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Several drugs targeting the FGF-FGFR signaling pathway have been developed and are classified into 4 different categories according to their mechanism of action. The first category includes the small-molecule FGFR tyrosine kinase inhibitors that act on the FGFR tyrosine kinase domains. These drugs are divided in 2 groups, selective and nonselective, according to whether the IC50 of inhibitory activity to other kinases is less than 10 nanomolar.
The second category is the FGFR antibodies targeted to the receptor. The third category, the FGF ligand traps, functions as a decoy to block ligand binding with FGFR, decreasing the hyperfunctioning component of the intracellular signaling pathways. The fourth category are the ADCs that are FGFR-directed monoclonal antibodies (mAbs) chemically linked to a cytotoxic drug.
The table shown here summarizes the development of compounds against FGFR.[18-20] Although there has been very intense clinical development, only 2 drugs are approved: erdafitinib, which is approved for FGFR-altered UC, and pemigatinib, which is approved for cholangiocarcinoma with FGFR2 fusion.[20-22]
mAbs target FGFR and can block activation of both the wild-type and the mutant receptors. Vofatamab, a fully humanized monoclonal anti-FGFR3, is the most well known of these compounds. The FIERCE-21 study showed that vofatamab was well tolerated in combination with docetaxel, with most treatment-emergent AEs being grade ≤2 . Treatment-emergent AEs that occurred in ≥5% of patients included asthenia (19.0%), chills (9.5%), diarrhea (9.5%), decreased appetite (19.0%), flushing (14.0%), hypotension (9.5%), and elevated creatinine (9.5%). The FIERCE-22 study showed that the combination of vofatamab with the checkpoint inhibitor pembrolizumab provided benefit even in patients with wild-type disease.
Other mAbs targeting FGFR are bemarituzumab, a first-in-class humanized IgG1 mAb specific to splice-variant FGFR2b that enhances antibody-dependent cellular cytotoxicity, and MGFR1877S that binds to FGFR3 to competitively inhibit native ligand binding and prevent receptor dimerization in cells with wild-type or mutant FGFR3.[25-27]
FGFR ligand traps provide an alternative mechanism to target FGFR whereby FGF is captured by a decoy receptor before it binds to FGFR. The decoy receptor lacks the transmembrane and cytoplasmic domains but has the extracellular FGFR domain, allowing for the interaction and sequestration of FGF ligands. The first example is FP-1039 (GSK 3052230), a soluble fusion of the extracellular ligand binding domain of FGFR1 linked to a modified hinge and native Fc regions of human IgG1. In a phase I clinical trial in unselected patients with cancer, FP-1039 was well tolerated and AEs were mostly hyperphosphatemia and retinal changes, and no skin AEs or nail issues were observed. A second ligand trap in development is the small-molecule NSC12 that inhibits FGF2-FGFR interactions.[30,31]
Aprutumab ixadotin is an ADC, using a derivative of the highly potent microtubule-disrupting agent auristatin as the cytotoxic payload. The auristatin payload is attached to the antibody that is selective for FGFR2 IIIb and FGFR2 IIIc isoforms. Although this ADC showed interesting preclinical results, early attempts in clinical development failed, making it an ADC to be considered with caution.
LY3076226 is a FGFR3-specific ADC conjugated to ravtansine, a derivative of maytansine that showed interesting activity in preclinical models of triple-negative breast cancer and gastric cancer with FGFR3 and TACC3 fusion or in G370-, S249-, or R248-mutant models as mentioned earlier. We are awaiting the results from a recently concluded phase I trial.
In summary, we have tyrosine kinase inhibitors that are at a more advanced stage of development. We also have mAbs targeting FGFR and FGFR ligand traps, and ADCs are in development. Now let’s focus on the tyrosine kinase inhibitors and specifically on erdafitinib.
Erdafitinib is a small-molecule tyrosine kinase inhibitor that binds to and inhibits the enzymatic activity of FGFR1, FGFR2, FGFR3, and FGFR4. It also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2, although with a lower affinity.
Erdafitinib inhibits FGFR phosphorylation and signaling, resulting in decreased cell viability in cell lines expressing FGFR genetic alterations (eg, point mutations, amplifications, and fusions). The results of a phase I study with erdafitinib in multiple tumor types, including cholangiocarcinoma, breast cancer, and UC, revealed a strong erdafitinib signal in these 3 specific cancers and that led to further clinical development.
Erdafitinib is an oral drug with a primarily hepatic metabolism via CYP2C9 and CYP3A4. This is important to know as drug–drug interactions can occur when using erdafitinib. Half‑life elimination is 59 hours and time to peak is 2.5 hours.