At the Cholangiocarcinoma Foundation 2024 Annual Conference, Funda Meric-Bernstam, MD, presented the mechanisms of fibroblast growth factor receptor (FGFR) inhibitor resistance. In cholangiocarcinoma (CCA), the frequency of targets varies depending on the site of the disease.
For example, FGFR2 is an important driver in intrahepatic CCA (iCCA), and FGFR2 fusions are present in 5% to 7% of all cases of CCA and present in 10% to 20% of patients with iCCA.1
In 2018, a study showed the durable response of an FGFR inhibitor, infigratinib (no longer Food and Drug Administration–approved), in patients with CCA harboring FGFR2 alterations.
Following the study, the efficacy of the FGFR inhibitor pemigatinib was evaluated in patients with CCA and FGFR2 fusions or rearrangements. The objective response rate was 35.5%. More recently, futibatinib, an irreversible FGFR inhibitor, was evaluated in patients with CCA and FGFR2 fusions or rearrangements. Analysis revealed that the objective response rate was 42%.
Although many patients benefit clinically from FGFR inhibitors, resistance to these therapies can ultimately develop. Liquid biopsies play an important role in detecting genomic evolution and heterogeneity. Unlike tissue biopsies, they are noninvasive and have a quick turnaround time. This type of biopsy can also be used to understand the mechanisms of acquired resistance. Some disadvantages of liquid biopsies include smaller panels, tumor shedding that may depend on the type of tumor, and copy number alterations, in addition to fusions, that are more difficult to distinguish.
Investigational trials evaluating the time after disease progression are important for understanding the mechanisms of acquired resistance. One study of 3 patients reported the molecular basis of acquired resistance to BGJ398 (infigratinib), an FGFR inhibitor. The results highlighted a variety of emerging mutations in patients who received an FGFR inhibitor. Multiple mutations were seen in the same gene and even in the same pathway, conferring resistance to the FGFR inhibitor.
A few years after futibatinib entered clinical trials, investigators reported results of clinical and translational studies of TAS-120 (an FGFR inhibitor) for the treatment of patients with FGFR2 fusion–positive iCCA who progressed on BGJ398 or Debio247 inhibitors. Analysis showed a clinical response to futibatinib followed by the development of resistance to futibatinib. A clinical response was seen again after treatment with TAS-120.
Recently, a published paper evaluated the spectrum of acquired resistance mechanisms detected in circulating tumor DNA upon disease progression following FGFR inhibition. In total, 82 patients with FGFR2-altered CCA from 12 published reports were included in this analysis. Following the acquisition of resistance, 49 of 82 patients (60%) had ≥1 detectable secondary FGFR2 kinase domain (KD) mutations.
The N550 molecular brake and V565 gatekeeper mutations were the most common, representing 63% and 47% of all FGFR2 KD mutations, respectively.
Agents can be used to overcome resistance to FGFR2 mutations. One such inhibitor is KIN-3248, an FGFR1-3 inhibitor.
There are also selective inhibitors of FGFR2, such as RLY-4008, and multikinase inhibitors, such as lenvatinib and tinengotinib. RLY-4008 has activity across several FGFR2 resistance mutations.
Dr Meric-Bernstam and her team conducted a retrospective analysis, investigating mechanisms of acquired resistance to FGFR inhibitors in patients with FGFR2 fusion–positive CCA. This study found that FGFR signaling predominantly occurs through the mitogen-activated protein kinase (MAPK) pathway.
Notably, a patient with CCA had multiple convergent MAPK alterations and an FGFR2-CTNNA3 fusion. Several other MAPK pathway mutations emerged during disease progression, including BRAF V600E, NRAS G12C, and NRAS G12D mutations.
Altogether, different FGFR inhibitors may exhibit varying effectiveness against distinct mutations. Liquid biopsies are useful in identifying the reasons behind a patient’s development of drug resistance. There is a continued need to explore new mechanisms of action of CCA and novel combinations of treatment options.2
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