Biliary tract cancers (BTC) comprise a rare and diverse group of malignancies that involve the gallbladder and biliary tree. These cancers typically present in later stages because they are aggressive in nature and affected patients are often asymptomatic in earlier stages of disease. Moreover, BTCs are generally refractory to cytotoxic chemotherapy, which further contributes to their associated poor survival outcomes. Novel therapy approaches are clearly needed. Molecular targeted agents have been developed based on our expanding knowledge of the genetic mutations underlying BTCs and represent a promising treatment strategy in molecularly selected subgroups of patients. In addition, the advent of immunotherapy over recent years has dramatically changed the bleak outcomes observed in malignancies such as melanoma. Our growing understanding of the complex tumor microenvironment in BTC has identified mechanisms of tumor immune evasion that could potentially be targeted with immunotherapy. As a result, different immunotherapeutic approaches including immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapy, have been investigated. The use of immunotherapeutic agents is currently only approved for a small subset of treatment-refractory BTCs based on microsatellite instability (MSI) status and tumor mutational burden (TMB), but this will likely change with the potential approval of immunotherapy plus chemotherapy as a result of the TOPAZ-1 trial.

Introduction: Fibrolamellar carcinoma (FLC) is a rare liver cancer that predominantly affects younger patients without a history of liver disease. Surgical resection is the cornerstone of therapy and represents the best potentially curative treatment option. Modest objective responses with cytotoxic chemotherapy alone or combined with immune checkpoint inhibitors (ICIs) have been reported; however, there are no established systemic therapy regimens for unresectable or metastatic FLC. Case Presentation: We report a case of a 23-year-old woman with FLC who presented with a 11.5 × 8.3 cm left liver mass and subsequently underwent resection as initial therapy. Molecular analysis of her surgical tissue revealed a DNAJB1-PRKACA fusion gene. The patient developed biopsy-proven recurrent FLC with multiple liver lesions but without any distant metastatic disease only 3 months after initial resection. In light of emerging data, the patient was treated with a novel triple therapy regimen including 5-fluorouracil (5-FU), interferon (IFN) alfa-2b, and nivolumab. Partial radiographic response was achieved after 4 treatments and complete response was achieved after 12 cycles with the combination. The patient received 2 more doses of 5-FU/IFN alfa-2b without nivolumab and underwent orthotopic liver transplantation (OLT) 6 months after the last dose of ICI. Pathological examination of the explanted liver remarkably confirmed pathologic complete response. She remains recurrence-free and is on active surveillance. Discussion/Conclusion: For patients with unresectable/recurrent FLC with no distant disease, the combination of 5-FU, IFN alfa-2b, and nivolumab could be an effective systemic therapy option. The use of this chemoimmunotherapy regimen to downstage FLC prior to OLT may be worth investigating further.