BTCRC-GI20-457: A phase II study of atezolizumab and bevacizumab in Child-Pugh B7 hepatocellular carcinoma (the AB7 Trial)

TPS493 Background: Both the incidence and death rate of hepatocellular carcinoma (HCC) are on the rise in the United States, and overall, the prognosis is grim. First-line treatment options for patients with advanced disease previously included tyrosine kinase inhibitors (TKIs) which have resulted in a median overall survival (OS) of less than a year. Combinations of immune checkpoint inhibitors (CPIs) with vascular endothelial growth factor (VEGFR) inhibitors are of interest given the known effects of VEGF in the tumor microenvironment, including promoting inhibitory immune cells, suppressing maturation of dendritic cells, decreasing cytotoxic T cell responses, and altering lymphocyte development and trafficking. The phase III IMbrave150 trial investigated the combination of atezolizumab (A) and bevacizumab (B) as compared to sorafenib (S) in previously untreated locally advanced or metastatic HCC patients, and resulted in significantly improved OS (mOS: 19.2 mos AB vs 13.4 mos S), PFS (mPFS: 6.9 mos AB vs 4.3 mos S), and response rates (ORR: 29.8% AB vs 11.3% S), and a meaningful improvement in duration of response (mDOR: 18.1 mos AB vs 14.9 mos S). Notably, patients with class Child-Pugh B liver dysfunction were excluded from this study, although they are clinically abundant. We hypothesize the combination of AB will be safe and well tolerated in patients with locally advanced or metastatic HCC with Child-Pugh class B7 liver dysfunction. In addition, we expect efficacy will be similar to that demonstrated by the IMbrave150 study, and that ctDNA will correlate with, and possibly predict, clinical outcomes. Methods: This will be a single arm phase II study investigating the safety of the combination of AB in patients with previously untreated locally advanced or metastatic HCC with Child-Pugh B7 liver dysfunction. Patients must also be ECOG PS 0-1 and without clinically significant ascites or hepatic encephalopathy, untreated esophageal/gastric varices (assessed by EGD within the prior 6 months), or recent significant bleeding. We will enroll 50 patients with the primary endpoint of grade 3-5 treatment-related adverse event rate by CTCAE v5. Secondary endpoints include ORR, disease control rate (DCR), DOR, progression free survival (PFS), and OS. Correlative studies include tumor molecular signature by next generation sequencing (NGS) tissue analysis and ctDNA levels to correlate both with each other and with clinical benefit. Patients will receive A 1,200 mg IV and B 15 mg/kg IV every 3 weeks until disease progression or intolerable toxicity. Tumor imaging reassessment will occur every 3 cycles. Archival or fresh tumor biopsy will be required at baseline, and plasma for ctDNA will be collected with each imaging reassessment. The trial is being conducted at sites throughout the Big Ten Cancer Research Consortium (Big Ten CRC) and is currently screening eligible subjects (NCT04829383). Clinical trial information: NCT04829383.