Effect of Atezolizumab plus Bevacizumab in Patients with Hepatocellular Carcinoma Harboring CTNNB1 Mutation in Early Clinical Experience

Abstract

Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of CTNNB1 contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether CTNNB1 mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of CTNNB1 locus. A total of eight patients (24.2%) exhibited at least one CTNNB1 mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) CTNNB1 was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT CTNNB1 was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT CTNNB1 (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT CTNNB1 was comparable to those patients with WT CTNNB1 . These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by CTNNB1 mutation.

Predicting Outcomes of Atezolizumab and Bevacizumab Treatment in Patients with Hepatocellular Carcinoma

“…When ultradeep sequencing was performed, the TERT promoter, tumor protein 53 (TP53), and catenin beta 1 (CTNNB1) were frequently mutated, but TERT ctDNA mutation was an independent factor predicting poor OS. CTNNB1 mutation was not a significant factor, as found in another study [100]. These findings imply that measuring and profiling ctDNA should be researched with a larger sample size in future studies.…”

Prognostic significance of CTNNB1 mutation in hepatocellular carcinoma: a systematic review and meta-analysis

“…Of note, the treatment effect of Atezolizumab plus bevacizumab in patients with HCC with MT CTNNB1 was comparable to those patients with WT CTNNB1 . These results further implicate that bevacizumab added to Atezolizumab might improve immunosuppressive tumor microenvironment caused by CTNNB1 mutation [ 51 ]. In addition, Chen et al proved that CTNNB1 alternation is a potential biomarker for immunotherapy prognosis in patients with HCC [ 52 ].…”

Effectiveness and safety of atezolizumab-bevacizumab in patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis

“…Four abstracts (through manual search) were also included in the analysis. In total, 47 studies, including 5400 patients with HCC treated with atezo-bev, were included in the analysis 11 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ( Fig. 1 :Flow chart) ( Table 1 and Supplementary Table S1 ).…”

“…Five studies reported types of iRAE. 32 , 33 , 39 , 51 , 66 The most common iRAE was hepatitis in 10 patients, followed by hypothyroidism in nine, rheumatological and musculoskeletal injury in five, skin toxicity and diarrhoea in four each, hypopituitarism, cholangitis, and rush in two each. The remaining iRAEs (pulmonary and neurologic toxicity, colitis, nephritis, mucositis, hyperparathyroidism, and type 1 diabetes mellitus) were reported in one patient each.…”