression-evoked oncogenic effects in gastric cancer cells. Additionally, gastric cancer cells with RASAL2 silencing exhibited a reduced ability to form xenograft tumors in nude mice. Collectively, our data demonstrate that the silencing of RASAL2 has noteworthy antitumor effects in gastric cancer cells via the suppression of YAP1 activation. This project underscores a vital role of the RASAL2/YAP1 axis in gastric progression and indicates that targeting this oncogenic axis may be applied as a potential therapeutic option for gastric cancer.

Background Current treatment options for human epidermal growth factor receptor 2 (HER2)‐overexpressing gastric cancer at third‐line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in‐situ hybridization‐negative patients. Here, we report the efficacy and safety of a novel anti‐HER2 antibody RC48 for patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer. Methods Patients with HER2‐overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second‐line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression‐free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety. Results Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%‐33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7‐4.9 months) and 7.9 months (95% CI: 6.7‐9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48‐related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48‐related. Conclusions RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy., RC48 is safe and efficacious for HER2‐overexpressing gastric cancer patients. Patients received trastuzumab showed similar efficacy with trastuzumab‐naïve patients. HER2 status doesn't have significant effect on clinical outcomes.

Purpose: Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancers and it is rapidly fatal without any effective therapeutic regimens. There are some clinical trials showing that paclitaxel-based chemotherapy for ATC can achieve a relatively high response rate and low incidence of adverse reaction. The aim of this study was to evaluate potential therapeutic activity of novel taxoids in ATC cells.Methods: We evaluated antitumor activity of five novel 3’-difluorovinyltaxoids (DFV-taxoids) in anaplastic thyroid cancer cells by a series of in vitro and in vivo experiments. Besides, we also explored the potential mechanism underlying the difference among the taxoids and paclitaxel by molecular docking and tubulin polymerization assays.Results: Our data showed that these novel DFV-taxoids were more effective than paclitaxel in ATC cell lines and xenografts, as reflected by the inhibition of cell proliferation, colony formation and tumorigenic potential in nude mice, and the induction of G2/M phase arrest and cell apoptosis. Using tubulin polymerization assays and molecular docking analysis, we found that these DFV-taxoids promoted more rapid polymerization of β-tubulin than paclitaxel.Conclusions: Our data demonstrate that these novel taxoids exhibit stronger antitumor activity in ATC cells than paclitaxel, thereby providing a promising therapeutic strategy for the patients with ATC.

Introduction: In a multicenter, open-label, parallel-group, randomized, phase 2 study for pretreated advanced hepatocellular carcinoma (HCC), camrelizumab showed potent antitumor activity and acceptable safety profile. The aim of this report was to provide long-term data and evaluate potential benefit of treatment with camrelizumab beyond progression. Methods: From November 15, 2016, to November 16, 2017, 217 patients received camrelizumab 3 mg/kg intravenously every 2 or 3 weeks. Treatment beyond first Response Evaluation Criteria in Solid Tumors (RECIST)-defined progression (TBP) with camrelizumab was allowed. Results: At data cutoff of December 16, 2019 (>2 years after the last patient enrollment; median duration of follow-up, 13.2 months [IQR 5.7–25.8]), 14 (43.8%) of the 32 responses per blinded independent central review were ongoing. The median duration of response was not reached (range 2.5–30.5 + months). The ongoing response rates at 12, 18, and 24 months were 68.3% (95% confidence interval [CI] 47.7–82.2), 59.8% (95% CI 38.8–75.6), and 53.1% (95% CI 31.0–71.0), respectively. The median overall survival (OS) was 14.2 months (95% CI 11.5–16.3). The 18- and 24-month OS rates were 41.3% (95% CI 34.6–47.9) and 33.7% (95% CI 27.3–40.2), respectively. Of the 172 patients who experienced RECIST-defined progression per investigator, 102 received TBP, while 70 did not (non-TBP). The median OS was 16.9 months (95% CI 13.3–22.6) in the TBP group versus 9.4 months (95% CI 5.8–14.8) in the non-TBP group, and the 18- and 24-month OS rates were 47.5% (95% CI 37.3–56.9) versus 33.1% (95% CI 22.3–44.3) and 38.8% (95% CI 29.2–48.4) versus 23.2% (95% CI 13.8–34.1), respectively. No new safety signals of camrelizumab were observed. Conclusions: With prolonged follow-up, camrelizumab continues to demonstrate the durable response and long survival in pretreated advanced HCC patients with manageable toxicities, especially in those who continued the treatment beyond first RECIST-defined progression.

High rates of de novo lipid synthesis have been discovered in certain kinds of tumours, including gallbladder cancer (GBC). Unlike several other tumours, GBC is highly insensitive to standard adjuvant therapy, which makes its treatment even more challenging. Although several potential targets and signalling pathways underlying GBC chemoresistance have been revealed, the precise mechanisms are still elusive. In this study, we found that α‐Mangostin, as a dietary xanthone, repressed the proliferation and clone formation ability, induced cell cycle arrest and the apoptosis, and suppressed de novo lipogenesis of gallbladder cancer cells. The underlying mechanisms might involve the activation of AMPK and, therefore, the suppression of SREBP1 nuclear translocation to blunt de novo lipogenesis. Furthermore, SREBP1 silencing by siRNA or α‐mangostin enhanced the sensitivity of gemcitabine in gallbladder cancer cells. In vivo studies also displayed that MA or gemcitabine administration to nude mice harbouring NOZ tumours can reduce tumour growth, and moreover, MA administration can significantly potentiate gemcitabine‐induced inhibition of tumour growth. Corroborating in vitro findings, tumours from mice treated with MA or gemcitabine alone showed decreased levels of proliferation with reduced Ki‐67 expression and elevated apoptosis confirmed by TUNEL staining, furthermore, the proliferation inhibition and apoptosis up‐regulation were obviously observed in MA combined with gemcitabine treatment group. Therefore, inhibiting de novo lipogenesis via targeting the AMPK/SREBP1 signalling by MA might provide insights into a potential strategy for sensitizing GBC cells to chemotherapy.

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. Electronic supplementary material The online version of this article (10.1186/s13045-019-0702-0) contains supplementary material, which is available to authorized users.

4126 Background: Surufatinib is a small-molecule inhibitor of VEGFR1, 2, & 3, FGFR1, and CSF-1R. Surufatinib demonstrated prolonged PFS and tolerable safety in two phase 3 studies in advanced neuroendocrine tumors (NETs) of pancreatic (SANET-p; NCT02589821) and extrapancreatic (SANET-ep; NCT02588170) origin (Xu, 2020 Lancet Oncology). Detailed outcomes on safety from these 2 studies are reported here as a pooled analysis. Methods: Data is pooled from SANET-p and SANET-ep studies which have similar designs including a 2:1 randomization of surufatinib to placebo in patients ≥18 years with advanced, well differentiated NETs, progressing on or after ≤2 prior therapies. Surufatinib 300 mg or placebo, was administered once daily until disease progression or unacceptable toxicity. Safety outcomes for each pooled treatment group are reported as treatment-emergent adverse events (TEAE) assessed by NCI-CTC 4.03. Patients were included if they had received study treatment during the double-blinded phase of the studies. Results: As of 30th June 2020, 396 patients were assigned to the surufatinib (n = 263) and placebo (n = 133) groups. Median treatment duration was longer with surufatinib 7.4 months (range 0.1–41.4) compared with placebo 4.6 months (range 0.1–39.9). 29% of patients reached more than 12 months of treatment with surufatinib group compared to 11% with placebo. The mean relative dose intensity was 87.56% in the surufatinib group and 97.01% in the placebo group. Most common TEAEs (surufatinib vs placebo) were proteinuria 68.8% vs 54.9%, hypertension 68.4% vs 27.1%, and diarrhea 49% vs 22.6%. Most common grade ≥3 TEAE were hypertension 38.8% vs 13.5%, proteinuria 14.8% vs 0.8% and hypertriglyceridaemia 5.3% vs 0%. Deaths due to TEAEs were comparable between groups 2.7% vs 2.3%. TEAEs led to dose reductions in 43.0% vs 6.8% of patients and dose interruptions in 47.1% vs 29.3% of patients. The majority of patients (83.3% vs 93.2%) were managed without discontinuation because of TEAE. Median onset of proteinuria and hypertension were < 1 month in both groups. Median (range) onset was 0.95 months (0.16–30.36) vs 0.95 months (0.23–16.95) for proteinuria and 0.49 months (0.03–31.18) vs 0.89 months (0.03–14.75) for hypertension. Among patients with hypertension, 59% (n = 111) vs 28% (n = 11) received antihypertensive medication. Conclusions: Surufatinib was generally well tolerated in this pooled analysis and the safety profile was consistent with its previously reported data. The monitoring and management of hypertension and proteinuria are important for patients receiving surufatinib. Clinical trial information: NCT02589821; NCT02588170. [Table: see text]

Background Cancer-associated fibroblasts (CAFs), the primary component of tumor stroma in tumor microenvironments, are well-known contributors to the malignant progression of gallbladder cancer (GBC). Thrombospondins (THBSs or TSPs) comprise a family of five adhesive glycoproteins that are overexpressed in many types of cancers. However, the expression and potential roles of TSPs in the crosstalk between CAFs and GBC cells has remained unclear. Methods Peritumoral fibroblasts (PTFs) and CAFs were extracted from GBC tissues. Thrombospondin expression in GBC was screened by RT-qPCR. MTT viability assay, colony formation, EdU incorporation assay, flow cytometry analysis, Transwell assay, tumorsphere formation and western blot assays were performed to investigate the effects of CAF-derived TSP-4 on GBC cell proliferation, EMT and cancer stem-like features. Subcutaneous tumor formation models were established by co-implanting CAFs and GBC cells or GBC cells overexpressing heat shock factor 1 (HSF1) to evaluate the roles of TSP-4 and HSF1 in vivo. To characterize the mechanism by which TSP-4 is involved in the crosstalk between CAFs and GBC cells, the levels of a variety of signaling molecules were detected by coimmunoprecipitation, immunofluorescence staining, and ELISA assays. Results In the present study, we showed that TSP-4, as the stromal glycoprotein, is highly expressed in CAFs from GBC and that CAF-derived TSP-4 induces the proliferation, EMT and cancer stem-like features of GBC cells. Mechanistically, CAF-secreted TSP-4 binds to the transmembrane receptor integrin α2 on GBC cells to induce the phosphorylation of HSF1 at S326 and maintain the malignant phenotypes of GBC cells. Moreover, the TSP-4/integrin α2 axis-induced phosphorylation of HSF1 at S326 is mediated by Akt activation (p-Akt at S473) in GBC cells. In addition, activated HSF1 signaling increased the expression and paracrine signaling of TGF-β1 to induce the transdifferentiation of PTFs into CAFs, leading to their recruitment into GBC and increased TSP-4 expression in CAFs, thereby forming a positive feedback loop to drive the malignant progression of GBC. Conclusions Our data indicate that a complex TSP-4/integrin α2/HSF1/TGF-β cascade mediates reciprocal interactions between GBC cells and CAFs, providing a promising therapeutic target for gallbladder cancer patients.

Additional file 2: Table S2. Primers sequences for real-time PCR analysis.

Additional file 3: Table S3. High expression of TSP4 in GBC stroma predicts poor prognosis.

Additional file 1: Table S1. A list of the utilized primary antibodies.

Summary Background Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. Methods SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov , NCT02589821 . Findings Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3–19·4) in the surufatinib group and 11·1 months (5·7–35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5–13·8) for surufatinib versus 3·7 months (2·8–5·6) for placebo (hazard ratio 0·49, 95% CI 0·32–0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. Interpretation Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. Funding Hutchison MediPharma.

Background Association of immune-related adverse events with tumor response has been reported. Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event related to camrelizumab, an immune checkpoint inhibitor, but lack of comprehensive analyses. In this study, we conducted comprehensive analyses on RCCEP in advanced hepatocellular carcinoma (HCC) patients treated with camrelizumab monotherapy. Methods Data were derived from a Chinese nationwide, multicenter phase 2 trial of camrelizumab in pre-treated advanced HCC. The occurrence, clinicopathological characteristics, and prognostic value of RCCEP were analyzed. Results With a median follow-up of 12.5 months, 145 of the 217 camrelizumab-treated patients (66.8%) experienced RCCEP (all grade 1 or 2). RCCEP occurred on the skin surface, mainly on the skin surface of head, face, and trunk. RCCEP could be divided into 5 types including “red-nevus-like,” “pearl-like,” “mulberry-like,” “patch-like,” and “tumor-like,” according to the morphological features. RCCEP biopsy and pathology showed capillary endothelial hyperplasia and capillary hyperplasia in dermis. Significant association between RCCEP occurrence with higher objective response rate was observed (19.3% vs. 5.6%; one-sided p = 0.0044). Compared with those without RCCEP, patients with RCCEP had prolonged progression-free survival (median PFS; 3.2 months vs. 1.9 months; one-sided p < 0.0001) and overall survival (median OS; 17.0 months vs. 5.8 months; one-sided p < 0.0001). In multivariable analyses, the development of RCCEP was significantly associated with prolonged PFS and OS after adjusting for baseline covariates. In addition, the landmark analyses of PFS and OS were consistent with the unadjusted analysis. Conclusions RCCEP occurred on the skin surface and was an immune response of skin capillary endothelial cells. RCCEP occurrence positively associated with outcomes of camrelizumab in advanced HCC.

Supplemental material, Supplemental_table_search_strategy_in_Pubmed_Regorafenib for Efficacy and safety of regorafenib as beyond second-line therapy in patients with metastatic colorectal cancer: an adjusted indirect meta-analysis and systematic review by Yinying Wu, Yangwei Fan, Danfeng Dong, Xuyuan Dong, Yuan Hu, Yu Shi, Jiayu Jing and Enxiao Li in Therapeutic Advances in Medical Oncology