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 superselective 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, superselective 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 3 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.

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.

Keywords: Ablation; Atezolizumab plus bevacizumab; Cancer-free; Curative conversion; Hepatocellular carcinoma; Resection; Transarterial chemoembolization; Treatment-free.

Fig. 1.

ABC conversion: Patient flow. Atezolizumab followed by curative conversion was performed in 39 patients. Of them, 35 patients achieved clinical complete response (CR) defined by CR per mRECIST and normalized 3 tumor markers ≥6 weeks. Clinical CR with drug-free status was achieved 25 of 38 patients.

Fig. 2.

Achievement rate of complete response in intermediate-stage HCC. Among 110 Child-Pugh A transarterial chemoembolization (TACE)-unsuitable intermediate-stage HCC patients who received Atezo/Bev therapy as first-line treatment, 38 (35%) achieved complete response by curative conversion. Among the 38 patients, 25 (25/110, 23%) are currently drug-free status. ABC, Atezo/Bev therapy followed by curative conversion; HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; MWA, microwave ablation.

Fig. 3.

Swimmer plot of 38 patients who achieved complete response with or without drug-free status. Complete response was achieved with resection, superselective TACE with curative intent, RFA, and MWA, and 25 cases reached drug-free status (blue color). RFA, radiofrequency ablation; MWA, microwave ablation; LEN-TACE, lenvatinib-transarterial chemoembolization; Dx, diagnosis; ATZ+BV, atezolizumab plus bevacizumab.

Fig. 4.

PFS (CR maintenance rate). a Median PFS of the 38 cases that achieved clinical CR was not reached. b There was no recurrence from the patients with CR and drug-free status. There were 3 recurrences, who received TACE alone (n = 2) or Atezo/Bev alone (n = 1). c Median PFS since atezolizumab plus bevacizumab initiation. Median PFS in patients who achieved clinical CR by curative conversion was much better than those who did not receive curative conversion or did not achieve CR (HR 0.031, p < 0.001). d Median OS since atezolizumab plus bevacizumab initiation. Median OS in patients who did not receive curative conversion or did not achieve clinical CR was 18.5 months (95% CI, 13.4–23.7). There was no death who achieved clinical CR by curative conversion. CR, complete response; ABC, atezolizumab plus bevacizumab followed by curative conversion; OS, overall survival; PFS, progression-free survival.

Fig. 5.

Case of a patient with PET-positive HCC who underwent ABC conversion. a A solitary HCC measuring 12 cm in size was observed in segment 8. Heterogeneous staining is shown in the arterial phase of dynamic CT. A necrotic area was observed in the tumor. b Heterogeneous morphology, suggesting confluent multinodular gross pathological type, is also observed in the equilibrium phase of dynamic CT. A necrotic portion was also observed in the tumor. c FDG-PET showed an extremely strong accumulation of FDG except in the necrotic area. d Coronal image of FDG-PET before Atezo/Bev therapy. e Coronal image of FDG-PET-CT 6 months after six cycles of Atezo/Bev therapy followed by LEN-TACE sequential therapy. Disappearance of FDG accumulation and tumor shrinkage is observed. f Laparoscopic subsegmentectomy was performed. A microscopic image of the resected specimen shows complete pathological necrosis. g The tumor was necrotic in a low-magnification view of the resected specimen. h No viable tumor was found in the high-magnification image of the resected specimen. FDG-PET, fluorodeoxyglucose-positron emission tomography; LEN-TACE, lenvatinib-transarterial chemoembolization; HCC, hepatocellular carcinoma; CT, computed tomography.

Fig. 6.

Time to complete response by FDG-PET positivity. PET-CT was performed in 20 cases. Seven cases were PET-positive HCCs, and 13 were PET-negative HCCs. The time to complete response evaluated by CT/MRI and 3 tumor markers in FDG-PET-positive HCCs was 6.7 months, which was faster than the 8.8 months in PET-negative HCCs (HR = 5.0; 95% CI, 1.4–17.6, p = 0.012). FDG-PET, fluorodeoxyglucose-positron emission tomography.

Fig. 7.

Heterogeneity and possibility of curative conversion in intermediate-stage HCC. TACE is technically possible in intermediate-stage HCC. However, since selective TACE is not possible in some population of intermediate-stage HCC, TACE is not suitable oncologically. Curative conversion can achieve complete response in such cases. Curative conversion might be difficult in very high tumor burden, especially in bilobar multifocal disease (>10 nodules) or exceeding up-to-11 criteria. CMN, confluent multinodular type; SNEG, simple nodular with extra growth type.