Early Experiences with Triple Immunochemotherapy in Adolescents and Young Adults with High-Risk Fibrolamellar Carcinoma

Abstract

Introduction: There are no standard systemic therapies for the treatment of fibrolamellar carcinoma (FLC), as surgery remains the only definitive option. We share our experiences using systemic “triple therapy” (TT) with 5-fluorouracil, interferon, and nivolumab for the treatment of relapsed, refractory, metastatic, or unresectable FLC. Methods: Data from all patients who received TT from May 2018 to July 2020 were reviewed to assess response, survival, and toxicity. Results: A total of 22 patients were treated with TT, of which 14 (median age of 21 years) were evaluable. They received a median of 18 cycles (8–44). At the time of analysis, the median progression-free survival was 9 months (4.5–26), 29% longer than prior to TT, with 5 patients achieving clinical remission, 8 patients stable or improving, and 1 progression. Overall objective response (clinical remission + partial response) was 50% and tumor control rate (clinical remission + partial response + stable disease) was 93%. Two patients withdrew from treatment due to side effects. Discussion/Conclusion: Our early results support TT as a promising medical option to slow disease progression and prolong survival in high-risk patients with FLC. TT can be administered in the outpatient setting and has shown good tolerability. Further longitudinal data is needed to confirm outcomes, especially in patients still early in their treatment.

Polyendocrine Autoimmunity and Diabetic Ketoacidosis Following Anti-PD-1 and Interferon α

“…Interferon a-therapy has also been associated with the development of autoimmune DM with an estimated prevalence of 0.34%. 21 Early analyses from patients undergoing triple therapy, 13 as well as studies of patients being treated with checkpoint inhibitors in combination with interferon a, show high rates of IRAEs, but there are no reported cases of similar autoimmune ICI-T1DM. 22,23 The presence of one IRAE should increase providers' suspicion of another.…”

“…She underwent a right hepatic lobectomy for a 14-cm liver mass and received 6 cycles of systemic therapy with nivolumab (anti-PD1), pegylated interferon a, and capecitabine. 13 After the initiation of therapy, monitoring laboratory data showed normal serum blood glucose levels, electrolytes, and thyroid function up to 4 weeks before DKA presentation. An elevated random serum blood glucose level of 221 mg/dL was noted at the time of her sixth cycle of nivolumab and pegylated interferon a, 2 weeks before onset of DKA.…”

Successful Liver Transplantation of Recurrent Fibrolamellar Carcinoma following Clinical and Pathologic Complete Response to Triple Immunochemotherapy: A Case Report

“…One case report described a patient with metastatic FLC who achieved a near-complete response with the combination of nivolumab and ipilimumab [25]. Gottlieb and colleagues [20] recently reported data on 22 patients with relapsed, unresectable, and metastatic FLC who were treated with triple therapy using 5-FU, IFN alfa-2b, and nivolumab. The rationale for this combination is that the drugs work synergistically to create a potent anti-tumor immune response.…”

“…Immunotherapeutic approaches help overcome tumor immune evasion by blocking natural brakes of the immune system (i.e., immune checkpoint molecules) that normally prevent autoimmunity and by modulating the tumor microenvironment among a variety of other mechanisms. The efficacy of IFN alfa-2b demonstrated in previous studies suggests immune evasion may be important for FLC oncogenesis; however, the immunological features of this cancer are not well known [17, 20]. One study examining FLC tumor specimens found two-thirds of the cases exhibited expression of PD-L1 as well as other immune checkpoint proteins, including indoleamine 2,3-dioxygenase (IDO) and B7-H3, on tumor cells, tumor-infiltrating lymphocytes, and tumor-associated macrophages.…”

“…ICIs work by blocking the immune system’s natural brakes such as programmed cell death protein-1 (PD-1), so that immune cells can recognize and attack cancer cells. One recent study reported promising clinical outcomes in refractory and advanced FLC with a novel triple chemoimmunotherapy combination of 5-fluorouracil (5-FU), interferon (IFN) alfa-2b, and anti-PD-1 inhibitor nivolumab [20]. Here, we report the outcome of the 5-FU, IFN alfa-2b, and nivolumab regimen in a patient with recurrent and unresectable FLC who achieved radiographic and pathological complete response and successfully underwent OLT.…”