Background: Fibrolamellar Carcinoma (FLC) is a rare form of primary liver cancer affecting children and young adults that often presents at an advanced stage and even with surgery has an 80% relapse rate. Unresectable FLC patients are considered incurable and have short life expectancy. Effective neoadjuvant and adjuvant systemic therapies are needed to increase chances at remission and protect against relapse. Because of success as single agents in HCC, we tried the combination of nivolumab (NIV) and lenvatanib (LEN) in FLC patients who had exhausted more common therapies. Our objective is to describe our experience using combination NIV-LEN in FLC patients. Methods: Over the last 5 years we have seen over 90 patients with FLC at our institution. After securing IRB approval, (ORA Number: 19071603-IRB01), we collected data in a de-identified fashion for all patients who had received NIV-LEN. Results: Twenty patients (6M/14F), median age at diagnosis/start of NIV-LEN 17/20 (7-52) have received at total of 349 cycles of NIV-LEN (NIVO 3mg/kg IV q2 weeks) and lenvatanib 8mg po daily, 5 adjuvant, 14 neoadjuvant and one both. All had cross sectional imaging every 3 months with independent review. The median number of cycles/months of follow up was 19.5 (3-43)/13.5 (3-31) respectively. The median number of prior relapses, systemic therapies, prior abdominal surgeries, and prior radiation (IR ablations, TARE, TACE, SBRT) were 3.5 (0-7), 3 (0-11), 2 (0-6), and 2.5 (0-13) respectively. Three patients had gemcitabine added to NIVO-LEN for part ( < 1/3) of their regimen. The best response by RECIST 1.1 of the 14 neoadjuvant patients was 3 CR, 3 PR, 7 SD and 2 PD, for an overall response rate (PR + CR) of 40% and overall control rate (CR + PR + SD) of 87%. Seven of 20 (30%) stopped NIVO-LEN [PD (3), infection (2), or patients’ wishes (2)] while 14 (70%) continue, including all adjuvant patients who remain in CR (median follow-up of 10 months). The 6-, 12-, and 24-month progression free survival (PFS) and overall survival (OS) were: (70%,49%,49%) and (94%,94%,73%) respectively. For 14 of 17 (82%) relapsed patients, the PFS was longer than the patients’ most recent PFS, and longest ever in 9 (53%). Six of the 14 initial non-surgical candidates (43%) either had surgery (2), or avoided surgery (3 CR, 1 ablation). There were 2 grade 3 toxicities (both infections) and no grade 4 toxicities. The most common toxicities were hypertension and fatigue in 25% and 20% respectively. One patient, after 5 relapses, had more than 120 lung nodules > 1cm that after 14 months of NIVO-LEN achieved CR and has remained in CR for another 14 months. Conclusions: Our retrospective experience with the novel immune-chemotherapy combination of NIV-LEN for FLC in an extremely rare disease with no proven systemic therapies is encouraging, especially for those who are not surgical candidates or in a surgical remission. We hope this report can inform future prospective trials in treating this deadly disease.