A Prospective, Single-Arm, Phase 2 Study of Modified Transarterial Chemoembolization Using Low-Dose Chemotherapy with Blank Microspheres Plus Low-Dose Lenvatinib and Microwave Ablation in Patients with Large (≥7 cm) Unresectable Hepatocellular Carcinoma: The TALEM Trial

Abstract

Introduction: For patients with large unresectable hepatocellular carcinoma (HCC), the effectiveness of conventional transarterial chemoembolization (cTACE) remains suboptimal. This study investigated the efficacy and safety of modified TACE using low-dose chemotherapy with blank microspheres (BMS-TACE) plus low-dose lenvatinib (LD-LEN) and microwave ablation (MWA) in patients with large unresectable HCC.

Methods: In this prospective, single-arm, phase 2 study, patients with unresectable HCC exceeding the up-to-seven criteria, with maximum tumor diameter ≥7 cm, and without macrovascular invasion or extrahepatic metastases, received initial BMS-TACE (lipiodol, low-dose doxorubicin, and lobaplatin up to 30 mg each, and blank microspheres; subsequently modified and repeated in most patients) plus LD-LEN (4-8 mg/day) and MWA. The primary endpoint was downstaging rate (DSR); secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events.

Results: From November 2019 to March 2022, 43 patients were enrolled. Median follow-up was 21.2 months. Median largest tumor diameter was 11.2 cm (interquartile range [IQR], 7-25). Following BMS-TACE and LD-LEN, downstaging occurred in 37 (86.0%) patients, 32 of whom received MWA, and 8 of whom had a complete response (CR) without MWA. ORR was 93.0% (CR in 32 [74.4%] and partial response in 8 [18.6%] patients). The 1-, 2-, and 3-year PFS rates were 57.5%, 25.9%, and 18.1%, respectively (median PFS, 14.7 months [95% CI: 8.1-19.5]). The 1-, 2-, and 3-year OS rates were 85.8%, 67.7%, and 61.6%, respectively (median OS, 36.4 months [95% CI: 26.8-not reached]). After BMS-TACE, a significant decline in CD11b+/CD33+/HLA-DR- myeloid-derived suppressor cells and early elevation in CXCR5+/CD8+ and CXCR5+/CD4+ T cells were observed (both p < 0.05).

Conclusion: BMS-TACE plus LD-LEN and MWA resulted in promising efficacy and tolerable toxicity in patients with large unresectable HCC exceeding the up-to-seven criteria with a maximum tumor diameter ≥7 cm and without macrovascular invasion or extrahepatic metastases.

Keywords: Blank microsphere transarterial chemoembolization; Large unresectable hepatocellular carcinoma; Levatinib.

Fig. 1.

Schematic representations of treatment protocol and patient disposition in the TALEM Trial.

Fig. 2.

Treatment responses and changes in tumor sizes, based on mRECIST, after treatment with the TALEM protocol, of 43 patients with HCC. a Bar graph of changes from baseline of sums of diameters of target tumors of patients, shown by individual patient response (i.e., CR, PR, SD, or PD). b Swimmer’s Plot showing clinical course tracking of each patient, demonstrating clinical characteristics, treatments received, timing of TACE and MWA treatments, responses to treatment, and overall durations of treatment and follow-up. c Scatter plot of changes from baseline of sums of diameters of target tumors of all patients over the duration of the study and by type of patient response (i.e., CR, PR, SD, or PD).

Fig. 3.

Kaplan-Meier estimates of OS and PFS rates, based on mRECIST, of 43 patients with HCC who were enrolled in the TALEM Trial from November 2019 through March 2022.

Fig. 4.

Variations in systemic immunity in 18 patients with HCC after initial BMS-TACE treatment as part of the TALEM Trial. a Phenotypic marker expression patterns are shown in tSNE plots of PBMCs. b Heat map of the changes in peripheral T-cell subsets and myeloid cell subsets in patients before and after BMS-TACE. c Proportions of T-cell and myeloid cell subgroups on Day 0 before and Day 1 after BMS-TACE, compared using one-way ANOVA analysis with Bonferroni post hoc test, with p < 0.05 designated by asterisk (*). d Kaplan-Meier overall survival curves comparing the patient subgroup in which CXCR5+CD8 increased with the subgroup in which it decreased, demonstrating a non-significant (p = 0.15) survival advantage in the subgroup in which CXCR5+CD8 increased. e Kaplan-Meier overall survival curves comparing the patient subgroup in which M-MDSCs increased with the subgroup in which they decreased, demonstrating a significant (p = 0.02) survival advantage in the subgroup in which M-MDSCs decreased.