Atezolizumab and bevacizumab plus TACE improves TACE-PFS to 11.30 months versus 7.03 monthsAdding two drugs to TACE improves progression-free survival

BACKGROUND: TACE is the standard treatment for intermediate-stage hepatocellular carcinoma but has limited survival benefits. TALENTACE evaluated adding atezolizumab and bevacizumab to on-demand TACE versus on-demand TACE alone in patients with systemically untreated, intermediate-to-high tumour burden unresectable hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 study at 40 centres in China and Japan, patients aged 18 years or older with confirmed, unresectable hepatocellular carcinoma and an anticipated life expectancy of 12 months or more were eligible for inclusion. Eligible patients were required to have an Eastern Cooperative Oncology Group performance status of 0-1, Child-Pugh class A liver function, no previous systemic therapy, and a sum of tumour maximum diameter (cm) and lesion number of six or more based on the six-and-twelve score. Patients were randomly assigned (1:1), using a permuted-block method implemented via an interactive voice and web response system, to on-demand TACE plus atezolizumab 1200 mg intravenously and bevacizumab 15 mg/kg intravenously once every 3 weeks (initiated 14 days to 8 weeks after TACE), or on-demand TACE alone, with TACE administered at the investigators' discretion. The randomisation sequence was generated by an independent biostatistician at the system vendor and was concealed from the sponsor study team and investigators until randomisation; allocation was stratified by baseline α-fetoprotein, prior locoregional therapy, and baseline Vp1/2 (and geographic region in earlier protocol versions). Primary endpoints were investigator-assessed TACE progression-free survival (TACE-PFS; time from randomisation to untreatable [unTACEable] progression, TACE failure or refractoriness, or death), and overall survival, both analysed in the intention-to-treat population. Overall survival was assessed under a prespecified adaptive (group sequential) design comprising two interim analyses and one final analysis. Safety was evaluated in the as-treated population, defined as all randomised patients who received any study treatment, analysed according to the treatment received. This study is registered with ClinicalTrials.gov (NCT04712643) and is ongoing. FINDINGS: Between Feb 23, 2021, and August 11, 2023, 342 patients were randomly assigned to TACE plus atezolizumab and bevacizumab (n=171) or on-demand TACE alone (n=171). Median age was 61·0 years (range 21·0-90·0), 66 (19%) of 342 participants were female, 276 (81%) were male, 308 (90%) were Chinese, and 34 (10%) were Japanese. The mean size of the largest target lesion per RECIST 1.1 was 7·7 cm (SD 4·3) in both arms. In the TACE plus atezolizumab and bevacizumab group, 36 (21%) of 171 patients were Barcelona Clinic Liver Cancer stage A, 100 (58%) were stage B, and 35 (20%) were stage C; in the TACE alone group, 42 (25%) of 171 patients were Barcelona Clinic Liver Cancer stage A, 105 (61%) were stage B, and 24 (14%) were stage C. At data cutoff (Feb 28, 2025; median follow-up 26·25 months [IQR 21·16-33·74]), median TACE-PFS was 11·30 months (95% CI 7·52-15·01) with TACE plus atezolizumab and bevacizumab versus 7·03 months (95% CI 5·32-8·41) with TACE alone (hazard ratio [HR] 0·71 [95% CI 0·55-0·92]; two-sided stratified log-rank p=0·0089). Overall survival remains immature and was assessed at the first of the prespecified interim analyses; median overall survival was 34·53 months (99·62% CI 24·80-not evaluable) in the TACE plus atezolizumab and bevacizumab group compared with 35·38 months (99·62% CI 24·74-not evaluable) in the TACE alone group (HR 0·96 [99·62% CI 0·58-1·58]). The most common grade 3-4 adverse events in the TACE plus atezolizumab and bevacizumab group were decreased platelet count (23 [14%] of 166), hypertension (23 [14%]), and post-embolisation syndrome (21 [13%]); in the TACE alone group, the most common were post-embolisation syndrome (23 [13%] of 173), decreased platelet count (12 [7%]), and increased aspartate aminotransferase (12 [7%]). The most common serious adverse event was ascites (eight [5%]) in the TACE plus atezolizumab and bevacizumab group and post-embolisation syndrome (six [3%]) in the TACE alone group. Treatment-related deaths occurred in five patients in the TACE plus atezolizumab and bevacizumab group (gastrointestinal haemorrhage, liver abscess, haemolytic anaemia, hypertension, and unknown death) and three patients in the TACE alone group (post-procedural haemorrhage, ascites, and unknown death). No new safety signals were identified. INTERPRETATION: On-demand TACE plus atezolizumab and bevacizumab significantly improved TACE-PFS versus on-demand TACE alone. Overall survival follow-up is ongoing. FUNDING: Shanghai Roche Pharmaceuticals.