Background: SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report planned interim analysis for our first-line cohort. Methods: Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, response by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Planned interim efficacy and safety analysis approved by DSMB is reported here. Results: For cohort 1, n = 19. Median age 63.5 (51-80). 80% Male; 65% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 32%. Etiology of cirrhosis: HCV 84%, ETOH 26%, NASH 5%. BCLC B 21%, C 70%. AFP > 400: 47%, PVT: 32%, metastases: 64%, post-transplant: 21%. Reason off study: PD (n = 10), toxicity (n = 2), lost to f/u (n = 1), withdrew (n = 1). N = 16 completed C1, n = 2 remain on study. mTTP is 4.2 months (95% CI: 3.7-NA). mOS 13.8 months (95% CI: 13.8-NA). Response Rate (CR+PR): 25%. Best response: CR n = 1 (6%), PR n = 3 (19%), SD n = 7 (44%). 4+ cycles: n = 9 (56%). % alive. Median duration of response 7.6 months (3.67-20). Gr 1/2 AEs as expected from SOR. Gr 3: AST elevated (n = 1), diarrhea (n = 1) due to SOR. Gr 2 rash (n = 1) due to HCQ. No Gr 4/5. Dose reduction: 70% for SOR, 0% for HCQ. PD analysis on the 3 responders show favorable immune profile changes (increase in cytotoxic T cells and decrease T Regs). Conclusions: SOR/HCQ had a better response rate (25%) than historically SOR alone (2%) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may have a role in patients with CP B cirrhosis, transplant or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing. Clinical trial information: NCT03037437