- Intrahepatic cholangiocarcinoma (ICC) is a rare cancer with a poor prognosis. Surgery is the main curative option but up to two thirds of patients have disease recurrence. A 5-year survival rate is less than 8%, and in patients with advanced disease median overall survival is approximately 1 year.
- Upon progression on first-line chemotherapy, there is currently no effective second-line treatment for this patient population. FGFR2 mutations occur in up to 14% of patients with ICC and are consequently emerging as promising drug targets for this malignancy.
- Results of the phase II FOENIX-CCA2 study, recently published in The New England Journal of Medicine* and co-first authored by VHIO’s Director Josep Tabernero, point to the clinical promise of next-generation FGFR inhibitor futibatinib in previously treated patients with alterations in FGFR2, identified by circulating tumor DNA (ctDNA) profiling.
- The FOENIX-CCA2 Study Investigators led by Lipika Goyal at the Stanford Cancer Center in Palo Alto, USA, also show that ctDNA profiling provides a non-invasive and more precise approach in identifying tumors that are likely to respond to FGFR2
Intrahepatic cholangiocarcinoma (ICC) is a rare, primary liver cancer with a poor prognosis. ICC incidence is increasing globally because of metabolic and infectious etiologic factors. Surgery is the main curative option but up to two thirds of patients have disease recurrence. A 5-year survival rate is less than 8%, and in patients with advanced disease the median overall survival is approximately 1 year.
“Upon progression on first-line chemotherapy, there are currently no effective second-line treatments for these patients. The lack of more effective, targeted therapies therefore represents an unmet, urgent clinical need,” says Josep Tabernero, Director of the Vall d’Hebron Institute of Oncology (VHIO), and Head of the Medical Oncology Department at the Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Barcelona Hospital Campus.
Fibroblast growth factor receptor 2 (FGRF2) mutations: promising drug targets for ICC
“Alterations in FGFR2 occur in up to 14% of patients with intrahepatic cholangiocarcinoma and have consequently emerged as promising drug targets against this disease. The next-generation highly selective FGFR inhibitor futibatinib has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mechanisms,” adds Tabernero.
Recently published in The New England Journal of Medicine as an Original Article*, co-first authored by Josep Tabernero, data from the FOENIX-CCA2, multinational, open-label, phase II study show response in 42% of patients with previously treated FGFR2 fusion or rearrangement-positive ICC who were treated with oral covalent futibatinib, with durable responses and survival surpassing those indicated by historical data with chemotherapy.
Led by Corresponding Author Lipika Goyal, Stanford University School of Medicine and Stanford Cancer Center, Palo Alto, USA, this single-group study enrolled a total of 103 patients with unresectable or metastatic ICC and disease progression after one or more previous lines of systemic therapy excluding FGFR inhibitors, who received futibatinib at a dose of 20 mg once daily in a continuous regimen.
The primary endpoint was objective response (partial or complete response), as assessed by independent central review, and secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. Data show a median duration of response of 9.7 months, and that responses were consistent across patient subgroups, including those with heavily pretreated disease, older patients, and those with co-occurring TP53 mutations.
“At a median follow-up of 17.1 months, the median progression-free survival was 9 months and overall survival was 21.7 months. Futibatinib-related adverse events were common and consistent with those reported with other FGFR inhibitors, and quality of life remained stable for a median of 9 months from the start of the treatment,” observes Teresa Macarulla, Principal Investigator of VHIO’s Upper Gastrointestinal and Endocrine Tumors Group and a Medical Oncologist at HUVH, who also participated in this present study.
The use of ctDNA as a less invasive biomarker for ICC mutation profiling
Tissue-biopsy profiling was carried out to identify patients with FGFR2 fusions or rearrangements. Liquid biopsies were also performed to analyze the genetic profile of ctDNA in blood. This technique is less invasive than tumor tissue biopsy and could even be applied before surgery to identify patient tumors that are likely to respond to FGFR2 inhibition.
While further studies are warranted to establish the clinical value of using ctDNA profiling to identify those patients who could benefit from treatment with FGFR inhibitors, this study’s correlative biomarker analysis represents progress in delivering on the promise of precision medicine for the treatment of ICC.
“Also aimed at improving outcomes for patients with intrahepatic cholangiocarcinoma, other studies are evaluating different therapies matched to other patients’ genetic profiles. These efforts represent important next steps in seeking out new, more effective, and precise treatment avenues for our patients,” concludes Josep Tabernero.
The FOENIX-CCA2 phase II study was supported by Taiho Oncology and Taiho Pharmaceutical.
Goyal L, Meric-Bernstam F, Hollebecque A, Valle JW, Morizane C, Karasic TB, Abrams TA, Furuse J, Kelley RK, Cassier PA, Klümpen HJ, Chang HM, Chen LT, Tabernero J, Oh DY, Mahipal A, Moehler M, Mitchell EP, Komatsu Y, Masuda K, Ahn D, Epstein RS, Halim AB, Fu Y, Salimi T, Wacheck V, He Y, Liu M, Benhadji KA, Bridgewater JA; FOENIX-CCA2 Study Investigators. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med. 2023 Jan 19;388(3):228-239.