Hepatocellular carcinoma (HCC) is the most common primary malignant tumor. Although sorafenib and regorafenib have been approved for first-line and second-line treatment, respectively, of patients ...with advanced HCC, long-term treatment often results in acquired resistance. Given that glycolysis-mediated lactate production can contribute to drug resistance and impair HCC treatment efficacy, we investigated the effects of ketone body treatment on the metabolic shift in sorafenib-resistant HCC cells. We discovered differential expression of 3-hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) and the ketone body D-β-hydroxybutyrate (β-HB) in four sorafenib-resistant HCC cell lines. In sorafenib-resistant HCC cells, lower HMGCS2 and β-HB levels were correlated with more glycolytic alterations and higher lactate production. β-HB treatment enhanced pyruvate dehydrogenase (PDH) expression and decreased lactate dehydrogenase (LDHA) expression and lactate production in sorafenib-resistant HCC cells. Additionally, β-HB combined with sorafenib or regorafenib promoted the antiproliferative and antimigratory abilities of sorafenib-resistant HCC cells by inhibiting the B-raf/mitogen-activated protein kinase pathway and mesenchymal N-cadherin-vimentin axis. Although the in vivo β-HB administration did not affect tumor growth, the expression of proliferative and glycolytic proteins was inhibited in subcutaneous sorafenib-resistant tumors. In conclusion, exogenous β-HB treatment can reduce lactate production and reverse sorafenib resistance by inducing a glycolytic shift; it can also synergize with regorafenib for treating sorafenib-resistant HCC.
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•Lower HMGCS2/β-HB levels are related to higher glycolytic status in HCC-SR cells.•β-HB treatment reverses sorafenib resistance by inhibiting glycolysis-lactate metabolism in HCC.•β-HB enhances second-line drug sensitivity through suppressing B-Raf/MAPK pathway.•β-HB treatment inhibits mesenchymal N-cadherin-vimentin mediated metastatic ability.•β-HB administration alleviated SR tumor proliferation by inhibiting the glycolysis genes expressions.
•TKIs for advanced HCC are associated with a range of adverse events.•Adverse events may lead to TKI treatment discontinuation.•Concomitant medications and comorbidities may influence adverse ...events.•Prevention and management of adverse events can help to maintain full dose treatment.•The literature contains approaches for adverse event management.
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Sorafenib, regorafenib, lenvatinib and cabozantinib are tyrosine kinase inhibitors (TKIs) that target, in part, vascular endothelial growth factor receptors, and are approved in various regions of the world for the treatment of advanced HCC. All these agents are associated with a range of adverse events (AEs) that can have a substantial impact on patients’ health-related quality of life. Fatigue, diarrhoea, hand–foot skin reaction, nausea, vomiting, decreased appetite, hypertension and weight loss are among the most common AEs experienced with these four TKIs. In this review, we discuss strategies for the management of these AEs in patients with advanced HCC, with the aim of maximizing treatment benefits and minimizing the need for TKI treatment discontinuation. We also consider potential TKI–drug interactions and discuss the use of TKIs in patients with liver dysfunction or who have experienced tumour recurrence after liver transplantation. Use of appropriate AE management strategies and avoidance of contraindicated drugs should help patients with advanced HCC to achieve optimal outcomes with TKIs.
•Precise, accurate and sensitive method to quantify two multikinase inhibitors and their 3 active metabolites simultaneously.•Using confirmation/quantification ion ratios criteria to improve ...specificity.•Dynamic range of the concentrations carrying out some pharmacokinetics studies.
A new liquid chromatography-tandem mass spectrometry (LC–MS/MS) method, performed by electrospray ionization in positive mode using a triple quadrupole mass spectrometry, has been developed and validated for the simultaneous determination of regorafenib (REGO), its two metabolites regorafenib-M2 and regorafenib-M5, sorafenib (SORA), and its N-oxide metabolite in human plasma. Separation is achieved on an Hypersil Gold® column using a gradient elution of 10mM ammonium formate containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) at a flow rate of 0.3mL/min. After addition of two internal standards and a protein precipitation, the supernatant is diluted two-fold in a 0.1% (v/v) formic acid solution. Two selected reaction monitoring transitions are used, for each analyte, one for quantitation and the second one for confirmation. The standard curves are ranged from 50 to 5 000ng/mL for REGO and its metabolites and 80 to 5 000ng/mL for SORA and its metabolite and were fitted to a 1/x weighted linear regression model. The method also showed satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day CV from 2.4 to 10.2%), accuracy (from 91.0 to 111.7%), recovery as well as stability of the analytes under various conditions. The method is usually used in clinical practice in order to improve the SORA treatment for renal carcinoma, REGO treatment for colorectal cancer and both for hepatocellular carcinoma.
Sorafenib is the first-line drug used for patients with advanced hepatocellular carcinoma (HCC). However, acquired sorafenib resistance in cancer patients limits its efficacy. Here, we performed the ...first genome-wide CRISPR/Cas9-based screening on sorafenib-treated HCC cells to identify essential genes for non-mutational mechanisms related to acquired sorafenib resistance and/or sensitivity in HCC cells. KEAP1 was identified as the top candidate gene by Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout (MAGeCK). KEAP1 disrupted HCC cells were less sensitive than wild-type cells in short- and long-term sorafenib treatments. Compared to wild-type cells, KEAP1-disrupted cells showed lower basal and sorafenib-induced reactive oxygen species (ROS) levels and were more resistant to oxidative stress-induced cell death. The absence of KEAP1 led to increased activity of Nrf2, a key transcription factor controlling antioxidant responses, as further evidenced by increased expression of Nrf2-controlled genes including NQO1, GPX2 and TXNRD1, which were positively associated with chemoresistance. In addition, KEAP1 disruption counteracted the reduction of cell viability and the elevation of ROS caused by lenvatinib, a drug that recently showed clinical efficacy as a first-line treatment for unresectable HCC. Finally, Keap1 disruption also increased the resistance of cells to regorafenib, a recently approved drug to treat HCC as a second line therapy. Taken together, our data indicate that deregulation of the KEAP1/Nrf2 pathway following KEAP1 inactivation contributes to sorafenib, lenvatinib, and regorafenib resistance in human HCC cells through up-regulation of Nrf2 downstream genes and decreased ROS levels.
•Regorafenib inhibits a broad spectrum of kinases involved in cancer pathogenesis.•The clinical benefit of regorafenib is well established in mCRC, GIST, and HCC.•Emerging data show activity of ...regorafenib in aGEC, sarcoma, BTC, and glioblastoma.•Clinical experience has enabled dose optimization and improved patient management.•Combination studies of immuno-oncology agents with regorafenib are ongoing.
Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of refractory metastatic colorectal cancer (mCRC), advanced gastrointestinal stromal tumors (GIST) previously treated with imatinib and sunitinib, and unresectable hepatocellular carcinoma (HCC) following progression on sorafenib. Regorafenib was initially approved for mCRC based on improved overall survival (OS) in the randomized, placebo-controlled, phase 3 CORRECT trial, which was confirmed in an expanded population of Asian patients in the randomized, placebo-controlled phase 3 CONCUR trial. Approvals in GIST, and more recently in HCC, were based on the results from the randomized, placebo-controlled, phase 3 GRID and RESORCE trials, respectively. In this review, we provide a comprehensive summary of the clinical evidence for approval of regorafenib in mCRC, GIST, and HCC, present emerging evidence of regorafenib activity in other tumor types (namely, gastroesophageal cancer, sarcomas, biliary tract cancer, and glioblastoma), and discuss trials in progress within the context of regorafenib’s mechanism of action. We describe recent advances and key lessons learned with regorafenib, including the importance of managing common drug-related toxicities using dose-optimization strategies, the search for biomarkers to predict response to treatment, and highlight some of the unaddressed questions and future directions for regorafenib across tumors.
Background
This study compared the efficacy of regorafenib and trifluridine/tipiracil (TFTD) in patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy, because ...despite their clinical approval, it still remains unclear which of these two drugs should be used as initial treatment.
Materials and Methods
The clinical data of patients with mCRC who were treated with regorafenib or TFTD and those of drug‐naive patients, between June 2014 and September 2015, were retrospectively collected from 24 institutions in Japan. Overall survival (OS) was evaluated using the Cox's proportional hazard models based on propensity score adjustment for baseline characteristics.
Results
A total of 550 patients (223 patients in the regorafenib group and 327 patients in the TFTD group) met all criteria. The median OS was 7.9 months (95% confidence interval CI, 6.8–9.2) in the regorafenib group and 7.4 months (95% CI, 6.6–8.3) in the TFTD group. The propensity score adjusted analysis showed that OS was similar between the two groups (adjusted hazard ratio HR, 0.96; 95% CI, 0.78–1.18). In the subgroup analysis, a significant interaction with age was observed. Regorafenib showed favorable survival in patients aged <65 years (HR, 1.29; 95% CI, 0.98–1.69), whereas TFTD was favored in patients aged ≥65 years (HR, 0.78; 95% CI, 0.59–1.03).
Conclusion
No significant difference in OS between regorafenib and TFTD was observed in patients with mCRC. Although the choice of the drug by age might affect survival, a clearly predictive biomarker to distinguish the two drugs should be identified in further studies.
Implications for Practice
Previous studies of patients with metastatic colorectal cancer refractory to standard chemotherapy had demonstrated that both regorafenib and trifluridine/tipiracil could result in increased overall survival compared with placebo, but there are no head‐to‐head trials. This large, multicenter, observational study retrospectively compared the efficacy of regorafenib and trifluridine/tipiracil in 550 patients with metastatic colorectal cancer refractory to standard chemotherapy who had access to both drugs. Although no difference in overall survival was found between the two drugs in adjusted analysis using propensity score, regorafenib showed favorable survival in patients aged <65 years, whereas trifluridine/tipiracil was favored in patients aged ≥65 years in the subgroup analysis.
摘要
背景.本研究比较瑞戈非尼与曲氟尿苷/Tipiracil（TFTD）治疗接受标准化疗无效的转移性结直肠癌（mCRC）患者的疗效, 尽管这两种药物已经获批准用于临床用途, 但尚不清楚应将哪种药物用于初始治疗。
材料与方法.从日本的24家机构回顾性地收集了2014年6月至2015年9月间接受瑞戈非尼或TFTD治疗的mCRC患者和未接受药物治疗患者的临床数据。对倾向评分进行基线特征校正, 使用Cox比例风险模型, 评价总生存期（OS）。
结果.共550例患者（瑞戈非尼组223例, TFTD组327例）满足所有标准。瑞戈非尼组与TFTD组的中位OS分别为7.9个月95%置信区间（CI）为6.8‐9.2和7.4个月（95% CI, 6.6‐8.3）。校正后的倾向评分分析表明, 两组间的OS相似校正后的风险比（HR）为0.96, 95% CI, 0.78–1.18。在亚组分析中观察到与年龄间有显著相互作用。瑞戈非尼显示在年龄<65岁患者中的生存率更高（HR, 1.29；95%CI, 0.98–1.69）, 而TFTD显示年龄≥65岁患者中的生存率更高（HR, 0.78；95%CI, 0.59–1.03）。
结论.瑞戈非尼组与TFTD组mCRC患者间的OS没有显著差异。按年龄选择药物可能影响生存率, 在将来的研究中应确定区分这两种药物的明确预测性生物标志物。
对临床实践的启示：关于接受标准化疗无效的转移性结直肠癌患者的既往研究证实, 与安慰剂相比, 瑞戈非尼和曲氟尿苷/Tipiracil均可提高总生存率, 但尚未开展头对头试验。本项大型、多中心、观察性研究回顾性地比较了瑞戈非尼与曲氟尿苷/Tipiracil治疗550例接受标准化疗无效的转移性结直肠癌（mCRC）患者的疗效, 这些患者均可以获得这两种药物。虽然在校正倾向评分的分析中未发现这两种药物的总生存率存在差异, 但亚组分析中瑞戈非尼组显示年龄<65岁的患者的生存率更高, 而曲氟尿苷/Tipiracil组显示年龄≥65岁的患者的生存率更高。
This article compares the efficacy between regorafenib and trifluridine/tipiracil in patients with metastatic colorectal cancer refractory to standard chemotherapy, who had access to both drugs, to determine whether a further prospective comparative trial should be conducted.
•Sorafenib is indicated for advanced and intermediate (post-TACE failure) HCC.•Sorafenib should be given early to ensure patients can benefit from all therapies.•Sorafenib toxicities can be ...effectively prevented and managed for treatment benefit.•Sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab improve survival.•New systemic agents are emerging for the treatment of patients with advanced HCC.
The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago, with sorafenib demonstrating survival benefit in the first-line setting and becoming the first systemic therapy to be approved for HCC. More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). A key recommendation in the management of patients receiving sorafenib is to promote close communication between the patient and the physician so that adverse events (AEs) are detected early and severe AEs can be prevented. Sorafenib-related AEs have been identified as clinical biomarkers for sorafenib efficacy. Healthcare professionals have become more efficient in managing AEs, identifying patients who are likely to benefit from treatment, and assessing response to treatment, resulting in a trend towards increased overall survival in the sorafenib arms of clinical studies. The rapidly changing treatment landscape due to the emergence of new treatment options (sorafenib and lenvatinib equally effective in first line; regorafenib, cabozantinib, and ramucirumab showing OS benefit in second line with nivolumab approved by the FDA based on response rate) underscores the importance of re-assessing the role of the first approved systemic agent in HCC, sorafenib.
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