Efficacy of targeted drugs for metastatic non-clear cell renal cell carcinoma:a Meta-analysis / 现代泌尿外科杂志

【Objective】 To systematically evaluate the efficacy and safety of targeted drugs in the treatment of metastatic non-clear cell renal cell carcinoma (nccRCC) and to provide guidance for clinical treatment. 【Methods】 All observational studies and randomized controlled trials (RCTs) of nccRCC treated with targeted drugs were retrieved from the PubMed, Embase, the Cochrane Library and Web of Science. Three independent investigators screened the literature, extracted data and evaluated the quality of literature. The RCTs were evaluated using the Cochrane Handbook. One research with insufficient outcome data (follow-up bias) was assessed as high risk, and the other studies showed low or uncertain risk. The non-RCTs were evaluated with the JBI Quality Assessment Tool, and all studies displayed a low risk of bias. The data were analyzed with Stata 17.0 software. 【Results】 A total of 16 studies involving 989 patients were included. Meta-analysis showed that the objective response rate (ORR) was 12.6% (95%CI:8.1%-17.9%), the total disease control rate (DCR) was 65.3% (95%CI:58.3%-72.1%), the total median progression-free survival (PFS) was 5.80 (95%CI:4.69-6.91) months, and the median overall survival (OS) was 15.93 (95%CI:12.17-19.68) months. In subgroup analysis, the total ORR of patients with metastatic nccRCC treated with sunitinib and cabozantinib were 11.7% (95%CI:6.5%-18.0%) and 17.2% (95%CI:8.4%-28.2%), respectively. The total ORR of patients with papillary renal cell carcinoma was 9.1% (95%CI:2.4%-18.9%). 【Conclusion】 Targeted drugs have a significant effect on patients with metastatic nccRCC, but adverse reactions may occur. Targeted drugs have poor effects on metastatic papillary renal cell carcinoma, and cabozantinib may have greater survival benefits.

LDHA inhibitor combined with targeted drugs synergistically inhibit the proliferation of fumarate hydratase-deficient renal cell carcinoma cells / 现代泌尿外科杂志

【Objective】 To explore the therapeutic effects of lactate dehydrogenase A (LDHA) inhibitor and targeted drugs on fumarate-hydratase-deficient renal cell carcinoma (FH-d RCC). 【Methods】 RNA-sequencing was used to detect the mRNA expression in FH-d RCC tissues, which was further validated with real-time fluorescence quantitative PCR and immunohistochemistry. Human-derived FH-d RCC cell line UOK262 and murine-derived FH-d RCC cell line FH1-/-CL19 (CL19) were treated with LDHA inhibitor [(R)-GNE-140] and listed kidney cancer targeted drugs (Axitinib, Cabozantinib, Sunitinib, Sorafenib, Pazopanib, Everolimus) respectively, and then treated with LHDA inhibitor in combination with the targeted drugs to observe the alteration of cell proliferation. The combination index (CI) of different dose groups of the combination drugs were analyzed with CompuSyn software to determine the optimal combination regimen. 【Results】 LDHA inhibitor and targeted drugs, including Cabozantinib, Sorafenib and Sunitinib, had a significant inhibitory effect on the proliferation of FH-d RCC cells, and the combination of Cabozantinib and Sorafenib or Pazopanib had a significant anti-tumor effect. 【Conclusion】 LDHA inhibitor combined with targeted drugs can significantly inhibit the growth of FH-d RCC cells, indicating that LDHA may be a potential therapeutic target of FH-d RCC.

Meta-analysis of efficacy and safety of cabozantinib in the treatment of advanced thyroid cancer / 中国药房

OBJECTIVE To review the efficacy and safety of cabozantinib in the treatment of advanced thyroid cancer. METHODS Retrieved from PubMed， the Cochrane Library， Embase， ClinicalTrials.gov， Wanfang data， VIP， CNKI and China Clinical Trials Registry， randomized controlled trials （RCTs） about cabozantinib （trial group） versus placebo （control group） were collected from the inception to Nov. 2022. After literature screening， data extraction and quality evaluation， meta-analysis was performed by using RevMan 5.4 software. RESULTS A total of 4 RCTs were included involving 588 patients. The results of the meta-analysis showed that the progression free survival （PFS） [HR＝0.24， 95%CI （0.19，0.31）， P＜0.000 01]， objective response rate （ORR） [RR＝31.46， 95%CI （6.32，156.75）， P＜0.000 1]， the incidence of grade 3-4 adverse event （AE） [RR＝2.15，95%CI （1.76，2.61），P＜0.000 01]， severe adverse event [RR＝1.78，95%CI （1.11，2.83），P＝0.02]， diarrhea [RR＝3.29，95%CI（1.62， 6.66），P＝0.001]， palmar-plantar erythrodysesthesia syndrome [RR＝28.19，95%CI （12.25，64.88），P＜0.000 01]， and hypertension [RR＝6.50，95%CI （3.90，10.83），P＜0.000 01] in trial group were significantly higher than control group； there was no statistical significance in overall survival （OS） [HR＝0.83，95%CI （0.67，1.02）， P＝0.07] or the incidence of fatigue [RR＝1.25，95%CI （0.78，1.98），P＝0.35] between the two groups. Subgroup analysis showed that PFS and ORR in patients with differentiated thyroid carcinoma （DTC） and medullary thyroid carcinoma （MTC） in the trial group were significantly higher than control group （P＜ 0.05）. There was no significant difference in OS of DTC and MTC patients in the trial group compared with the control group （P＞ 0.05）. CONCLUSIONS Cabozantinib can prolong PFS and increase ORR in patients with advanced thyroid cancer， but the incidence of AE is high.

Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma / 医学前沿

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.

Custo-efetividade e impacto orçamentário da introdução do cabozantinibe no tratamento de carcinoma de células renais avançado no sistema de saúde suplementar no Brasil / Cost-effectiveness and budgetary impact of introducing cabozantinib in the treatment of advanced renal cell carcinoma in the supplementary health system in Brazil

Objetivo: Este trabalho teve por objetivo determinar o custo-efetividade e o impacto orçamentário do cabozantinibe para o sistema de saúde suplementar no Brasil, no tratamento de carcinoma de células renais (RCC) avançado ou metastático, após falha de tratamento com inibidor do fator de crescimento endotelial vascular (VEGF), quando comparado ao atual tratamento aprovado: nivolumabe. Métodos: Foram utilizados custos referentes ao uso de recursos, tratamento médico, eventos adversos e qualidade de vida, calculados por estado de saúde. Foi considerado o tempo horizonte de 20 anos para análise de custo-efetividade e 5 anos para impacto orçamentário, e foi realizado um cenário alternativo comparando o cabozantinibe ao nivolumabe e axitinibe. Resultados: O cabozantinibe apresentou eficácia superior quando comparado ao nivolumabe e ao axitinibe e representa uma redução de custos comparado ao nivolumabe. Em relação aos eventos adversos, o cabozantinibe apresenta redução dos gastos quando comparado ao nivolumabe. Conclusão: Esses resultados mostram um potencial de economia ao sistema de saúde suplementar com a adoção do cabozantinibe no tratamento para RCC avançado ou metastático em segunda linha no Brasil.

Objective: This study aimed to determine the cost-effectiveness and budgetary impact of cabozantinib for the supplementary health system in Brazil, in the treatment of advanced or metastatic renal cell carcinoma (RCC) after treatment failure with vascular endothelial growth factor (VEGF) inhibitor, when compared current approved treatment: nivolumab. Methods: Costs related to the use of resources, medical treatment, adverse events and quality of life were used, calculated by health status. The horizon time of 20 years was considered for cost-effectiveness analysis and 5 years for budgetary impact, and an alternative scenario was carried out comparing cabozantinib to nivolumab and axitinib. Results: Cabozantinib showed superior efficacy when compared to nivolumab and axitinib and represents a cost reduction compared to nivolumab. In relation to adverse events, cabozantinib shows a reduction in costs when compared to nivolumab. Conclusion: These results show a potential savings for the supplementary health system with the adoption of cabozantinib in the treatment for advanced or metastatic second-line RCC in Brazil.

New progress of cabozantinib in the treatment of metastatic renal cell carcinoma / 国际肿瘤学杂志

Renal cell carcinoma (RCC), the most common form of kidney cancer, is characteristic by difficult in diagnosis at an early stage, insensitivity to chemoradiotherapy, poor prognosis, etc.. Localized RCC is treated by surgery while advanced RCC is mainly treated by immunotherapy and targeted therapy. With the ongoing in-depth researches on targeted therapy in recent years, plenty of targeted drugs come into the market in succession. Cabozantinib has been approved for the treatment of advanced RCC in the first/second line setting. It′s safety profile and efficiency have been demonstrated in Ⅱ-Ⅲ clinical trials.

New progress of cabozantinib in the treatment of metastatic renal cell carcinoma / 国际肿瘤学杂志

Renal cell carcinoma (RCC),the most common form of kidney cancer,is characteristic by difficult in diagnosis at an early stage,insensitivity to chemoradiotherapy,poor prognosis,etc. . Localized RCC is treated by surgery while advanced RCC is mainly treated by immunotherapy and targeted therapy. With the ongoing in-depth researches on targeted therapy in recent years,plenty of targeted drugs come into the market in succession. Cabozantinib has been approved for the treatment of advanced RCC in the first/ second line setting. It's safety profile and efficiency have been demonstrated in Ⅱ-Ⅲ clinical trials.

A sensitive bioanalytical method development and validation of cabozantinib in human plasma by LC-ESI-MS/MS

ABSTRACT A simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of cabozantinib (CZ) in human plasma using cabozantinib-d4 (CZD4) as an internal standard (IS). Chromatographic separation was performed on Xbridge C18, 50 x 4.6 mm, 5 mm column with an isocratic mobile phase composed of 10mM Ammonium formate and Methanol in the ratio of (20:80 v/v), at a flow-rate of 0.7 mL/min. CZ and CZD4 were detected with proton adducts at m/z 502.2 ® 391.1 and 506.3 ® 391.2 in multiple reaction monitoring (MRM) positive mode respectively. Liquid-Liquid extraction method was used to extract the drug and IS. The method was validated over a linear concentration range of 5.0-5000.0 pg/mL with correlation coefficient (r2) ≥ 0.9994. This method demonstrated intra and inter-day precision within 1.95 to 2.37 and 2.93 to 9.3 % and Accuracy within 101.4 to 102.4 and 99.5 to 104.8 %. Cabozantinib was found to be stable throughout freeze-thawing cycles, bench top and postoperative stability studies

Content Determination of Cabozantinib in Its Raw Material by RP-HPLC / 中国药房

OBJECTIVE:To establish a method for the content determination of cabozantinib in its raw material. METHODS:RP-HPLC method was adopted. The determination was performed on Inertsil ODS-SP C18 column with mobile phase consisted of acetonitrile-0.02 mol/L ammonium acetate buffer (pH 5.2,52:48,V/V) at the flow rate of 1.0 mL/min. Detection wavelength was set at 241 nm,the column temperature was 38 ℃,and sample size was 20 μL. RESULTS:The linear range of cabozantinib were 9.88-49.40 μg/mL(r=0.9999). The limit of quantitation was 11.46 ng,and the limit of detection was 3.36 ng. The RSDs of preci-sion,stability,repeatability tests were all lower than 2.0%;recoveries were 98.5%-101.7%(RSD=1.2%,n=9). CONCLU-SIONS:The method is simple,accurate and suitable for the content determination of cabozantinib in its raw material.

Advances on receptor tyrosine kinase inhibitors taking c-Met as anti-tumor target / 中国药科大学学报

@#c-Met receptor tyrosine kinase plays an important role in signaling pathways including cell proliferation, metabolism as well as tumorigenic growth, migration and angiogenesis. c-Met has emerged as an attractive target for cancer therapy. Moreover, the interactive cross-talk between c-Met signaling and several other signaling pathways underlies a key effect for resistance of anti-cancer drugs. Thus, multi-target inhibitors become a new approach to cancer therapy. This paper introduces the c-Met signaling pathway and the resistance of kinase inhibitors caused by the cross-talk between c-Met and other membrane receptors and then will reviews the progress of single-target and multi-target c-Met inhibitors.