Atezolizumab + bevacizumab vs sorafenib in locally advanced or metastatic hepatocellular carcinoma: The randomised phase III study IMbrave150

Abstract

Background: Advanced hepatocellular carcinoma (HCC) is a disease of high unmet medical need. Despite considerable toxicities, sorafenib (sor) is the 1L standard of care. Single‐agent inhibition of PD‐L1/PD‐1 or VEGF signalling has only modest activity in HCC, but in a Phase Ib study of atezolizumab (atezo; anti‐PD‐L1)+ bevacizumab (bev; anti‐VEGF) combination, a response rate of 61% with a manageable safety profile (Pishvaian ESMO 2018, submitted) is observed. Clinical benefit with atezo + bev was also seen in 1L renal cell carcinoma and 1L non‐small cell lung cancer (Motzer ASCO GU 2018, Reck ESMO IO 2017). The potential synergy between atezo and bev may stem from bev's additional immunomodulatory effects in the tumour microenvironment (increased DC maturation, enhanced T‐cell infiltration, reduced MDSCs and Tregs in tumours) that may potentiate the efficacy of atezo in re‐invigorating the antitumour T‐cell response. Trial design: IMbrave150 is a global, multicentre, randomised, open‐label, Phase III trial enrolling 1L patients (pts) with locally advanced or metastatic and/or unresectable HCC. Key inclusion/exclusion criteria are shown in the table. Pts will be randomised 2:1 to receive atezo (1200 mg) plus bev (15 mg/kg) IV Q3W or sor (400 mg) PO BID until loss of clinical benefit or unacceptable toxicity. Crossover is not allowed. Stratification factors are ECOG PS (0 vs 1), baseline alpha fetoprotein level (< 400 vs ≥ 400 ng/mL), macrovascular invasion and/or extrahepatic spread (presence vs absence) and region (Asia excluding Japan vs rest of world). Co‐primary endpoints are investigator (INV)‐assessed ORR (RECIST v1.1) and OS, which will be tested in parallel. Secondary endpoints are INV‐assessed PFS, DOR and time to progression (TTP; RECIST v1.1), along with independent review facility (IRF)‐assessed ORR, PFS, DOR and TTP (RECIST v1.1 and HCC mRECIST). Approximately 480 pts will be enrolled globally. .