Peripheral naive CD8+ T cells as a predictive biomarker of response to lenvatinib plus an anti-PD-1 antibody in advanced hepatocellular carcinoma: a biomarker study.
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SUBMITTER: Huang C
PROVIDER: S-EPMC9648393 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
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Peripheral naïve CD8<sup>+</sup> T cells as a predictive biomarker of response to lenvatinib plus an anti-PD-1 antibody in advanced hepatocellular carcinoma: a biomarker study.
Huang Cheng C Xu Bin B Zhu Xiao-Dong XD Shen Ying-Hao YH Li Mei-Ling ML Zhu Jin-Jin JJ Zhou Jian J Fan Jia J Sun Hui-Chuan HC
Cancer communications (London, England) 20220822 11
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Project description:BackgroundLenvatinib combined with pembrolizumab showed a promising result in an early phase study for hepatocellular carcinoma (HCC). The efficacy and safety of lenvatinib plus pembrolizumab for patients with unresectable HCC (uHCC) beyond the first-line setting were unclear.MethodsSeventy-one consecutive patients who received lenvatinib plus pembrolizumab for uHCC were prospectively enrolled. Effect of lenvatinib combinations on Albumin-Bilirubin (ALBI) score and factors associated with progression-free survival (PFS) and overall survival (OS) were analyzed.ResultsOf the 71 cases, 58 (81.7%) were in BCLC C. There were 44 (62%) for the first-line systemic treatment, and 27 (38%) had experienced targeted therapy or nivolumab treatment. The objective response rate and disease control rate (DCR) were 34.1% and 84.1% for the first-line setting, and 18.5% and 70.4% for systemic therapy-experienced cases (Response Evaluation Criteria in Solid Tumors version 1.1, RECIST v1.1), respectively. The mean ALBI score was stable during the treatment course. After a median of 9.3 months of follow-up, the median PFS was 9.3 months versus 4.4 months, and the median OS was not estimable yet versus 12 months for Child-Pugh A versus B patients, respectively. Prior nivolumab failure was the only significant factor associated with poorer PFS (HR = 3.253, p = 0.004). Child-Pugh class B (HR = 2.646, p = 0.039) and prior nivolumab failure (HR = 3.340, p = 0.014) were independent factors for poorer OS in multivariate analysis.ConclusionsA high DCR was observed by lenvatinib/pembrolizumab combination without adverse effect on ALBI score for systemic therapy-naïve and -experienced uHCC. Suboptimal response to prior nivolumab-failed patients requires further exploration.
| S-EPMC9519717 | biostudies-literature
Project description:BackgroundLenvatinib combined with programmed cell death protein-1 (PD-1) inhibitors has resulted in good survival outcomes in the treatment of unresectable hepatocellular carcinoma (HCC). Hepatic artery infusion chemotherapy (HAIC) has also attracted attention due to its high response rates and favorable survival for advanced HCC patients. The present study aimed to compare the efficacy of HAIC combined with PD-1 inhibitors plus lenvatinib (HPL) and PD-1 inhibitors plus lenvatinib (PL) in patients with advanced HCC.MethodsBetween July 2018 and December 2019, patients diagnosed with advanced HCC who initially received HPL or PL treatment were reviewed for eligibility. Efficacy was evaluated according to tumor response and survival.ResultsIn total, 70 patients met the criteria and were included in the present study, and they were divided into the HPL group (n = 45) and PL group (n = 25). The overall response rate (40.0 vs. 16.0%, respectively; p = 0.038) and disease control rate (77.6 vs. 44.0%, respectively; p < 0.001) were higher in the HPL group than in the PL group. The median overall survival was 15.9 months in the HPL group and 8.6 months in the PL group (p = 0.0015; HR = 0.6; 95% CI 0.43-0.83). The median progression-free survival was 8.8 months in the HPL group and 5.4 months in the PL group (p = 0.0320; HR = 0.74; 95% CI 0.55-0.98).ConclusionCompared to PL, HPL was associated with a significantly better treatment response and survival benefits for patients with advanced HCC.
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Project description:Background: Programmed cell death protein-1 inhibitors combined with lenvatinib have become a popular treatment option for patients with unresectable hepatocellular carcinoma. Transarterial chemoembolization combined with programmed cell death protein-1 inhibitors and lenvatinib has also shown preliminary efficacy in the unresectable hepatocellular carcinoma. We conducted this observational, retrospective, cohort study to compare the clinical outcomes and safety of transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib versus programmed cell death protein-1 inhibitors plus lenvatinib in patients with unresectable hepatocellular carcinoma. Methods: Between November 2019 and November 2021, patients who were diagnosed with unresectable hepatocellular carcinoma and received transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib or programmed cell death protein-1 inhibitors plus lenvatinib treatment were reviewed for eligibility. The primary endpoints included objective response rate, overall survival, and progression-free survival. The secondary endpoint was the frequency of key adverse events. Results: In total, 105 patients were eligible for the present study, and they were divided into the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group (n = 46) and the programmed cell death protein-1 inhibitors plus lenvatinib group (n = 59). The patient cohort after a one-to-one propensity score matching (n = 86) was also analyzed. The transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had a higher objective response rate both in the patient cohort before propensity score matching (54.3% vs 25.4%, P = .002) and after propensity score matching (55.8% vs 30.2%, P = .017). The patients in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had prolonged overall survival (median, 20.5 vs 12.6 months, P = .015) and progression-free survival (median, 10.2 vs 7.4 months, P = .035). For patient cohort- propensity score matching, the overall survival (20.5 vs 12.8 months, P = .013) and progression-free survival (12.1 vs 7.8 months, P = .030) were also significantly better in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group than in the programmed cell death protein-1 inhibitors plus lenvatinib group. There were no significant differences between the 2 groups concerning adverse reactions caused by immunotherapy and lenvatinib. The adverse reactions caused by transarterial chemoembolization were transient and were quickly reversed. Conclusions: Compared to programmed cell death protein-1 inhibitors plus lenvatinib, transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib may provide better treatment response and survival benefits for patients with unresectable hepatocellular carcinoma, and the adverse events were manageable.
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Project description:Background Lenvatinib, regorafenib and anti-programmed cell death protein-1 (PD-1) immunotherapy have shown promising clinical outcomes in patients with advanced hepatocellular carcinoma (HCC) after sorafenib failure, respectively. However, the combination of the two treatments has not been reported. We compared the efficacy of PD-1 inhibitors with lenvatinib (PL) and PD-1 inhibitors plus regorafenib (PR) in patients with advanced HCC in this study. Methods We conducted a retrospective study of advanced HCC patients who undergone PD-1 inhibitors combined with lenvatinib or regorafenib after failure of sorafenib at Second Affiliated Hospital of Nanchang University from July 2018 and December 2020. The overall survival (OS), progression-free survival (PFS), effective rates and treatment-related adverse events (TRAEs) were investigated. Results In total, 61 patients met the criteria and were included in the present study, and they were divided into the PL group (n = 32) and PR group (n = 29). The overall response rate (ORR) (12.5%vs. 10.3%, respectively; p = 0.557) and disease control rate (DCR) (71.9%vs. 58.6%, respectively; p < 0.207) were higher in the PL group than in the PR group, but there was no statistical difference. Furthermore, median PFS and OS were not significantly different between the two groups in Kaplan-Meier survival analysis (PFS: 5.3 months vs 4.0 months, p = 0.512; OS: 14.1 months vs 13.7 months, p = 0.764 for the PL group vs PR group). The most common treatment-related adverse events (TRAEs) were hand -foot skin reaction (24/61,39.3%), hypertension (20/61,32.8%) and hypothyroidism (13/61,21.3%). The frequent TRAEs (≥Grade 3) during PD-1 inhibitors plus lenvatinib or regorafenib treatment were hand-foot skin reaction (5/29,12.4%), thrombocytopenia (2/29 6.90%) and proteinuria (n =2/32,6.25%). Conclusions Combination of lenvatinib/regorafenib and PD-1 inhibitors is a promising therapy for HCC patients after sorafenib failure.
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Project description:BackgroundLocoregional treatment combined with systemic therapy is expected to play a synergistic anticancer role. We conducted this systemic meta-analysis to examine the efficacy and safety of transarterial chemoembolization (TACE) plus lenvatinib with or without programmed cell death protein-1 (PD-1) inhibitors (TLP group) compared with TACE + lenvatinib (TL group) for unresectable hepatocellular carcinoma (uHCC).MethodsFrom the inception date to April 2024, the data from PubMed, EMBASE, the Cochrane Library, Ovid, Web of Science, and Clinical Trials. gov were used for meta-analysis. All clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). The hazard ratio (HR) and risk ratio (RR) with 95% confidence intervals (CI) were used to measure the pooled effect.ResultsThis study included 10 retrospective cohort studies, including 1128 patients. The OS (HR=0.51; 95% CI: 0.43-0.60, P < 0.05), PFS (HR=0.52; 95% CI: 0.45-0.61, P < 0.05), ORR (RR = 1.58; 95% CI: 1.37-1.83; P < 0.05) and DCR (RR = 1.31; 95% CI: 1.20-1.43; P < 0.05) were significantly higher in TLP group than in the TL group. The incidence of AEs was acceptable. Prognostic factor analysis identified that ECOG PS (1/0), Child-Pugh class (B/A), BCLC stage (C/B) and main portal vein invasion (yes/no) were independent prognostic factors for OS. BCLC stage (C/B) and main portal vein invasion (yes/no) were independent prognostic factors for PFS.ConclusionThe TLP group had better efficacy for uHCC than that of the TL group, with acceptable safety.Systematic review registrationPROSPERO, identifier (CRD42023420093).
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Project description:The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1+ CXCL10+ macrophages and, based on cell-cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3+ CD8+ effector-memory T cells (CD8 TEM) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 TEM preferentially differentiate into clonally-expanded PD1- CD45RA+ effector-memory CD8+ T cells (CD8 TEMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 TEM remain frozen in their effector-memory state. Finally, in responders, CD8 TEMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC.
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Project description: Not available
| S-EPMC11020267 | biostudies-literature
Project description:PurposeTo investigate the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus PD-1 inhibitor (TACE-L-P) versus TACE combined with lenvatinib (TACE-L) for patients with advanced hepatocellular carcinoma (HCC).Materials and methodsData of advanced HCC patients treated with TACE-L-P (TACE-L-P group) or TACE-L (TACE-L group) from January 2019 to December 2020 were prospectively collected and retrospectively analyzed. The differences in overall survival (OS), progression-free survival (PFS), tumor responses (based on modified Response Evaluation Criteria in Solid Tumors) and adverse events (AEs) were compared between the two groups. Potential factors affecting OS and PFS were determined.ResultsA total of 81 patients were included in this study. Among them, 41 received TACE-L-P and 40 received TACE-L. The patients in TACE-L-P group had prolonged OS (median, 16.9 vs. 12.1 months, P=0.009), longer PFS (median, 7.3 vs. 4.0 months, P=0.002) and higher objective response rate (56.1% vs. 32.5%, P=0.033) and disease control rate (85.4% vs. 62.5%, P=0.019) than those in TACE-L group. Multivariate analyses revealed that the treatment option of TACE-L, main portal vein invasion and extrahepatic metastasis were the independent risk factors for OS, while TACE-L and extrahepatic metastasis were the independent risk factors for PFS. In subgroup analyses, a superior survival benefit was achieved with TACE-L-P in patients with extrahepatic metastasis or tumor number >3 but not in those with main portal vein invasion. The incidence and severity of AEs in TACE-L-P group were comparable to those in TACE-L group (any grade, 92.7% vs. 95.0%, P=1.000; grade 3, 36.6% vs. 32.5%, P=0.699).ConclusionTACE-L-P significantly improved survival over TACE-L with an acceptable safety profile in advanced HCC patients, especially those with extrahepatic metastasis or tumor number >3 but without main portal vein invasion.
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Project description:BackgroundLenvatinib, a multi-targeted tyrosine kinase inhibitor (TKI), has proven efficacy as the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, there is no standard effective second-line treatment option following progression on lenvatinib therapy. Because of the comprehensive coverage of therapeutic targets of lenvatinib, the remission rate of other TKI treatments in HCC patients resistant to lenvatinib is quite low.MethodsIn this study, the effectiveness and safety of anti-programmed cell death protein-1 (PD-1) antibodies plus lenvatinib were assessed in 46 patients between April 2018 and April 2020 at the Zhongshan Hospital, Fudan University, by retrospectively reviewing their clinical data. Patients with unresectable HCC who progressed on lenvatinib were given standard doses of lenvatinib and anti-PD-1 antibodies. They were followed-up every 6-8 weeks with medical imaging and laboratory tests and treatment-related adverse reactions were investigated.ResultsThe objective response and the disease control rates were 23.9% (11/46) and 71.7% (33/46), respectively by Response Evaluation Criteria in Solid Tumours 1.1 (RECIST). After a median follow-up period of 15.6 [interquartile range (IQR), 11.2-22.0] months, the median progression-free survival (PFS) and overall survival (OS) were 6.9 months [95% confidence interval (CI): 2.1-11.8] and 14.5 months (95% CI: 6.8-22.3), respectively. The most common treatment-related adverse events were anorexia (43.5%), hypothyroidism (43.5%), hypertension (36.9%), fatigue (34.8%), and diarrhea (26.1%). Grade 3/4 events occurred in 16 patients (34.8%). Emotional functioning and overall quality of life were improved significantly following the initiation of anti-PD-1 antibodies plus lenvatinib therapy (fatigue, 4.9±7.5 vs. 11.1±12.7, P=0.03; diarrhea, 12.3±20.9 vs. 18.5±16.8, P=0.01; pain, 5.5±10.3 vs. 11.1±13.9, P=0.01).ConclusionsThe combination of anti-PD-1 antibodies and lenvatinib may benefit patients with unresectable HCC who progressed on lenvatinib. This study provides a real-world data and treatment choice for patients progressed with lenvatinib.
| S-EPMC9459189 | biostudies-literature
Project description:PurposeThe combination therapy of lenvatinib and immunotherapy as first-line treatment remains controversial in unresectable hepatocellular carcinoma (uHCC). This research aimed to compare the efficacy and safety of lenvatinib monotherapy (L) and combination therapy of lenvatinib and immune checkpoint inhibitor (LI) in lenvatinib-insensitive patients with uHCC.MethodsTwo hundred fifty-five uHCC patients were enrolled in this study. Patients were classified into two groups: (1) Lenvatinib monotherapy (L); (2) Combination therapy (LI). Patients who remained stable disease (SD) but did not achieve complete response (CR) or partial response (PR) or progression disease (PD) for at least 3 months after receiving lenvatinib monotherapy were defined as lenvatinib-insensitive. Overall survival (OS) and progression-free survival (PFS), baseline characteristics, and safety were compared between groups.ResultsThe LI group had longer OS (15.9 months vs. 11.9 months, P = 0.001) and PFS (12.6 months vs. 7.3 months, P < 0.001) than the L group. ECOG PS was an independent prognostic factor affecting OS and Up-to-seven was an independent prognostic factor affecting PFS. The frequency of grade ≥ 3 treatment-related adverse events (TRAEs) was not significantly different.ConclusionsOur study demonstrated that the combination therapy (LI) had longer OS and PFS than the lenvatinib monotherapy (L) in lenvatinib-insensitive patients with uHCC.
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