Milind Javle, MD
Given that few options are available for intrahepatic cholangiocarcinoma (ICC), investigators are excited about a phase III trial of the multikinase inhibitor derazantinib (ARQ 087) as a second-line treatment for patients with inoperable or advanced disease. Current options are particularly limited for patients who experience disease progression after standard-of-care first-line chemotherapy. In the single-arm trial (NCT03230318), derazantinib is being tested in patients who have a genetic aberration in the fibroblast growth factor receptor 2 (FGFR2
With this oral small-molecule inhibitor, investigators hope to treat what is currently considered an orphan disease. “Ten to 15% of patients with ICC may be effectively targeted with a specific FGFR inhibitor,” said Milind Javle, MD, a professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. Javle is the principal investigator for the trial.
Among gastrointestinal cancers, FGFR2 fusions occur most commonly in ICC and are believed to be drivers in oncogenesis. Cancer triggered by FGFR2
fusions tends to persist despite FGFR
-directed therapy, according to Javle. Also, mutations associated with a poor prognosis, such as KRAS
, are rarely seen in the presence of an FGFR2
fusion, which makes it important to treat specifically for FGFR2-related cancer. “One interesting factor about FGFR
fusions is that the patients are often younger, often women, and have a relatively indolent, slow-growth cholangiocarcinoma compared with the FGFR
wild-type,” Javle said. Selective FGFR
inhibitors have been very effective in ICC. A study of the FGFR inhibitor BGJ398 showed that patients with FGFR2
genetic fusions responded well, achieving partial responses (PRs) or stable disease (SD).1
Derazantinib inhibits FGFR
kinases. Fibroblast growth factors and their receptors tightly regulate cell proliferation, differentiation, migration, survival, and angiogenesis. In cancer, FGFR
genes have been found to be dysregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications.2
Activation of an FGFR
kinase, as with many tyrosine kinases, requires autophosphorylation, a process that the drug inhibits. Additionally, derazantinib binds to the unphosphorylated protein, delaying its activation or phosphorylation.
The phase III trial of derazantinib, which is currently enrolling, will test the agent’s anticancer activity in approximately 100 patients with an FGFR2
fusion (FIGURE). Objective response rate (ORR) is the primary endpoint.
Figure. Derazantinib in FGFR2 Gene Fusion-Positive ICC
Eligible patients will have histologically or cytologically confirmed locally advanced, inoperable, or metastatic ICC with FGFR2
gene fusion status confirmed by next-generation sequencing or fluorescence in situ hybridization testing. Participants must have received at least 1 regimen of prior systemic therapy, with evidence of radiographic progression. Patients who were not able to tolerate prior systemic therapy may also be enrolled.
Participants also cannot have evidence of corneal or retinal disorders. This is because FGFR
inhibitors have ocular toxicities, according to Javle, and so patients will undergo ophthalmologic examination before they go on the study and be regularly monitored during the study. In the phase I trial of derazantinib in 80 patients with advanced solid tumors, 67 of whom were evaluable for tumor response, toxicities were manageable and objective responses were achieved. There were 3 confirmed PRs, and 26 patients had a best response of SD. Sixteen patients, including 7 whose tumors were positive for FGFR
genetic alterations, received therapy for 16 weeks or longer.3
Results from the phase I/II clinical study of derazantinib in 35 patients with ICC and FGFR2 genetic alterations were presented at the 2017 ASCO Annual Meeting. The data demonstrated a robust response rate and a duration of therapy for these patients well in excess of that reported for second-line chemotherapy. The ORR for patients with FGFR2
fusions was 21%, and the disease control rate was 83%. The best responses were PRs in 6 patients, SD in 22, and progressive disease in 6.4