Background: Sorafenib or lenvatinib are the current frontline options for advanced HCC. Multiple biologic agents including multi-Tyrosine Kinase Inhibitors (TKI) cabozantinib & regorafenib have been recently approved for the previously treated population. Immunotherapy (IO) agent Nivolumab have also been approved in the same setting. Due to lack of prospective head to head comparison, there is no standardized way for alternating those agents beyond frontline. Methods: We performed a retrospective review of KU cancer registry. Patients with advanced HCC were divided into 2 groups based on the 2nd line systemic regimen (IO vs non-IO). Kaplan–Meier and Cox proportional hazards models were utilized to evaluate progression free survival (PFS) and overall survival (OS). Results: Between 2016-2019, 98 patients were identified, 41 received IO, while 57 received biologics. All patients had sorafinib as 1st line therapy. Most patients have ECOG 0-1 and Child-Pugh class A or B. 55% had hepatitis C, 6% hepatitis B and 27 % have history of alcohol misuse. Almost 50% of patients have received prior liver directed therapy. Comparing IO vs non-IO groups, median PFS was 3.9 months vs 3 months and median OS was 10 months vs 10 months. There was no statistically significant difference in PFS & OS but there was a delay separation in the survival curve favoring IO. Similar outcome was seen in a sub-group analysis of the hepatitis C patients. Conclusions: This retrospective comparative review of current 2nd line regimens is one of the first & largest studies reported. In this study population, IO was not superior to multi-TKI as a 2nd line regimen. The late survival curve separation favoring IO might suggest a delay IO effect in a subgroup of patients. Future studies should define specific biomarkers that could predict response and allow treatment to be optimized depending on patient and tumor characteristics. Furthermore, combining IO plus multi-TKI might be a promising next step in development. A number of ongoing trials are testing this strategy including our CAMILLA trial of Cabozantinib plus Durvalumab, currently enrolling patients at the University of Kansas Cancer Center NCT03539822.