The Guidelines recognize that this cancer is biologically distinct and should be treated differently from conventional HCC. Unfortunately, however, there is a lack of compelling clinical data to support an effective systemic therapy for FLC. Anecdotal reports frequently describe FLC as, at best, weakly responsive to the chemotherapy, targeted therapy, and immune therapy regimens used to treat HCC or hepatoblastoma. Also, there have been few clinical trials specifically focused on FLC.
Ironically, FLC patients generally have been explicitly excluded from the clinical trials of systemic therapies that led to regulatory approvals for HCC, yet they wind up being prescribed these drugs in the absence of known superior alternatives. An additional consideration is that insurance generally will cover the cost of HCC-approved drugs for FLC patients, in part because the name “fibrolamellar hepatocellular carcinoma” is commonly used in the published literature on FLC.
Effective Drug Combinations
Despite a paucity of clinical trial data on FLC, and the absence of “clear standards of care,” the Guideline’s authors note that
“Dramatic progress has been made in systemic therapy for patients with FLC in recent years.”
This reflects a consensus observation that “systemic therapy can play an important role in downstaging/bridge to surgery and inoperable metastatic… [“advanced”] and adjuvant setting.” The Guideline panel recommends three regimens for patients with advanced FLC:
- GEMOX (gemcitabine + oxaliplatin)
- GEMOX + Lenvatinib
- Ipilimumab + nivolumab
Gemcitabine and oxaliplatin are traditional chemotherapy drugs that attack a cell’s ability to copy or read DNA. Lenvatinib is a “targeted therapy” that inhibits the activities of several tyrosine kinase enzymes. (These fall in a general class with hundreds of other protein kinases, including PKA, but they are only very distant relatives of the FLC driver.) The primary means by which lenvatinib works against cancer is believed to be blocking signals that tumors use to grow new blood vessels, on which they depend for nutrition. It also may interfere with signals that directly stimulate the multiplication of the cancer cells. How or even if these drugs work effectively as a combination against FLC has not been tested rigorously in either laboratory models or patients.
Despite the absence of prospective clinical studies, or a mechanistic understanding of how the drugs may synergize, it is encouraging that clinicians are empirically identifying drug combinations that seem to have practical value in treating FLC. At the least, enabling surgery for patients who otherwise would be deemed inoperable is a positive step forward, and it helps to break through the previous sense of futility about systemic therapy for FLC.
The Guideline paper text describes additional efforts to devise effective combinations of chemotherapy and targeted drugs for FLC, with some signs of efficacy. However, most did not generate sufficient support to be presented as consensus recommendations. An overriding problem remains that most of the observations are retrospective, rather than coming from well-designed clinical trials. Furthermore, they do not take advantage of either the growing understanding of the biology of FLC or of the revolutionary advances that have been made in immune therapy of cancer over the past 15 years.
Immune Therapies
FDA approval of the drug ipilimumab, the first “Immune Checkpoint Inhibitor” (ICI) signaled the start of a new era in cancer therapy. ICIs work by enabling immune cells which can recognize cancer cells to do their job of killing those target cells. A cancer cell can often evade being wiped out by giving an attacking immune killer cell an overriding signal that communicates: “Check what you’re doing. You’re not supposed to kill me!” The ICIs are antibodies that block the checkpoint signal so that the killer cell can complete its “search and destroy” mission.
The combination of ipilimumab plus a second ICI, nivolumab (blocking two distinct checkpoints at the same time) received full approval from the FDA in 2023 as first-line therapy for HCC. Efficacy against FLC was not determined in the supporting clinical trial. However, two case reports of remarkable clinical responses to ipi/nivo in FLC patients with advanced disease, one a durable complete response (CR), sparked the recommendation of this combination in the Guideline. Some strong clinical responses to single ICIs have also been reported in small numbers of FLC patients as single agents or in combination with an antibody that inhibits the formation of tumor-supporting blood vessels, possibly with the same kind of antitumor effect as lenvatinib.
The success of ICI in certain cancers begs the question, “what antigens do T cells capable of killing a patient’s cancer cells recognize in the first place?” FLC is a genetically stable cancer with a low “tumor mutational burden” that does not randomly generate large numbers of abnormal proteins that can readily be “spotted” by T cells.
Two independent groups, cited in the Guideline paper, have shown that FLC patients can be immunized with a peptide (a protein fragment) to generate a strong immune response against the cancer-causing DP version of PKA present in FLC cells. The immunization specifically targets the junction between the “D” and “P” segments of the abnormal protein. A case report from 2022 and a new paper on a Phase 1 clinical trial published at the end of 2025 demonstrate that such immunization against DP, given in combination with the ipi/nivo ICI combination provokes a very strong immune response that, in some patients, leads to a deep, durable remission from advanced FLC.
The FCF is actively supporting clinical trials to advance this promising approach. Additional ongoing research focuses on other ways to overcome potentially immunosuppressive factors, beyond immune checkpoints, in the local environment of FLC tumors.