Colorectal cancer (CRC) is the third most common cancer, and is one of the leading causes of cancer-related death worldwide. At the time of diagnosis, about 20% of patients with CRC present ...metastatic disease. Regorafenib, an oral multi-kinase inhibitor, has been demonstrated the efficacy and tolerability in patients with metastatic CRC. Oxaliplatin is a frontline treatment regimen for CRC, and combination treatments with oxaliplatin and other chemotherapeutic agents exert superior therapeutic effects. However, side effects and drug resistance limited their further clinical application. Here, we found that combined treatment with regorafenib and oxaliplatin synergistically enhanced anti-tumor activities in CRC by activating reactive oxygen species (ROS) mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 signaling pathways. Regorafenib promoted ROS production by suppressing the expression of selenoprotein S (SELENOS). Knocking down SELENOS sensitized ROS-mediated anti-tumor effects of regorafenib in CRC cells. Furthermore, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with regorafenib and oxaliplatin. This study provided solid experimental evidences for the combined treatment with regorafenib and oxaliplatin in CRC.
BACKGROUNDTo investigate the activity of regorafenib in advanced solitary fibrous tumour (SFT).METHODSAn Italian monocentric investigator-initiated exploratory single-arm Phase II trial was conducted ...of regorafenib in adult patients with advanced and progressive SFT, until progression or limiting toxicity. Prior treatment with antiangiogenics was allowed. Primary and secondary end-points were: overall response rate (ORR) by Choi criteria, and ORR by RECIST, progression-free survival (PFS), overall survival (OS).RESULTSFrom January 2016 to February 2021, 18 patients were enroled malignant-SFT = 13; dedifferentiated-SFT (D-SFT) = 4; typical-SFT (T-SFT) = 1. Fourteen patients were pre-treated, in 12 cases with antiangiogenics (median m- lines of treatment = 3). Sixteen patients were evaluable for response (one screening failure; one early discontinuation). Six/16 (35.2%) required a definitive dose reduction. ORR by Choi was 37.5% (95% CI: 15.2-64.6), with 6/16 (37.5%) partial responses (PR), 6/16 (37.5%) stable disease (SD) and 4/16 (25%) progressions; 5/6 responses occurred in patients pre-treated with antiangiogenics. No responses were detected in D-SFT. Best RECIST responses were: 1/16 (6.2%) PR, 12/16 (75%) SD, 3/16 (18.8%) progressions. At 48.4 month m-FU, m-PFS by Choi was 4.7 (inter-quartile range: 2.4-13.1) months, with 31.2% patients progression-free at 1 year.CONCLUSIONRegorafenib showed activity in SFT, with 30% patients free-from-progression at one year. Responses were observed also in patients pretreated and refractory to another antiangiogenic agents. However, ORR and m-PFS were lower than reported with other antiangiogenics, and this was possibly due to discrepancies in the patient population and the high-rate of dose reductions.
•pMMR/MSS CRCs are inherently resistant to ICIs.•Preclinical data suggest a synergism between multi-kinase inhibitors and ICIs.•Regorafenib plus ICIs has been investigated in pMMR/MSS CRC with ...variable results.•pMMR/MSS CRC patients without liver metastases benefit most from such combination.•Ongoing studies will shed further light into the potential of regorafenib plus ICIs in pMMR/MSS CRC.
Immune checkpoint inhibitors (ICIs) have marked a new era of cancer treatment, showing remarkable efficacy in a wide range of solid malignancies. In colorectal cancer (CRC), however, the therapeutic potential of ICIs is limited to the small group (≈5%) of patients with mismatch repair deficient (dMMR)/high microsatellite instable (MSI-H) tumours, which are characterised by high mutational/neo-antigen burden, and an inflammatory tumour microenvironment with abundant tumour-infiltrating lymphocytes. Over the last few years, research has focused on immuno-modulatory strategies that could overcome the inherent resistance to ICIs that is observed in the vast group (≈95%) of patients with mismatch repair proficient (pMMR)/microsatellite stable (MSS) tumours. Among these, the combination of ICIs with multi-kinase inhibitors has gained traction in preclinical studies and clinical trials. Thanks to their multiple targets and mechanisms of action, generally involving key cancer pathways such as oncogenesis, angiogenesis, metastasis, and tumour immunity, these agents can exert synergistic effects with ICIs, eventually turning inherently cold cancers into hot tumours, that can be efficiently recognised and targeted by an activated immune system. Regorafenib is routinely used for chemorefractory CRC with limited efficacy. Preliminary evidence, however, suggests that this multi-kinase inhibitor could be an optimal combination partner for ICIs. In this review article, we explain the biological rationale underlying the synergism between regorafenib and ICIs, discuss the available clinical data in CRC, and take a glance into future perspectives by presenting ongoing trials and possible research developments in this setting.
c-KIT mutations are found in approximately 15% of patients with malignant melanoma in the Asian population. Regorafenib, an oral multikinase inhibitor, acts against both wild-type and mutant KIT.
...This multi-institutional, phase II, single-arm study aimed to evaluate the efficacy of regorafenib against metastatic malignant melanoma harbouring c-KIT mutations.
Patients with metastatic melanoma positive for c-KIT mutations, upon progression after at least one line of systemic treatment, were enroled. Patients received oral regorafenib 160 mg once daily for 3 weeks (4-week cycle). The primary endpoint was disease control rate (DCR), and secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
In total, 23 patients were enrolled. c-KIT mutations were frequently reported in exon 11 (14/23, 60.9%), followed by exons 13, 17, and 9 in 5 (21.7%), 5 (21.7%), and 2 (8.7%) patients, respectively. DCR at 8 weeks was 73.9%, with 2 patients (8.7%) achieving complete response, 5 (21.7%) achieving partial response, and 10 (43.5%) showing stable disease. ORR was 30.4% (7/23). The median follow-up period was 15.7 months (95% confidence interval CI, 9.6–21.3), and median OS and PFS were 21.5 months (95% CI, 15.1–27.9) and 7.1 months (95% CI, 5.0–9.2), respectively. Circulating tumour DNA analysis in selected patients showed high c-KIT correlation (85.7%) with tissue-based tumour mutational profiles. The most common adverse events (AEs) were skin reactions, including palmar-plantar erythrodysesthesia (52.2%), and grade 3 AEs were reported in 39.1% (9/23) of the patients.
Regorafenib in second- or later-line settings demonstrated significant activity in patients with metastatic melanoma harbouring c-KIT mutations.
•Regorafenib demonstrated 73.9% disease control rate in c-KIT mutated melanoma.•Overall response rate was 30.4%.•Palmar-plantar erythrodysesthesia was the most commonly reported adverse event (AE).•ctDNA analysis showed high c-KIT correlation (85.7%) with tumour mutational profile.
Background
TAS‐102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, available therapies. Given the complete inefficacy in ...half of patients, the lack of predictive factors, the palliative setting, and the financial and clinical toxicity, optimizing the cost‐benefit ratio is crucial. The “ColonLife” nomogram allows an estimate of the 12‐week life expectancy of patients with refractory mCRC.
Materials and Methods
We collected data from patients treated at eight Italian centers in the compassionate use program. Baseline characteristics of patients who were or were not progression free at 6 months were compared. The discriminative ability of the ColonLife nomogram was assessed. Among patients who received both TAS‐102 and regorafenib, clinical outcomes of the two sequences were compared.
Results
This study included 341 patients. Six (2%) and 93 (27%) patients achieved response and disease stabilization, respectively. The median progression‐free survival (PFS) was 2.4 months with an estimated 6‐month PFS rate of 19%; the median overall survival (OS) was 6.2 months. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, normal lactate dehydrogenase (LDH), and a time from the diagnosis of metastatic disease of >18 months were independently associated with higher chances of a patient being progression free at 6 months. The discriminative ability of ColonLife was confirmed. Among 121 patients who received both regorafenib and TAS‐102, no differences in first or second PFS or OS were reported between the two sequences.
Conclusion
One out of five patients achieves clinical benefit with TAS‐102. ECOG PS, LDH, and time from diagnosis of metastatic disease may help to identify these patients. Excluding patients with very short life expectancy appears a reasonable approach.
Implications for Practice
Improving the cost‐efficacy ratio of TAS‐102 in metastatic colorectal cancer is needed to spare useless toxicities in a definitely palliative setting. Eastern Cooperative Oncology Group performance status, lactate dehydrogenase levels, and time from the diagnosis of metastatic disease may help to identify patients more likely to achieve benefit. Properly designed prognostic tools (i.e., the “ColonLife” nomogram) may enable excluding from further treatments patients with very limited life expectancy.
摘要
背景。TAS‐102 适用于先前接受过现有疗法治疗或者被认定无法接受现有疗法治疗的转移性结直肠癌(mCRC)患者。由于对半数患者完全无效,缺乏预测因素,采取姑息治疗以及经济因素和临床毒性因素,因此,优化成本效益比显得至关重要。“ColonLife”列线图可以估算出难治性mCRC患者的预期寿命为 12 周。
材料和方法。我们收集了在8家参与同情使用计划的意大利中心接受治疗的患者的数据,并在 6 个月时对病情有进展与病情无进展的患者的基本特征进行了比较。我们还对 ColonLife 列线图的鉴别能力进行了评估。在同时服用 TAS‐102 和瑞格非尼的患者中,我们对两种服药顺序的临床效果进行了比较。
结果。本研究入组341名患者。其中分别有6名患者(2%)和93名患者(27%)的病情缓解及疾病稳定。中位无进展生存期(PFS)为2.4个月,估算的6个月PFS率为19%;中位总生存期(OS)为6.2个月。东部肿瘤协作组体能状态(ECOG PS)评分为0,乳酸脱氢酶(LDH)正常,诊断转移的时间超过18个月,均与患者在6个月时无疾病进展独立相关。ColonLife的鉴别能力得到了证实。在服用瑞格非尼和TAS‐102的121名患者中,未收到两种服药顺序在PFS或OS存在差异的报告。
结论。五分之一的患者在服用TAS‐102后得到临床受益。ECOG PS、LDH和诊断转移的时间可帮助确定这些患者。排除预期寿命很短的患者似乎是一种合理的方法。
实践意义
需要提高TAS‐102在治疗转移性结直肠癌过程中的成本疗效比率,进而消除其在明确姑息治疗环境中的无用毒性。东部肿瘤协作组体能状态评分、乳酸脱氢酶水平以及诊断转移的时间可帮助确定更有可能获得疗效的患者。设计合理的预后工具(如“ColonLife”列线图)可排除预期寿命非常有限的患者去接受进一步的治疗。
A new fluoropyrimidine recently entered the scene of metastatic colorectal cancer (mCRC): trifluridine/tipiracil, also known as TAS‐102. Improving the cost/efficacy ratio of TAS‐102 in mCRC is needed to avoid toxicities in a definitely palliative setting. ECOG performance score, LDH levels, and time from diagnosis of metastatic disease may help identify patients most likely to benefit. Properly designed prognostic tools, such as the "ColonLife" nomogram, may allow for better treatment decisions for patients with limited life expectancy.
Abstract
Objectives
Regorafenib is an oral multi-kinase inhibitor approved for various metastatic/advanced cancers, and has been investigated in clinical trials in many other tumour entities. The ...purpose of this study was to evaluate the therapeutic potential of regorafenib for nasopharyngeal carcinoma (NPC).
Methods
Cellular proliferation, survival, apoptosis and colony formation assays were performed and combination index was determined. NPC xenograft tumour models were established. In vitro and In vivo angiogenesis assays were performed.
Key findings
Regorafenib is effective against a panel of NPC cell lines regardless of cellular origin and genetic profiling while sparing normal nasal epithelial cells. The predominant inhibitory effects of regorafenib in NPC are anchorage-dependent and anchorage-independent growth rather than survival. Apart from tumour cells, regorafenib potently inhibits angiogenesis. Mechanistically, regorafenib inhibits multiple oncogenic pathways including Raf/Erk/Mek and PI3K/Akt/mTOR. Regorafenib decreases Bcl-2 but not Mcl-1 level in NPC cells. The in vitro observations are evident in in vivo NPC xenograft mouse model. The combination of Mcl-1 inhibitor with regorafenib is synergistic in inhibiting NPC growth without causing systemic toxicity in mice.
Conclusions
Our findings also support further clinical investigation of regorafenib and Mcl-1 inhibitor for NPC treatment.
Aim
Regorafenib is a tyrosine kinase inhibitor that is mainly metabolized by CYP3A4. The genetic polymorphism of CYP3A4 would contribute to differences in metabolism of regorafenib. Previously, we ...had discovered several novel CYP3A4 variants. However, the catalytic characteristics of these 27 CYP3A4 variants on oxidizing regorafenib have not being determined. The purpose of this study was to investigate the catalytic characteristics of 27 CYP3A4 protein variants on the oxidative metabolism of regorafenib in vitro.
Method
Wild‐type CYP3A4.1 or other variants was incubated with 0.5‐20 μmol/L regorafenib for 30 minutes. After sample processing, regorafenib‐N‐oxide, a primary metabolite, was detected by ultra‐performance liquid chromatography‐tandem mass spectrometry system.
Result
CYP3A4.20 had no detectable enzyme activity compared with wild‐type CYP3A4.1; five variants (CYP3A4.5, .16, .19, .24, .29) exhibited similar clearance value with CYP3A4.1; four variants (CYP3A4.14, .15, .28, .31) displayed increased enzymatic activities, while remaining variants showed markedly decreased intrinsic clearance values.
Conclusion
This study is the first to investigate the function of 27 CYP3A4 protein variants on the metabolism of regorafenib in vitro, and it may provide some valuable information for further research in clinic.
Angiogenesis, a critical driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin ...and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature. Regorafenib (BAY 73‐4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits additional angiogenic kinases (VEGFR1/3, platelet‐derived growth factor receptor‐β and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B‐RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast‐enhanced magnetic resonance imaging. Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)×4 dosing study, the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition (TGI). A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd×5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose‐dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages observed in breast MDA‐MB‐231 and renal 786‐O carcinoma models. Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki‐67 and phosphorylated extracellular regulated kinases 1/2. These data demonstrate that regorafenib is a well‐tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.
PDF
