Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma(uHCC)due to limited evidence supporting its efficacy.To address this gap,we initiated a prospective phase 2 multicente...Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma(uHCC)due to limited evidence supporting its efficacy.To address this gap,we initiated a prospective phase 2 multicenter trial(NCT04997850)comparing the LEN-TAP regimen,combining lenvatinib,transarterial chemoembolization(TACE),and PD-1 inhibitors,against TACE alone in uHCC patients.The study’s primary outcome was salvage liver resection(SLR)rate;secondary measures included objective response rate(ORR),overall survival(OS),event-free survival(EFS),recurrence-free survival(RFS),and safety profile.From October 2020 to November 2021,142 eligible participants were assigned to LEN-TAP(n=71)or TACE monotherapy(n=71).At a median follow-up of 24.2 months,the LEN-TAP cohort exhibited a significantly higher SLR rate(59.2%vs.18.3%,P<0.001)and ORR(78.9%vs.16.9%,P<0.001).Median OS,EFS,and RFS were also substantially prolonged in the LEN-TAP cohort(not reached vs.23.0 months,P<0.001;20.03 vs.6.52 months,P<0.001;36.6 vs.19.0 months,P=0.048).Although grade 3 treatment-related AEs occurred more frequently with LEN-TAP(60.6%vs.21.1%,P<0.001),no grade 4 or higher toxicities were observed.Exploratory biomarker assessments via single-cell sequencing and flow cytometry linked elevated levels of circulating HLA-DR+CD38+CD8+T cells with improved treatment response.These T cells appear to mediate antitumor activity potentially through the CXCR6-PI3K-AKT signaling axis.In summary,the LEN-TAP protocol demonstrates promising efficacy and acceptable tolerability as a conversion therapy in uHCC,with peripheral HLA-DR+CD38+CD8+T cell abundance serving as a potential predictor of therapeutic benefit.展开更多
基金supported in part by grants from the National Key R&D Program of China(No.2022YFC2503701)the Science and Technological Supports Project of Sichuan Province(No.2024YFFK0313)+2 种基金the 1·3·5 project for disciplines of excellence-Clinical Research Incubation Project,West China Hospital,Sichuan University(No.2022HXFH012)Preliminary findings from this study were previously disclosed at the ASCO Gastrointestinal Cancers Symposium(January 20-22,2022)the ESMO Congress on Hepatobiliary Cancers(September 9-13,2022).
文摘Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma(uHCC)due to limited evidence supporting its efficacy.To address this gap,we initiated a prospective phase 2 multicenter trial(NCT04997850)comparing the LEN-TAP regimen,combining lenvatinib,transarterial chemoembolization(TACE),and PD-1 inhibitors,against TACE alone in uHCC patients.The study’s primary outcome was salvage liver resection(SLR)rate;secondary measures included objective response rate(ORR),overall survival(OS),event-free survival(EFS),recurrence-free survival(RFS),and safety profile.From October 2020 to November 2021,142 eligible participants were assigned to LEN-TAP(n=71)or TACE monotherapy(n=71).At a median follow-up of 24.2 months,the LEN-TAP cohort exhibited a significantly higher SLR rate(59.2%vs.18.3%,P<0.001)and ORR(78.9%vs.16.9%,P<0.001).Median OS,EFS,and RFS were also substantially prolonged in the LEN-TAP cohort(not reached vs.23.0 months,P<0.001;20.03 vs.6.52 months,P<0.001;36.6 vs.19.0 months,P=0.048).Although grade 3 treatment-related AEs occurred more frequently with LEN-TAP(60.6%vs.21.1%,P<0.001),no grade 4 or higher toxicities were observed.Exploratory biomarker assessments via single-cell sequencing and flow cytometry linked elevated levels of circulating HLA-DR+CD38+CD8+T cells with improved treatment response.These T cells appear to mediate antitumor activity potentially through the CXCR6-PI3K-AKT signaling axis.In summary,the LEN-TAP protocol demonstrates promising efficacy and acceptable tolerability as a conversion therapy in uHCC,with peripheral HLA-DR+CD38+CD8+T cell abundance serving as a potential predictor of therapeutic benefit.
