Combination immunotherapy with anti-VEGF/TKI for hepatocellular carcinoma: present and future perspective

Abstract

The results of the Phase 3 IMbrave150 trial were published in the New England Journal of Medicine (1). The IMbrave150 trial is a global multicenter phase 3 comparative study conducted in patients with locally advanced or metastatic liver cancer and unresectable hepatocellular carcinoma (HCC). Patients were assigned, 2:1, to atezolizumab plus bevacizumab (Atezo + Beva) (n=336) and sorafenib (n=165) groups. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS) using the independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Stratification factors were geographic region (Asia excluding Japan vs. rest of world), Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 vs. 1), macrovascular invasion (MVI) and/or extrahepatic spread (EHS) (presence vs. absence), and serum alpha-fetoprotein (AFP) level (≤400 vs. >400 ng/mL). The proportion of patients with MVI was 38% (129/336), MVI and/or EHS was 78% (258/336), and AFP ≥400 ng/mL was 38% (126/336) in the IMbrave150 population and their prognosis was poor. Nevertheless, surprisingly good results were observed in the IMbrave150 trial. The OS in the Atezo + Beva group was not estimable (NE) and that in the sorafenib group was 13.2 months [95% confidence interval (CI), 10.4-NE]. Additionally, a surprising hazard ratio, of 0.58 (95% CI, 0.42-0.79, P=0.0006) was observed. It is worth noting that the α given to the OS for the 1 st interim analysis of this trial was 0.0033 and the results in this study sufficiently cleared this value (1). The PFS, by IRF-assessed RECIST v1.1, in the IMbrave150 trial was 6.8 months (95% CI, 5.7-8.3) in the Atezo + Beva group and 4.3 months (95% CI, 4.0-5.6) in the sorafenib group and the HR was 0.59 (95% CI, 0.47-0.76, P<0.0001). Although the Phase 1b Arm A (2) PFS value was lower at 7.3 months, this was considerably longer than the 5.6 months observed in Arm F (2). As the observation period for IMbrave150 (8.6 months) was shorter than that for Arm A (12.4 months) an extension of the observation period may result in a greater PFS. The objective response rate (ORR), by IRF-assessed RECIST v1.1, was significantly higher in the Atezo + Beva group (27%; 95% CI, 23-33) than in the sorafenib group (12%; 95% CI, 7-18) (stratified P value <0.0001). The ORR in the Atezo + Beva group was superior in Phase 1b Arm A (36%) than in Arm F (20%), and this may be further improved in the final analysis, in which the observation period is extended. A complete response was observed in 18 patients (6%), which was a promising result. The median duration of response (DOR) was NE and DOR >6 months was observed in 80% of responders, which indicated a durable response. A more favorable patient-reported outcome was observed in the Atezo + Beva group than in the sorafenib group. The decrease in quality of life (QOL) in the Atezo + Beva group was more favorable than that in the sorafenib group, with an HR of 0.63 (95% CI, 0.46-0.85, P=0.0028), which is comparable to that reported for a similar antibody, ramucirumab (3), and this cannot be achieved with tyrosine kinase inhibitors (TKIs), which induce adverse events (AEs). For example, time to symptomatic progression was examined in the SHARP trial but no improvements were observed. These favorable results observed in IMbrave150 may be caused by the delayed onset of symptoms owing to the drug and as this combination is an antibody-based Editorial