Background: Fibrolamellar Carcinoma (FLC) is a rare deadly form of liver cancer affecting adolescents and young adults (AYA), presenting at an advanced stage, with up to 80% relapse, and no proven systemic therapies. Effective systemic therapies could convert patients to resectable or prolong progression free survival (PFS) and overall survival. Because of reported successes with nivolumab + lenvatinib (LEN) and of Gemcitabine (GEM) + LEN, and the potential synergy of GEM with NIV through elimination of myeloid suppressor cells in the tumor microenvironment, we offered NIV+LEN+GEN (NLG) to relapsed/refractory FLC patients ineligible for clinical trials. Our objective is to describe our initial experience using NLG in high risk AYA FLC patients. Methods: We reviewed the records of all FLC patients discussed at the FibroFighters National Tumor Board who received NLG. Results: Twenty-five patients (10F,15M), median age 20 (7-56), all stage IV, received a total of 322 cycles of NLG (median 11 cycles/patient,19 neoadjuvant, 1 adjuvant, 4 both). The median number of relapses, prior systemic therapies, and surgeries were 2(0-6), 3(0-6), and 2(0-7) respectively. Most patients had failed NIV+LEN (n = 8) or GEM+LEN (n = 7) prior to starting NGL. The 17 patients with at least one evaluation had a mean follow up of 10 months (3-23) and 18 cycles (6-38) of NGL with the best response by RECIST 1.1 of CR(1), PR(6), SD(10), and PD(0), for an objective response rate (PR+CR) of 41% and disease control rate (CR+PR+SD) of 100%, and estimated best volume response median of -20% (-89%,+10%). There have not yet been any progressions. Three of the 7 who were too soon for imaging, have had resolution of ascites. The PFS and Overall Survival at 6, 9, and 12 months are: 1.0/1.0, 0.82/0.82, 0.67/0.67. Two of 17 with carcinomatosis have no evidence of disease on PET and MRI after 10 cycles. Twenty-two of 24 are continuing NGL. Nine of 16 unresectable patients became surgical candidates, of these 4 showed > 50% necrosis histologically at surgery. 13 of 17 showed necrosis on imaging. Eleven of 16 are currently in their longest PFS since diagnosis. Sixteen patients had serial tumor-informed circulating DNA (Signatera) during therapy: Five became negative (0.0 mean tumor molecules/ml plasma), and overall mean drop was -27% (-93%, +111%). No patients have stopped therapy. The most common toxicities were hypertension and fatigue in 25% and 20% respectively, grade 1 or 2. There have been no grade 3 or 4 toxicities to date. Conclusions: Our retrospective experience with NGL for FLC offers another potential systemic option for patients who are not surgical candidates or with multiple relapses. NGL was well tolerated and provided excellent disease control to patients with few options. Prospective trials are needed.