Background: Advanced HCC is a deadly disease with few systemic therapeutic options. VEGF blockade potentiates the effect of PD-1 inhibition by opposing the immunosuppressive effects of VEGF-A (increased DC maturation, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors). A sBLA has been submitted for an anti-PD-L1 + anti-VEGF combination as 1L treatment for advanced HCC. Penpulimab is a novel humanized anti-PD-1 IgG1 antibody with complete removal of Fc receptor mediated effect, and featuring slow antigen binding off-rate and high receptor occupancy. Anlotinib is a multi-targeted tyrosine kinase inhibitor selective for VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit. Methods: In this open-label, multicenter phase Ib/II study, treatment-naive pts with advanced HCC received penpulimab 200mg Q3W in combination with anlotinib 8mg QD (2 weeks on 1 week off) until loss of clinical benefit or unacceptable toxicity. The primary objectives were to assess antitumor activity by ORR (RECIST v1.1). The secondary objectives were to assess antitumor activity by DCR, DoR, TTP, and to assess the safety and tolerability of the combination. Results: As of Jan 14, 2020, 31 pts (median age 56 years [23-74], male 81%, ECOG 0/1 [64%/36%], BCLC B/C [23%/77%], HBV/HCV [61%/7%]) received combined therapy (a median of 6 [1-15] doses). Treatment-related adverse events (TRAEs) occurred in 93.5% of pts (G3 in 9.7% [3/31], no G4, and leading to treatment discontinuation in 6.5% [2/31]). Most frequent TRAEs were increased AST (35.5%), increased ALT (29%), asthenia (22.6%), decreased platelet count (19.4%), increased blood bilirubin (19.4%), increased bilirubin conjugated (19.4%), and rash (16.1%). Of 25 evaluable pts (with the opportunity to be followed-up for ≥2 scans, 12 weeks), confirmed ORR was 24% (6/25) and DCR was 84% (21/25). Five responders remained in response with DoR ranging 1.4+ to 6.9+ months. Median TTP was not reached and 6m-TTP rate was 63% (95% CI: 38%, 81%). Conclusions: Penpulimab in combination with anlotinib had a manageable safety profile and encouraging antitumor activities in patients with advanced HCC. No unexpected AEs were identified beyond the established safety profile for each agent. Evaluation of penpulimab + anlotinib (10 mg QD) in a phase 3 study for 1L HCC is currently underway. Clinical trial information: NCT04172571.