Achievement of Complete Response and Drug-Free Status by Atezolizumab plus Bevacizumab Combined with or without Curative Conversion in Patients with Transarterial Chemoembolization-Unsuitable, Intermediate-Stage Hepatocellular Carcinoma: A Multicenter Proof-Of-Concept Study

Abstract

Introduction: Atezolizumab plus bevacizumab therapy is extremely effective in the treatment of intermediate-stage hepatocellular carcinoma (HCC), with a response rate of 44%, as reported in the IMbrave150 trial. When tumor shrinkage is obtained, achieving complete response (CR) is possible in many cases using curative conversion with resection, ablation, or super selective transarterial chemoembolization (TACE) with curative intent. This concept, i.e., curative conversion by combining systemic therapy and locoregional therapy, has not been reported before. This multicenter proof-of-concept study was conducted to show the value of curative conversion in immunotherapy-treated intermediate-stage HCC meeting TACE-unsuitable criteria. Methods: This study included 110 consecutive Child-Pugh A patients who received atezolizumab plus bevacizumab as first-line treatment for unresectable and TACE-unsuitable intermediate-stage HCC at seven centers in Japan. CR rate, drug-free rate, time to CR, change in liver function, efficacy in positron emission tomography (PET)-positive HCC, progression-free survival (PFS), and overall survival (OS) were assessed in patients who achieved CR using resection, ablation, super selective TACE with curative intent following atezolizumab plus bevacizumab or atezolizumab plus bevacizumab alone. Results: Clinical or pathological CR was achieved in 38 patients (35%) (median observation period: 21.2 months). The modalities of curative conversion in 35 patients were as follows: resection, 7; ablation, 13; and superselective TACE, 15. Three patients achieved clinical CR with atezolizumab plus bevacizumab therapy alone. Among the 38 CR patients, 25 achieved drug-free status. PFS was not reached, and three patients experienced recurrence after reaching CR. Regarding OS, there were no deaths in any of the CR patients. The albumin-bilirubin score did not deteriorate after locoregional therapy or resection. Of seven PET-positive patients who achieved CR with atezolizumab plus bevacizumab followed by curative conversion, five achieved drug-free status. Discussion/Conclusion: The achievement of CR rate by curative conversion in patients treated with atezolizumab plus bevacizumab as the preceding therapy for unresectable and TACE-unsuitable intermediate-stage HCC was 35%. Overall, 23% of patients achieved drug-free status and no recurrence was observed from this patient subgroup with CR and drug free status. Thus, achieving CR and/or drug-free status should be a therapeutic goal for patients with intermediate-stage HCC without vascular invasion or extrahepatic spread.

Surveillance, Diagnosis, and Treatment Outcome of Hepatocellular Carcinoma in Japan: 2023 Update

“…The effectiveness of such systemic therapy has also contributed to the recent improvements in treatment outcomes for HCC. In Japan, sorafenib-TACE sequential therapy, which was initially investigated as a treatment for intermediate-stage HCC in patients unsuitable for TACE [45][46][47], stimulated the development and widespread adoption of similar approaches such as lenvatinib-TACE sequential therapy [48][49][50] and ABC conversion therapy [51][52][53], which have also produced favorable treatment outcomes.…”

The Society for Immunotherapy of Cancer clinical practice guideline on immunotherapy for hepatocellular carcinoma

“…This concept is also being demonstrated in clinical practice. Recent data shows that Atezo/Bev plus locoregional therapy resulted in curative conversion in 35% of patients and cancer-free status in 23% of patients (11)(12)(13)(14).…”

“…Atezo/Bev followed by curative conversion (ABC conversion) (combination of locoregional therapy with Atezo/Bev) is effective for intermediate-stage HCC ( 14 ).…”

Current Therapeutic Strategies for Hepatocellular Carcinoma in Japan

“…If tumor shrinkage is achieved with Atezo/Bev combination therapy, curative conversion should be considered while systemic therapy is effective to ensure the optimal timing for achieving clinical CR. Therefore, it is crucial to consider whether curative conversion is possible [62,[73][74][75]. Because OS is prolonged in patients who achieve curative conversion, the treatment strategy for intermediate-stage HCC should be different from the conventional sequential systemic therapy for advanced HCC [76].…”