Background: The field of systemic options in HCC therapy has significantly evolved in recent years, and first line options now include sorafenib, lenvatinib and bevacizumab plus atezolizumab. Nivolumab is a recombinant human IgG4 mAb targeting PD-1 with clinically meaningful activity in about 15-20% of HCC patients, but the confirmatory phase III trial Checkmate 459 failed to demonstrate superiority over sorafenib. VEGF signaling is not only a driver of tumor angiogenesis, but also contributes to the formation of an immunosuppressive microenvironment. Combinations of anti-angiogenic multikinase inhibitors, specifically lenvatinib, and PD-1/PD-L1 inhibitors have demonstrated remarkable antitumor activity and manageable toxicity in several tumor types, including HCC. We therefore aimed to evaluate the efficacy of nivolumab in combination with lenvatinib as first line treatment in patients with advanced HCC. Methods: This investigator-initiated single-armed phase II trial (NCT03841201) recruited 50 patients (pts) at 8 sites in Germany between 07/2019 and 05/2021. Primary endpoints were objective response rate (ORR) according to investigator assessed RECIST 1.1 and safety/tolerability. Secondary endpoints included ORR according to iRECIST, time to progression (TTP), progression free survival (PFS) and overall survival (OS). Recruitment of the trial was completed in 05/2021. At the time of analysis, 4 patients remained on treatment. Results: 50 pts (24 BCLC B, 24 BCLC C, 2 not evaluable) were enrolled and received at least one dose of the combination treatment. ORR by RECIST 1.1 was 28% (CR: 6.0%, PR: 22.0%, SD: 46.0%, PD: 12.0%). Median PFS was 9.0 mo (26 events). Median TTP was 11.5 mo (0.69 at 6 mo, 0.45 at 12 mo, 0.36 at 18 mo) and median OS was 27.1 mo (8 events). 45 (91.8%) pts experienced at least one TRAE, of which 29 pts (59.1%) encountered at least one TRAE ≥ grade 3. 17 (34.7%) pts had one or more SAE related to the study medication, whereof 15 pts (30.6%) experienced at least one treatment related SAE ≥ grade 3. Conclusions: No new safety signals were observed for the combination of nivolumab and lenvatinib. Although the study failed to reach its prespecified ORR of at least 40%, the high activity in all efficacy endpoints with a mOS of 27.1 mo supports the further investigation of the combination in HCC. Clinical trial information: NCT03841201.