Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma

Abstract

Introduction Several clinical trials comparing the efficacy and safety of transarterial chemoembolisation (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034). Methods Patients with unresectable HCC were randomised to a TACE plus sorafenib group(N=80) or a TACE alone group(N=76). Patients in the combination treatment group received sorafenib 400 mg once daily for 2–3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable (UnTACEable) progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs baseline) according to RECICL, the detection of extrahepatic spread, vascular invasion or transient deterioration of liver function to Child-Pugh C after TACE. Results At the cut-off date of 31 July 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR]=0.861; 95% confidence interval [CI), 0.607–1.223; P=0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR=0.661; 95% CI, 0.466–0.938; P=0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group (P=0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria. Conclusions In TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034

New treatment paradigm with systemic therapy in intermediate-stage hepatocellular carcinoma

“…However, since the TACTICS trial significantly prolonged the PFS, which was the primary endpoint, the OS result was anticipated, which was the coprimary endpoint. However, the final OS data made available during the ASCO-GI 2021 showed that patients treated with a combination of TACE plus sorafenib had an OS of 36.2 months (95% CI 30.5–44.1), while those with treated with TACE alone had an OS of 30.8 months (95% CI 23.5–40.8, HR 0.86, 95% CI 0.61–1.22; P = 0.40); therefore, the results were considered negative [ 65 ]. The factors contributing to this negative result were as follows: (1) 156 patients set as Phase 2 trial were underpowered to meet the OS endpoint and (2) 76.3% of patients in the TACE alone group received post-treatment (50% of whom were treated with sorafenib), resulting in an extremely long post-progression survival (PPS: 17.3 months).…”

“…The factors contributing to this negative result were as follows: (1) 156 patients set as Phase 2 trial were underpowered to meet the OS endpoint and (2) 76.3% of patients in the TACE alone group received post-treatment (50% of whom were treated with sorafenib), resulting in an extremely long post-progression survival (PPS: 17.3 months). However, considering that the OS results were negative despite the longest OS (36.2 months) and ΔOS (5.4 months) among previous combination trials of TACE and a molecular targeted agent, The results clearly showed it is no longer possible to use OS as the primary endpoint in future trials of TACE plus systemic therapy in an era with various many effective post-treatment options [ 65 ].…”

“…In any case, the results of the TACTICS trial proved that the combination of TACE and molecular targeted agents can prolong the PFS, which is the co-primary endpoint. Considering the correlation between OS HR and PFS HR in the six TACE combination trials to date, the correlation coefficient ( r ) is 0.56, clearly showing that PFS HR was poorly correlated with OS HR [ 65 ]. This result is in contrast to Llovet et al's plot of PFS HR and OS HR for primary and second-line agents used in patients with advanced HCC, which shows a moderate correlation coefficient of R =0.84 [ 57 , 66 ].…”

“…In the case of combination therapy with TACE and molecular targeted agents, the impact of PPS prolongation with post-treatment is much stronger than that with first- and second-line treatments for advanced HCC, and the actual impact of PFS on OS is much weaker, which possibly led to the negative results. In addition, the regression line of the correlation of the six trials to date are somewhat smoother than those for advanced HCC, suggesting that the TACE combination trial was more strongly influenced by PPS [ 65 ]. In the future, as recently stated in the AASLD guidelines, the PFS [ 57 ]or ORR [ 67 ] could be used as surrogate endpoint for TACE combination trial since PPS has improved and OS can no longer be verified due to the effect of multiple highly effective post-treatment therapies.…”

Trial Designs for Integrating Novel Therapeutics into the Management of Intermediate-Stage Hepatocellular Carcinoma

“… 91–94 The complexity of study design issues has been extensively reviewed elsewhere to get insight from previous trials. 22 , 95 Most trials incorporated more detailed definition of patient characteristics (e.g., ALBI grade, 96 , 97 HAP score, 6 , 98 , 99 AFP level 100 ) and treatment patterns (e.g., geographic regions or study sites, drug-eluting beads versus conventional TACE) in the hope of better stratification for this very heterogeneous patient population. Several trials incorporated TACE-specific endpoints, such as time to TACE progression (TTTP), to avoid confounding by post-progression therapy.…”