Cholangiocarcinoma, or bile duct cancer, is deadly even when caught early. The 5-year survival rate among those diagnosed early is 17% to 25%; for most patients, the rate is below 10%. Experts say the key to improving these dismal statistics is to focus on the many genetic mutations in cholangiocarcinoma—and find druggable targets to improve outcomes.
That’s why FDA’s approval of pemigatinib (Pemazyre, Incyte) to treat a patients with FGFR2 rearrangements or fusions is one of the more important advances in treating cholangiocarcinoma. Among 107 patients, 36% had a response to treatment, including 3 with complete responses. More exploration of these biomarkers was in order, and now a group of investigators from the Veneto Institute of Oncology (IOV) and the University of Padua in Italy have highlighted both the prevalence and prognostic value of FGFR2 mutations.
In the recently published BITCOIN study (BIliary Tract Cancers: mOlecular characterisation to Inform) the IOV team gathered medical records and tissue samples from 286 patients who were treated at this specialized cancer center between January 2008 and July 2019; the patients were prospectively followed through August 2020. They found that patients with FGFR2/3 alterations had a particular overall survival advantage—even before targeted treatment—compared with those who were FGFR wild-type.
“Our main and major finding was the demonstration of a better median OS in patients harbouring FGFR2/3 alterations,” they wrote.
Those with FGFR2/3 alterations had an OS of 29.2 months, compared with 14.4 months for wild-type cases. Investigators also found a survival advantage for patients with IDH1/2 mutations. The results were not affected by a small number of patients (n = 8) who received an FGFR2 inhibitor during the study; no patient received an IDH1/2 inhibitor, and no patients received targeted therapy in the first-line setting.
To conduct the study, investigators profiled the patients—who all had advanced or metastatic cancers—using targeted DNA/RNA next generation sequencing (NGS). A variety of tests were used, including FoundationOne CDX for DNA analysis and Archer FusionPlex for RNA analysis. (FDA approved FoundationOne CDX as the companion diagnostic for pemagitinib).
Results showed that FGFR2 rearrangements were found in 15 cases (5.2%); 1 case found an FGFR2 amplification and 3 cases showed point mutations. FGFR3 alterations were seen in 5 cases (1.7%). IDH1/2 mutations were seen in 35 of 223 cases (15.7%). In addition, 9 of 258 (3.5%) had ERBB2 mutations, and 6/260 had BRAF gene alterations.
Next, the investigators conducted a survival analysis of the group of 286 patients, with a median follow-up of 45.6 months; 219 patients had died. In this group, the OS from diagnosis with metastatic disease was 15.6 months.
Patients with FGFR2 2/3 alterations had a reduced risk of death compared with those with wild-type (HR, 0.42; 95% CI, 0.21-0.87; P = .003), with a median survival of 29.2 months. Those with IDH1/2 mutations had a reduced risk of death compared with wild type, with a median OS of 25.9 months, but just missing the mark for statistical significance (HR 0.63; 95% CI, 0.38-1.03; P = .06).
The IOV team suggests these data could be used to develop new clinical trial designs. “To date and to our knowledge, this is one of the largest studies providing insights into metastatic [biliary tract cancer] on the prognostic role of major druggable alterations,” they wrote. The data show that “FGFR2/3 aberrations (including FGFR2 rearrangements) and IDH1/2 mutations can be prognostic for better survival.”
Rizzato M, Brignola S, Munari G, et al. Prognostic impact of FGFR2/3 alterations in patients with biliary tract cancers receiving systemic chemotherapy: the BITCOIN study. Eur J Cancer. 2022;166:165-175. doi: 10.1016/j.ejca.2022.02.013