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ObjectiveThe objective of this study was to assess the comparative efficacy in third-line setting for metastatic CRC (mCRC) patients using matched population of FRESCO trial with fruquintinib and real-world data with other TKIs.Materials and methodsThe arm of fruquintinib from the FRESCO phase III trial (NCT02314819) included the data of patients with metastatic CRC that progressed after at least two lines of chemotherapy and received fruquintinib treatment. An external control arm was constructed using real-world data (RWD) of patients who received other TKIs based on key eligibility criteria of FRESCO. The baseline characteristics of two arms was balanced by propensity score matching (PSM). The Kaplan–Meier method and Cox proportional hazard model was used to evaluate progression free survival (PFS) and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), respectively.ResultsOverall, 128 patients were successfully matched by PSM in each, fruquintinib and other TKIs group. The patients in fruquintinib group showed significant increase in median PFS than other TKIs (3.71 vs. 2.49 months, HR = 0.67, 95%CI, 0.48-0.94, p = 0.019). In the subgroup analysis, fruquintinib showed a significant benefit in PFS compared with other TKIs among patients undergoing two or three previous chemotherapy regimens (HR 0.58, 95%CI 0.40-0.84; p=0.004), with rectum as primary disease site (HR 0.52, 95%CI 0.31-0.87; p=0.013), with left sided primary tumor location (HR 0.62, 95%CI 0.42-0.90; p=0.011), with multiple metastasis sites (HR 0.68, 95%CI 0.48-0.97; p=0.034) and with lung metastasis (HR 0.65, 95%CI 0.43-0.98; p=0.042).ConclusionWith the approach of establishing the external control arm from RWD, this study has demonstrated that treatment with fruquintinib significantly prolonged PFS as compared to other TKIs in patients as third-line mCRC treatment.

BackgroundPrimary liver cancer (PLC) is a common and highly lethal malignancy in the world. Approximately 85% of PLC is hepatocellular carcinoma (HCC), and this study mainly focuses on HCC. The onset of liver cancer is insidious and often complicated with basic liver disease. Meanwhile, its clinical symptoms are atypical, and the degree of malignancy is high. What is worse is that its treatment is difficult, and the prognosis is poor. All these factors make its mortality close to its incidence. AST-3424 is a prodrug of a potent nitrogen mustard, which targets the tumor by its specific and selective mode of activation and results in the concentration of the drug in the tumor and plays a higher intensity of antitumor effect with reduced side effects. The purpose of this study was to explore the in-vitro antitumor activity and mechanism of AST-3424 monotherapy and combination therapy with oxaliplatin (OXA) or 5-fluorouracil (5-Fu). Moreover, it can provide an experimental basis for further studies.MethodsTumor growth of HCC cells was examined by using the Cell Counting Kit-8 (CCK-8), flow cytometry, and clone formation assays. Tumor migration of HCC cells was examined by using the Transwell assay. The in-vitro antitumor activity of AST-3424 monotherapy and combination therapy with OXA and 5-Fu was quantified by growth and metastasis inhibition rate. The underlying molecular mechanism was investigated by using Western blotting.ResultsThe inhibiting effects of AST-3424 were significant in both HepG2 cells and PLC/PRF/5 cells. Moreover, HepG2 cells showed higher sensitivity to AST-3424. With increasing AST-3424 concentration, AKR1C3 protein expression level was downregulated significantly. The inhibition of AST-3424 was significantly higher than OXA, 5-Fu, Sor (sorafenib), and Apa (apatinib) in both HCC cells. AST-3424 monotherapy and combination therapy with OXA or 5-Fu all strongly inhibited the proliferation of HCC cells, blocked HCC cells in the S phase, promoted apoptosis induction, and suppressed the migration of HCC cells. Among them, the antitumor effect of AST-3424 in combination with OXA was obviously enhanced. Western blotting analysis demonstrated the regulation of P21, Bax, Caspase3, PARP, MMP-2, MMP-9, and p-Smad proteins in the presence of AST-3424 monotherapy and combination therapy with OXA or 5-Fu, indicating that its antitumor mechanisms may be associated with the regulation of the TGF-β signaling cascade.ConclusionThe in-vitro studies revealed that AST-3424 in combination with both OXA and 5-Fu showed an increased antitumor effect, and the combination with OXA resulted in a synergistic effect. Together with the in-vitro results, additional in-vitro and in-vivo studies are warranted to further certify its antitumor effects and explore more potential antitumor mechanisms.

Icaritin is a potential treatment option for hepatocellular carcinoma (HCC) based on the results of its phase 2 stage trial. Glucose transporter 1 (GLUT1), a critical gene in regulating glycolysis, has been recognized as a promising target in HCC treatment. Previous studies have reported that FAM99A, a new long noncoding (lncRNA), is associated with HCC metastasis. It has also been demonstrated that the JAK2/STAT3 pathway is related to HCC and is the target of icaritin treatment. However, whether FAM99A participates in icaritin treatment and regulates GLUT1-mediated glycolysis via the JAK2/STAT3 pathway in HCC cells remains to be explored. Our study aimed to clarify the mechanisms underlying glycolysis and understand the regulating effects of the FAM99A and JAK2/STAT3 pathway in HCC cells in icaritin treatment. Molecular mechanism studies were conducted to verify whether FAM99A could bind to the JAK2/STAT3 pathway and to identify the regulatory mechanisms in the HCC cells. It was revealed that icaritin inhibited proliferation, GLUT1 level, and the glycolysis of the HCC cells. FAM99A in HCC cells was upregulated after a high concentration treatment of icaritin. FAM99A inhibited GLUT1 by blocking the JAK2/STAT3 pathway. Mechanically, FAM99A interacted with EIF4B to inhibit gp130 and gp80 translation, which then interacted with miR-299-5p to upregulate SOCS3, causing the JAK2 pathway to inhibit STAT3 phosphorylation, so that JAK2/STAT3 was blocked in HCC cells. Overall, our study proved that icaritin-induced FAM99A can inhibit HCC cell viability and GLUT1-mediated glycolysis via blocking the JAK2/STAT3 pathway.

Introduction: Sequential therapy with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) is effective in some patients with metastatic renal cell carcinoma (mRCC) progressed from or were intolerant to a prior TKIs. Anlotinib is a multi-kinase inhibitor targeting VEGFR1/2/3, PDGFR and FGFR, which has demonstrated efficacy and safety in first-line treatment of mRCC. This study assessed the potential of anloitnib as second-line treatment for patients with mRCC after prior one VEGFR-TKI.Methods: This is a single-arm, open-label, phase 2 study. Patients progressed after or were intolerant to sorafenib or sunitinib were enrolled. Anlotinib was administrated orally 12 mg once daily for 14 days every 3 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), safety and quality of life (QoL).Results: Forty three patients were enrolled and 42 received anlotinib, of whom 32 progressed after and 10 were intolerant to sorafenib or sunitinib. Median PFS were 14.0 months (95% CI 8.3–20.3) and 8.5 months (95% CI 5.6–16.6) for overall population and patients progressed after a previous VEGFR-TKI, respectively. Median OS was 21.4 months (95% CI 16.0–34.5), confirmed ORR and DCR were 16.7 and 83.3% in overall population. The most common adverse events included diarrhea (47.6%), hypertension (45.2%), hand and foot syndrome (42.9%), and fatigue (40.5%). Grade 3 hematological adverse events occurred in four cases, while no grade 4 hematological adverse events was observed.Conclusions: Anlotinib showed promising efficacy as well as favorable safety as second-line treatment for patients with mRCC.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02072044.

Objective: The objective of this study was to assess the comparative efficacy in third-line setting for metastatic CRC (mCRC) patients using matched population of FRESCO trial with fruquintinib and real-world data with other TKIs. Materials and methods: The arm of fruquintinib from the FRESCO phase III trial (NCT02314819) included the data of patients with metastatic CRC that progressed after at least two lines of chemotherapy and received fruquintinib treatment. An external control arm was constructed using real-world data (RWD) of patients who received other TKIs based on key eligibility criteria of FRESCO. The baseline characteristics of two arms was balanced by propensity score matching (PSM). The Kaplan–Meier method and Cox proportional hazard model was used to evaluate progression free survival (PFS) and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), respectively. Results: Overall, 128 patients were successfully matched by PSM in each, fruquintinib and other TKIs group. The patients in fruquintinib group showed significant increase in median PFS than other TKIs (3.71 vs. 2.49 months, HR = 0.67, 95%CI, 0.48-0.94, p = 0.019). In the subgroup analysis, fruquintinib showed a significant benefit in PFS compared with other TKIs among patients undergoing two or three previous chemotherapy regimens (HR 0.58, 95%CI 0.40-0.84; p=0.004), with rectum as primary disease site (HR 0.52, 95% CI 0.31-0.87; p=0.013), with left sided primary tumor location (HR 0.62, 95%CI 0.42-0.90; p=0.011), with multiple metastasis sites (HR 0.68, 95%CI 0.48-0.97; p=0.034) and with lung metastasis (HR 0.65, 95%CI 0.43-0.98; p=0.042). Conclusion: With the approach of establishing the external control arm from RWD, this study has demonstrated that treatment with fruquintinib significantly prolonged PFS as compared to other TKIs in patients as thirdline mCRC treatment. [ABSTRACT FROM AUTHOR]