Clinical impact of extrahepatic metastatic patterns in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab

Background & aims We aim to analyze the impact on oncological outcomes of extrahepatic metastases (EM) in patients with unresectable hepatocellular carcinoma (HCC) treated by atezolizumab/bevacizumab (Atezo/Bev). Methods We retrospectively included patients with HCC treated with Atezo/Bev as first-line systemic treatment in 6 centers. EM patterns were assessed using the following definitions: 1) presence of EM, 2) number of EM sites (none, 1, 2, ≥ 3), 3) EM burden (total number of metastases) and 4) oligometastasis status (ESMO definition). We used cox and logistic regression to evaluate the associations between variables and overall survival (OS), progression free survival (PFS) and radiological progression (RECIST v1.1). Results 647 patients were enrolled with a median age of 67 years, 86% male and 74% of cirrhosis. Among the 197 patients with EM (30%), the most common metastatic sites were lymph nodes (49%), lung (39%), peritoneal (19%), and bone (19%) and 71% had a unique EM, 29% had ≥ 2 EM sites and 8.1% ≥ 3 EM sites. EM was not associated with OS but was associated with shorter PFS (adjusted hazard ratio [aHR]:1.23, 95%CI:1.01–1.49, p = 0.036) and lower disease control rate (DCR) (adjusted odds ratio [aOR]:0.62, 95%CI:0.44–0.89, p = 0.009). Three or more EM sites were associated with poorer OS (aHR: 2.44, 95%CI: 1.39–4.29, p = 0.02), PFS (aHR:2.22, 95%CI: 1.31–3.75, p < 0.01), and DCR (aOR: 0.28, 95%CI: 0.08–0.85, p = 0.035). Patients with oligometastasis have the same OS and PFS than patients without metastasis whereas patients with multiple metastasis have a shorter OS (P = 0.026) and PFS (P < 0.001). Conclusion Presence of high metastatic burden negatively affects the prognosis of patients with HCC under Atezo/Bev whereas patients with oligometastasis have the same oncological outcomes than patients without EM.