BACKGROUND Starting a second-line systemic treatment for hepatocellular carcinoma(HCC)is a common situation.The only therapeutic options in France are two broadspectrum tyrosine kinase inhibitors(TKIs),regorafenib(REG...BACKGROUND Starting a second-line systemic treatment for hepatocellular carcinoma(HCC)is a common situation.The only therapeutic options in France are two broadspectrum tyrosine kinase inhibitors(TKIs),regorafenib(REG)and cabozantinib(CBZ),but no comparative real-life studies are available.AIM To evaluate the progression-free survival(PFS)of patients treated with REG or CBZ,we investigated the disease control rate(DCR),overall survival(OS),and safety of both drugs.To identify the variables associated with disease progression over time.METHODS A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers(Avignon,Marseille,and Nice)between January 2017 and March 2021 using propensity score matching.PFS and OS were assessed using the Kaplan-Meier method.Multivariate analysis(MA)of progression risk factors over time was performed in matched-pair groups.RESULTS Fifty-eight patients 68(62-74)years old with HCC,Barcelona clinic liver cancer(BCLC)B/C(86%),Child-Pugh(CP)-A/B(24%)received REG for 3.4(1.4-10.5)mo as second-line therapy.Twentyeight patients 68(60-73)years,BCLC B/C(75%),CP-A/B(25%)received CBZ for 3.7(1.8-4.9)mo after first-line treatment with sorafenib[3(2-4)(CBZ)vs 4(2.9-11.8)mo(REG),P=0.0226].Twenty percent of patients received third-line therapy.After matching,PFS and DCR were not significantly different after a median follow-up of 6.2(2.7-11.7)mo(REG)vs 5.2(4-7.2)mo(CBZ),P=0.6925.There was no difference in grade 3/4 toxicities,dose reductions,or interruptions.The OS of CP-A patients was 8.3(5.2-24.8)vs 4.9(1.6-11.7)mo(CP-B),P=0.0468.The MA of risk factors for progression over time identified C-reactive protein(CRP)>10 mg/L,neutrophil-to-lymphocyte ratio(NLR)>3,and aspartate aminotransferase(AST)>45 IU as predictive factors.CONCLUSION This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC.Elevated levels of inflammatory markers(CRP and NLR)and AST were associated with non-control of TKIs over time.A 2-mo online progression risk calculation is proposed.展开更多
We report a case of a patient with c-MET amplified hepato-cellular carcinoma (HCC) who had a dramatic response to cabozantinib despite being refractory to four previous lines of systemic therapy. The patient had previ...We report a case of a patient with c-MET amplified hepato-cellular carcinoma (HCC) who had a dramatic response to cabozantinib despite being refractory to four previous lines of systemic therapy. The patient had previously received re-gorafenib plus nivolumab as first-line treatment, lenvatinib as second-line, sorafenib as third-line, and ipilimumab plus nivolumab as fourth-line treatment in sequence. However, all regimens showed early progression within 2 months. The pa-tient’s HCC was well-controlled, with a partial response (PR) of over 9 months after beginning cabozantinib treatment. Although there were mild adverse events such as diarrhea and elevated liver enzymes, they were tolerable. Next-gen-eration sequencing (NGS) of the patient’s previous surgical specimen indicated amplification of c-MET genes. Although it is well known that cabozantinib has excellent effectiveness for inhibiting c-MET at the preclinical level, to the best of our knowledge this is the first case of dramatic response to cabozantinib in a patient with advanced HCC with c-MET am-plification.展开更多
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...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.展开更多
目的系统评价靶向药物治疗转移性非透明细胞肾癌(nccRCC)患者的疗效和安全性,为临床治疗nccRCC提供指导。方法计算机检索2006年1月-2022年7月PubMed、Embase、Cochrane Library、web of science数据库中所有关于靶向药物治疗nccRCC患者...目的系统评价靶向药物治疗转移性非透明细胞肾癌(nccRCC)患者的疗效和安全性,为临床治疗nccRCC提供指导。方法计算机检索2006年1月-2022年7月PubMed、Embase、Cochrane Library、web of science数据库中所有关于靶向药物治疗nccRCC患者的观察性研究和随机对照试验,由3名独立研究者筛选文献、提取数据及评价文献质量,RCT研究使用Cochrane系统评价手册进行评估,只有一项研究结局数据不完整(随访偏倚)被评估为高风险,其余为低风险和不确定风险,非RCT研究经JBI质量评价工具评估,所有研究均显示偏倚风险低。使用Stata.17软件对结果进行Meta分析。结果共纳入16项研究,涉及989例患者。Meta分析结果显示,靶向药物治疗转移性nccRCC患者的总客观缓解率(ORR)为12.6%(95%CI:8.1%~17.9%),总疾病控制率(DCR)为65.3%(95%CI:58.3%~72.1%),总中位无进展生存期(PFS)为5.80(95%CI:4.69~6.91)个月,总中位总生存期(OS)为15.93(95%CI:12.17~19.68)个月。亚组分析中:舒尼替尼及卡博替尼治疗转移性nccRCC患者的总ORR分别为11.7%(95%CI:6.5%~18.0%)和17.2%(95%CI:8.4%~28.2%),乳头状肾细胞癌患者的总ORR为9.1%(95%CI:2.4%~18.9%)。结论靶向药物对于转移性nccRCC患者疗效显著,但患者可能会发生不良反应,其中转移性乳头状肾细胞癌效果较差,卡博替尼能使患者生存获益更大。展开更多
Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) app...Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) approved as first line systemic treatment in HCC. Regorafenib and nivolumab are the only FDA approved second line treatment after progression on sorafenib. We will discuss all potential first and second line options in HCC. In addition, we also will explore sequencing treatment options in HCC, and examine biomarkers that can potentially predict benefits from treatments such as immune checkpoint inhibitor. This minireview summarizes potential treatments in HCC based on clinical trials that have been published in manuscript or abstract format from 1994-2018.展开更多
The current standard treatment option for advanced hepatocellular carcinoma(HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of surviv...The current standard treatment option for advanced hepatocellular carcinoma(HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of survival as the first- or second-line therapy of choice in phase Ⅲ randomized controlled trials. Recently, the subgroup analysis of a phase Ⅱ randomized controlled trial has shown that tivantinib, a selective MET inhibitor, can significantly improve the overall survival in patients with MET-positive advanced HCC after the failure or intolerance of a prior systemic therapy. These findings enlighten the role of MET inhibitors in the treatment of advanced HCC. In this paper, we review all ongoing and completed clinical trials regarding this topic. As for the first-line therapy of advanced HCC, INC280 and foretinib are being evaluated in 2 phase Ⅱ single-arm trials; and MSC2156119 J and golvatinib plus sorafenib are being compared with sorafenib alone in 2 phase Ⅱ randomized controlled trials. As for the second-line therapy of advanced HCC, tivantinib and cabozantinib are being compared with placebo in 2 phase Ⅲrandomized controlled trials.展开更多
BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and ...BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and is the leading cause of death from malignant thyroid tumors.The one-year survival rate is 20%,with a median overall survival(OS)of only 5 mo[2].The aim of this report is to provide our experience in the diagnosis and treatment of ATC.CASE SUMMARY A patient with a thyroid mass underwent surgical treatment after developing symptoms of hoarseness.The resected tumor was pathologically diagnosed as ATC.Imaging examination revealed organ and lymph node metastasis.After multiple cycles of chemotherapy and local radiotherapy,the metastases were not relieved and gradually increased in size and new metastases appeared.The patient immediately received immunotherapy combined with targeted therapy.During treatment,immune-related adverse reactions occurred,which were improved after symptomatic treatment,and tolerated by the patient.The OS of the patient was more than 30 mo after immunotherapy combined with targeted therapy.CONCLUSION For metastatic ATC,surgical treatment,radiotherapy and chemotherapy have no significant effect on remission of the disease.However,immunotherapy has made a breakthrough in the treatment of ATC。展开更多
The therapeutic options for patients with metastatic renal cell carcinoma(mRCC) have completely changed during the last ten years. With the sequential use of targeted therapies, median overall survival has increased i...The therapeutic options for patients with metastatic renal cell carcinoma(mRCC) have completely changed during the last ten years. With the sequential use of targeted therapies, median overall survival has increased in daily practice and now it is not uncommon to see patients surviving kidney cancer for more than four to five years. Once treatment fails with the first line targeted therapy, head to head comparisons have shown that cabozantinib, nivolumab and the combination of lenvatinib plus everolimus are more effective than everolimus alone and that axitinib is more active than sorafenib. Unfortunately, it is very unlikely that we will ever have prospective data comparing the activity of axitinib, cabozantinib, lenvatinib or nivolumab. It is frustrating to observe the lack of biomarkers that we have in this field, thus there is no firm recommendation about the optimal sequence of treatment in the second line. In the absence of reliable biomarkers, there are several clinical endpoints that can help physicians to make decisions for an individual patient, such as the tumor burden, the expected response rate and the time to achieve the response to each agent, the prior response to the agent administered, the toxicity profile of the different compounds and patient preference. Here, we propose the introduction of the tumor-growth rate(TGR) during first-line treatment as a new tool to be used to select the second line strategy in m RCC. The rapidness of TGR before the onset of the treatment reflects the variability between patients in terms of tumor growth kinetics and it could be a surrogate marker of tumor aggressiveness that may guide treatment decisions.展开更多
Systemic therapy for metastatic renal cell carcinoma(mRCC)has evolved drastically,with agents targeting vascular endothelial growth factor(VEGF)and the mammalian target of rapamycin(mTOR)now representing a standard of...Systemic therapy for metastatic renal cell carcinoma(mRCC)has evolved drastically,with agents targeting vascular endothelial growth factor(VEGF)and the mammalian target of rapamycin(mTOR)now representing a standard of care.The present paper is to review the current status of relevant clinical trials that were either recently completed or ongoing.(1)Though observation remains a standard of care following resection of localized disease,multiple trials are underway to assess VEGF-and mTOR-directed therapies in this setting.(2)While the preponderance of retrospective data favors cytoreductive nephrectomy in the context of targeted agents,prospective data to support this approach is still forthcoming.(3)The first-line management of mRCC may change substantially with multiple studies exploring vaccines,immune checkpoint inhibitors,and novel targeted agents currently underway.In general,prospective studies that will report within the next several years will be critical in defining the role of adjuvant therapy and cytoreductive nephrectomy.Over the same span of time,the current treatment paradigm for first-line therapy may evolve.展开更多
文摘BACKGROUND Starting a second-line systemic treatment for hepatocellular carcinoma(HCC)is a common situation.The only therapeutic options in France are two broadspectrum tyrosine kinase inhibitors(TKIs),regorafenib(REG)and cabozantinib(CBZ),but no comparative real-life studies are available.AIM To evaluate the progression-free survival(PFS)of patients treated with REG or CBZ,we investigated the disease control rate(DCR),overall survival(OS),and safety of both drugs.To identify the variables associated with disease progression over time.METHODS A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers(Avignon,Marseille,and Nice)between January 2017 and March 2021 using propensity score matching.PFS and OS were assessed using the Kaplan-Meier method.Multivariate analysis(MA)of progression risk factors over time was performed in matched-pair groups.RESULTS Fifty-eight patients 68(62-74)years old with HCC,Barcelona clinic liver cancer(BCLC)B/C(86%),Child-Pugh(CP)-A/B(24%)received REG for 3.4(1.4-10.5)mo as second-line therapy.Twentyeight patients 68(60-73)years,BCLC B/C(75%),CP-A/B(25%)received CBZ for 3.7(1.8-4.9)mo after first-line treatment with sorafenib[3(2-4)(CBZ)vs 4(2.9-11.8)mo(REG),P=0.0226].Twenty percent of patients received third-line therapy.After matching,PFS and DCR were not significantly different after a median follow-up of 6.2(2.7-11.7)mo(REG)vs 5.2(4-7.2)mo(CBZ),P=0.6925.There was no difference in grade 3/4 toxicities,dose reductions,or interruptions.The OS of CP-A patients was 8.3(5.2-24.8)vs 4.9(1.6-11.7)mo(CP-B),P=0.0468.The MA of risk factors for progression over time identified C-reactive protein(CRP)>10 mg/L,neutrophil-to-lymphocyte ratio(NLR)>3,and aspartate aminotransferase(AST)>45 IU as predictive factors.CONCLUSION This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC.Elevated levels of inflammatory markers(CRP and NLR)and AST were associated with non-control of TKIs over time.A 2-mo online progression risk calculation is proposed.
基金the National Research Founda-tion of Korea(NRF)grant funded by the Korea government(MSIT)(NRF-2020R1C1C1010722 to HJC).
文摘We report a case of a patient with c-MET amplified hepato-cellular carcinoma (HCC) who had a dramatic response to cabozantinib despite being refractory to four previous lines of systemic therapy. The patient had previously received re-gorafenib plus nivolumab as first-line treatment, lenvatinib as second-line, sorafenib as third-line, and ipilimumab plus nivolumab as fourth-line treatment in sequence. However, all regimens showed early progression within 2 months. The pa-tient’s HCC was well-controlled, with a partial response (PR) of over 9 months after beginning cabozantinib treatment. Although there were mild adverse events such as diarrhea and elevated liver enzymes, they were tolerable. Next-gen-eration sequencing (NGS) of the patient’s previous surgical specimen indicated amplification of c-MET genes. Although it is well known that cabozantinib has excellent effectiveness for inhibiting c-MET at the preclinical level, to the best of our knowledge this is the first case of dramatic response to cabozantinib in a patient with advanced HCC with c-MET am-plification.
基金supported by grants from the National Key Project for Infectious Disease of China(No.2017ZX 10203207)and the National Natural Science Foundation of China(Nos.81972737.81930074,91959203,and 81872356).
文摘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.
文摘目的系统评价靶向药物治疗转移性非透明细胞肾癌(nccRCC)患者的疗效和安全性,为临床治疗nccRCC提供指导。方法计算机检索2006年1月-2022年7月PubMed、Embase、Cochrane Library、web of science数据库中所有关于靶向药物治疗nccRCC患者的观察性研究和随机对照试验,由3名独立研究者筛选文献、提取数据及评价文献质量,RCT研究使用Cochrane系统评价手册进行评估,只有一项研究结局数据不完整(随访偏倚)被评估为高风险,其余为低风险和不确定风险,非RCT研究经JBI质量评价工具评估,所有研究均显示偏倚风险低。使用Stata.17软件对结果进行Meta分析。结果共纳入16项研究,涉及989例患者。Meta分析结果显示,靶向药物治疗转移性nccRCC患者的总客观缓解率(ORR)为12.6%(95%CI:8.1%~17.9%),总疾病控制率(DCR)为65.3%(95%CI:58.3%~72.1%),总中位无进展生存期(PFS)为5.80(95%CI:4.69~6.91)个月,总中位总生存期(OS)为15.93(95%CI:12.17~19.68)个月。亚组分析中:舒尼替尼及卡博替尼治疗转移性nccRCC患者的总ORR分别为11.7%(95%CI:6.5%~18.0%)和17.2%(95%CI:8.4%~28.2%),乳头状肾细胞癌患者的总ORR为9.1%(95%CI:2.4%~18.9%)。结论靶向药物对于转移性nccRCC患者疗效显著,但患者可能会发生不良反应,其中转移性乳头状肾细胞癌效果较差,卡博替尼能使患者生存获益更大。
文摘Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) approved as first line systemic treatment in HCC. Regorafenib and nivolumab are the only FDA approved second line treatment after progression on sorafenib. We will discuss all potential first and second line options in HCC. In addition, we also will explore sequencing treatment options in HCC, and examine biomarkers that can potentially predict benefits from treatments such as immune checkpoint inhibitor. This minireview summarizes potential treatments in HCC based on clinical trials that have been published in manuscript or abstract format from 1994-2018.
文摘The current standard treatment option for advanced hepatocellular carcinoma(HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of survival as the first- or second-line therapy of choice in phase Ⅲ randomized controlled trials. Recently, the subgroup analysis of a phase Ⅱ randomized controlled trial has shown that tivantinib, a selective MET inhibitor, can significantly improve the overall survival in patients with MET-positive advanced HCC after the failure or intolerance of a prior systemic therapy. These findings enlighten the role of MET inhibitors in the treatment of advanced HCC. In this paper, we review all ongoing and completed clinical trials regarding this topic. As for the first-line therapy of advanced HCC, INC280 and foretinib are being evaluated in 2 phase Ⅱ single-arm trials; and MSC2156119 J and golvatinib plus sorafenib are being compared with sorafenib alone in 2 phase Ⅱ randomized controlled trials. As for the second-line therapy of advanced HCC, tivantinib and cabozantinib are being compared with placebo in 2 phase Ⅲrandomized controlled trials.
文摘BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and is the leading cause of death from malignant thyroid tumors.The one-year survival rate is 20%,with a median overall survival(OS)of only 5 mo[2].The aim of this report is to provide our experience in the diagnosis and treatment of ATC.CASE SUMMARY A patient with a thyroid mass underwent surgical treatment after developing symptoms of hoarseness.The resected tumor was pathologically diagnosed as ATC.Imaging examination revealed organ and lymph node metastasis.After multiple cycles of chemotherapy and local radiotherapy,the metastases were not relieved and gradually increased in size and new metastases appeared.The patient immediately received immunotherapy combined with targeted therapy.During treatment,immune-related adverse reactions occurred,which were improved after symptomatic treatment,and tolerated by the patient.The OS of the patient was more than 30 mo after immunotherapy combined with targeted therapy.CONCLUSION For metastatic ATC,surgical treatment,radiotherapy and chemotherapy have no significant effect on remission of the disease.However,immunotherapy has made a breakthrough in the treatment of ATC。
文摘The therapeutic options for patients with metastatic renal cell carcinoma(mRCC) have completely changed during the last ten years. With the sequential use of targeted therapies, median overall survival has increased in daily practice and now it is not uncommon to see patients surviving kidney cancer for more than four to five years. Once treatment fails with the first line targeted therapy, head to head comparisons have shown that cabozantinib, nivolumab and the combination of lenvatinib plus everolimus are more effective than everolimus alone and that axitinib is more active than sorafenib. Unfortunately, it is very unlikely that we will ever have prospective data comparing the activity of axitinib, cabozantinib, lenvatinib or nivolumab. It is frustrating to observe the lack of biomarkers that we have in this field, thus there is no firm recommendation about the optimal sequence of treatment in the second line. In the absence of reliable biomarkers, there are several clinical endpoints that can help physicians to make decisions for an individual patient, such as the tumor burden, the expected response rate and the time to achieve the response to each agent, the prior response to the agent administered, the toxicity profile of the different compounds and patient preference. Here, we propose the introduction of the tumor-growth rate(TGR) during first-line treatment as a new tool to be used to select the second line strategy in m RCC. The rapidness of TGR before the onset of the treatment reflects the variability between patients in terms of tumor growth kinetics and it could be a surrogate marker of tumor aggressiveness that may guide treatment decisions.
文摘Systemic therapy for metastatic renal cell carcinoma(mRCC)has evolved drastically,with agents targeting vascular endothelial growth factor(VEGF)and the mammalian target of rapamycin(mTOR)now representing a standard of care.The present paper is to review the current status of relevant clinical trials that were either recently completed or ongoing.(1)Though observation remains a standard of care following resection of localized disease,multiple trials are underway to assess VEGF-and mTOR-directed therapies in this setting.(2)While the preponderance of retrospective data favors cytoreductive nephrectomy in the context of targeted agents,prospective data to support this approach is still forthcoming.(3)The first-line management of mRCC may change substantially with multiple studies exploring vaccines,immune checkpoint inhibitors,and novel targeted agents currently underway.In general,prospective studies that will report within the next several years will be critical in defining the role of adjuvant therapy and cytoreductive nephrectomy.Over the same span of time,the current treatment paradigm for first-line therapy may evolve.
