The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially increased.Approximately 10%of patients with DTC exhibit recurrent or metastatic dise...The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially increased.Approximately 10%of patients with DTC exhibit recurrent or metastatic disease,and about two-thirds of the latter will be defined as refractory to radioactive iodine(RAIR)treatment.Since this condition implies 10-year survival rates less than 10% after detection,using available treatments,such as systemic and targeted therapies,have become increasingly relevant.The initiation of these treatments aims to reach stabilization,tumor volume reduction,and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient’s features.Considering that despite enlarged progression-free survival was proven,multikinase inhibitors remain non-curative,their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction.In this context,molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy,progression free survival,overall survival and adverse events profile.This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC,including approved target therapies as well as those for off-label use,RAI resensitization agents,and immunotherapy.展开更多
Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different mult...Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different multikinase inhibitor,was shown to be non-inferior to sorafenib,in terms of survival,while all other agents previously tested failed to prove non-inferiority(or superiority)when compared to sorafenib.Similarly,in the second-line setting,most investigational drugs failed to provide better survival outcomes than placebo.However,in the last 2 years three positive phase III trials have been published in this setting.The RESORCE trial,a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib,showed better outcomes with regorafenib compared to placebo.More recently,the phase III CELESTIAL trial demonstrated the superiority of cabozantinib,a multikinase inhibitor targeting vascular endothelial growth factor receptor,MET,and AXL,vs placebo in the second-and third-line setting in patients progressing on or intolerant to sorafenib.The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels.Overall,the adverse events reported in these trials were in line with the known safety profiles of the tested agents.After nearly a decade of a certain degree of stagnation,we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.展开更多
Objective:To examine the efficacy and safety of anlotinib as first-line therapy to treat locally advanced or metastatic soft-tissue sarcoma.Methods:This is a single-arm trial.Treatment-naïve patients(≥14 years)w...Objective:To examine the efficacy and safety of anlotinib as first-line therapy to treat locally advanced or metastatic soft-tissue sarcoma.Methods:This is a single-arm trial.Treatment-naïve patients(≥14 years)with locally advanced or metastatic soft tissue sarcoma were eligible.Each treatment cycle lasted for 3 weeks,and included liposomal doxorubicin(40-50 mg/m^(2))on day 1 and anlotinib(12 mg)on days 8-21.Starting from the 9th cycle,treatment consisted of only anlotinib.Treatment continued until disease progression or intolerable toxicities.The primary efficacy end point was progression-free survival(PFS).Results:Eight patients were enrolled between July 25,2019 and January 8,2020.The median number of treatment cycles was 5.5.Within 5.9 months median follow-up,PFS events occurred in 4(4/8,50%)patients.The median PFS was 11.3 months and the 6-month PFS rate was 56%.No patients attained complete response and 2 patients(fibrosarcoma,1 patient and undifferentiated pleomorphic sarcoma,1 patient)achieved partial response.Three patients(fibrosarcoma,2 patients and synovial sarcoma,1 patient)had stable disease.The objective response rate was 25%(2/8)for the study population,and the disease control rate was 75%(6/8).No new safety concerns emerged.Conclusions:Anlotinib plus liposomal doxorubicin demonstrated antitumor activities in previously untreated locally advanced or metastatic soft tissue sarcomas.Due to the small sample size,further investigations with a larger population should be undertaken to confirm the study findings.展开更多
BACKGROUND Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer(mCRC).Regorafenib has shown significant benefits in ov...BACKGROUND Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer(mCRC).Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy.AIM To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib.METHODS Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers.The proteins evaluated(TNF-α,TGF-β,VEGF,CCL-2,CCL-4,and CCL-5)were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis.RESULTS We found that TNF-αbasal level was significantly higher in mCRC patients compared to healthy individuals.Non Responder(NR)patients showing progression of disease(n=12)had higher basal level of TGF-β,TNF-α,VEGF,CCL-2 and CCL-5 compared to Responder(R)patients(complete response CR,n=1;partial response PR,n=1;Stable Disease SD,n=3).On the contrary,plasma basal level of CCL-4 was higher in R compared to NR patients.High values of TGF-βand TNF-αnegatively correlated with progression free survival.CONCLUSION These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.展开更多
The current landscape for advanced hepatocellular carcinoma(HCC)has evolved drastically in recent years,with the ever-increasing development of novel standard first-line therapeutic strategies(e.g.,the combination of ...The current landscape for advanced hepatocellular carcinoma(HCC)has evolved drastically in recent years,with the ever-increasing development of novel standard first-line therapeutic strategies(e.g.,the combination of atezolizumab and bevacizumab)and the approval of several new agents for second line strategies,such as regorafenib and cabozantinib(1,2).Although a large number of treatment options are available for advanced HCC patients,multikinase inhibitor(MKI)-based immunotherapy doublet has become notably complex,especially after the publication of the COSMIC-312 trial(3).This study evaluated the efficacy and safety of cabozantinib combined with atezolizumab versus sorafenib as the first-line treatment of patients with advanced HCC.Although the primary endpoint of progression-free survival(PFS)was significantly improved with treatment using cabozantinib combined with atezolizumab compared with sorafenib in the COSMIC-312 trial,the overall survival(OS)did not improve,and the response rate was lower than expected(3).Nevertheless,this was a crucial randomized controlled trial(RCT)evaluating the efficacy of MKI-based immunotherapy doublet as the first-line systemic therapy for advanced HCC,paving the way for future investigations to determine the underlying mechanism of these connections.We have several concerns with the interpretation of this study.展开更多
Succinate dehydrogenase(SDH)-deficient gastrointestinal stromal tumors(GISTs)are generally resistant to targeted therapy with tyrosine kinase inhibitors(TKIs),such as imatinib,and there are no standard therapeutic opt...Succinate dehydrogenase(SDH)-deficient gastrointestinal stromal tumors(GISTs)are generally resistant to targeted therapy with tyrosine kinase inhibitors(TKIs),such as imatinib,and there are no standard therapeutic options for advanced SDH-deficient GISTs.The precise oncogenic mechanisms of SDH mutations in GIST have not been elucidated.Olverembatinib,a novel multikinase inhibitor,has shown promising activity in treating imatinib-resistant GIST.We conducted a phase 1 study(NCT03594422)to evaluate the safety and antitumor activity of olverembatinib in 66 patients with unresectable/metastatic GIST/other solid tumors,including 26 with TKI-failed SDH-deficient GISTs.To our knowledge,this is the largest prospective clinical trial for this rare GIST subtype.The median follow-up was 14.5(0.9–57.5)months.Olverembatinib was well tolerated;treatment-emergent adverse events(≥20%)included increases in hepatic transaminases,increases in leukocytes and neutrophils,anemia,and pyrexia.For SDH-deficient GISTs,confirmed partial responses were observed in 6 of the 26 evaluable patients(objective response rate,23.1%;95%CI,9–43.7);an additional 16(61.5%)did not progress during the first 6 months of treatment.This resulted in a clinical benefit rate of 84.6%(95%CI,65.1–95.6),and the median progression-free survival was 25.7 months(95%CI,12.9–NR).As a putative mechanism of action,translational research revealed significant lipid enrichment with the overexpression of lipid uptake-related genes and proteins,including CD36,fatty acid binding proteins,fatty acid transport proteins,and lipid metabolites,in SDH-deficient GIST patients,and olverembatinib suppressed lipid uptake and CD36 expression in GIST cells.Olverembatinib also exerts antitumor effects by inhibiting tumorigenic signaling pathways associated with hypoxia,angiogenesis,proliferation,and survival.展开更多
文摘The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially increased.Approximately 10%of patients with DTC exhibit recurrent or metastatic disease,and about two-thirds of the latter will be defined as refractory to radioactive iodine(RAIR)treatment.Since this condition implies 10-year survival rates less than 10% after detection,using available treatments,such as systemic and targeted therapies,have become increasingly relevant.The initiation of these treatments aims to reach stabilization,tumor volume reduction,and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient’s features.Considering that despite enlarged progression-free survival was proven,multikinase inhibitors remain non-curative,their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction.In this context,molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy,progression free survival,overall survival and adverse events profile.This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC,including approved target therapies as well as those for off-label use,RAI resensitization agents,and immunotherapy.
文摘Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different multikinase inhibitor,was shown to be non-inferior to sorafenib,in terms of survival,while all other agents previously tested failed to prove non-inferiority(or superiority)when compared to sorafenib.Similarly,in the second-line setting,most investigational drugs failed to provide better survival outcomes than placebo.However,in the last 2 years three positive phase III trials have been published in this setting.The RESORCE trial,a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib,showed better outcomes with regorafenib compared to placebo.More recently,the phase III CELESTIAL trial demonstrated the superiority of cabozantinib,a multikinase inhibitor targeting vascular endothelial growth factor receptor,MET,and AXL,vs placebo in the second-and third-line setting in patients progressing on or intolerant to sorafenib.The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels.Overall,the adverse events reported in these trials were in line with the known safety profiles of the tested agents.After nearly a decade of a certain degree of stagnation,we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.
文摘Objective:To examine the efficacy and safety of anlotinib as first-line therapy to treat locally advanced or metastatic soft-tissue sarcoma.Methods:This is a single-arm trial.Treatment-naïve patients(≥14 years)with locally advanced or metastatic soft tissue sarcoma were eligible.Each treatment cycle lasted for 3 weeks,and included liposomal doxorubicin(40-50 mg/m^(2))on day 1 and anlotinib(12 mg)on days 8-21.Starting from the 9th cycle,treatment consisted of only anlotinib.Treatment continued until disease progression or intolerable toxicities.The primary efficacy end point was progression-free survival(PFS).Results:Eight patients were enrolled between July 25,2019 and January 8,2020.The median number of treatment cycles was 5.5.Within 5.9 months median follow-up,PFS events occurred in 4(4/8,50%)patients.The median PFS was 11.3 months and the 6-month PFS rate was 56%.No patients attained complete response and 2 patients(fibrosarcoma,1 patient and undifferentiated pleomorphic sarcoma,1 patient)achieved partial response.Three patients(fibrosarcoma,2 patients and synovial sarcoma,1 patient)had stable disease.The objective response rate was 25%(2/8)for the study population,and the disease control rate was 75%(6/8).No new safety concerns emerged.Conclusions:Anlotinib plus liposomal doxorubicin demonstrated antitumor activities in previously untreated locally advanced or metastatic soft tissue sarcomas.Due to the small sample size,further investigations with a larger population should be undertaken to confirm the study findings.
文摘BACKGROUND Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer(mCRC).Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy.AIM To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib.METHODS Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers.The proteins evaluated(TNF-α,TGF-β,VEGF,CCL-2,CCL-4,and CCL-5)were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis.RESULTS We found that TNF-αbasal level was significantly higher in mCRC patients compared to healthy individuals.Non Responder(NR)patients showing progression of disease(n=12)had higher basal level of TGF-β,TNF-α,VEGF,CCL-2 and CCL-5 compared to Responder(R)patients(complete response CR,n=1;partial response PR,n=1;Stable Disease SD,n=3).On the contrary,plasma basal level of CCL-4 was higher in R compared to NR patients.High values of TGF-βand TNF-αnegatively correlated with progression free survival.CONCLUSION These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.
文摘The current landscape for advanced hepatocellular carcinoma(HCC)has evolved drastically in recent years,with the ever-increasing development of novel standard first-line therapeutic strategies(e.g.,the combination of atezolizumab and bevacizumab)and the approval of several new agents for second line strategies,such as regorafenib and cabozantinib(1,2).Although a large number of treatment options are available for advanced HCC patients,multikinase inhibitor(MKI)-based immunotherapy doublet has become notably complex,especially after the publication of the COSMIC-312 trial(3).This study evaluated the efficacy and safety of cabozantinib combined with atezolizumab versus sorafenib as the first-line treatment of patients with advanced HCC.Although the primary endpoint of progression-free survival(PFS)was significantly improved with treatment using cabozantinib combined with atezolizumab compared with sorafenib in the COSMIC-312 trial,the overall survival(OS)did not improve,and the response rate was lower than expected(3).Nevertheless,this was a crucial randomized controlled trial(RCT)evaluating the efficacy of MKI-based immunotherapy doublet as the first-line systemic therapy for advanced HCC,paving the way for future investigations to determine the underlying mechanism of these connections.We have several concerns with the interpretation of this study.
基金supported by Ascentage Pharma Group Corp.Ltd.(Hong Kong)and the National Natural Science Foundation of China(82573567)。
文摘Succinate dehydrogenase(SDH)-deficient gastrointestinal stromal tumors(GISTs)are generally resistant to targeted therapy with tyrosine kinase inhibitors(TKIs),such as imatinib,and there are no standard therapeutic options for advanced SDH-deficient GISTs.The precise oncogenic mechanisms of SDH mutations in GIST have not been elucidated.Olverembatinib,a novel multikinase inhibitor,has shown promising activity in treating imatinib-resistant GIST.We conducted a phase 1 study(NCT03594422)to evaluate the safety and antitumor activity of olverembatinib in 66 patients with unresectable/metastatic GIST/other solid tumors,including 26 with TKI-failed SDH-deficient GISTs.To our knowledge,this is the largest prospective clinical trial for this rare GIST subtype.The median follow-up was 14.5(0.9–57.5)months.Olverembatinib was well tolerated;treatment-emergent adverse events(≥20%)included increases in hepatic transaminases,increases in leukocytes and neutrophils,anemia,and pyrexia.For SDH-deficient GISTs,confirmed partial responses were observed in 6 of the 26 evaluable patients(objective response rate,23.1%;95%CI,9–43.7);an additional 16(61.5%)did not progress during the first 6 months of treatment.This resulted in a clinical benefit rate of 84.6%(95%CI,65.1–95.6),and the median progression-free survival was 25.7 months(95%CI,12.9–NR).As a putative mechanism of action,translational research revealed significant lipid enrichment with the overexpression of lipid uptake-related genes and proteins,including CD36,fatty acid binding proteins,fatty acid transport proteins,and lipid metabolites,in SDH-deficient GIST patients,and olverembatinib suppressed lipid uptake and CD36 expression in GIST cells.Olverembatinib also exerts antitumor effects by inhibiting tumorigenic signaling pathways associated with hypoxia,angiogenesis,proliferation,and survival.
