How FGFR Inhibitors Work in Cholangiocarcioma, and What Comes Next

Drugs targeting FGFR mutations, which are seen in patients with intrahepatic cholangiocarcinoma (CCA), have generated particular excitement; the authors note that prior to the approval of pemigatinib, the first targeted therapy approved by FDA, only 15% to 25% of patients with CCA were “fit enough to receive second-line chemotherapy.”

For years, patients with cholangiocarcinoma (CCA) had few treatment options and little hope. In most cases, a bile duct cancer was discovered too late for surgery to offer a cure; even when surgery was possible, recurrence was frequent.

More recently, advances in genomic profiling have revealed more about how CCA progresses, and this has highlighted the role of fibroblast growth factor receptors (FGFR). Development of a class of targeted therapies called FGFR inhibitors, which target FGFR2 fusions and rearrangements, have produced significant responses in patients previously treated with chemotherapy. Pemigatinib (Pemazyre), is approved for use in the United States, Europe, Japan, and Hong Kong; infigratinib (Truseltiq) is approved in the United States and Canada.

What is next for this group of medications? Authors Sakti Chakrabarti, MD, of the Medical College of Wisconsin; along with Heidi D. Finnes, PharmD, BCOP, FHOPA, and Amit Mahipal, MBBS, MPH, of the Mayo Clinic, have published an overview these therapies in Expert Opinion on Drug Metabolism and Toxicology. Here, the authors reviewed studies from 2015 to 2021 and discuss the clinical and biological knowledge on FGFR-driven CCA along with a pharmacological explanation of how FGFR inhibitors work and how resistance develops. They also discussed the potential for using these drugs in the first line of treatment.

CCA covers a group of bile duct cancers that include intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA), based on location. About 8000 new cases are diagnosed each year in the United States; while still uncommon, incidence is rising, especially for iCCA. The authors described the prognosis for most patients as “dismal,” since CCA is typically already advanced when diagnosed and most patients develop resistance to the drugs that are available.

The discovery that about half of patients have actionable genomic alterations has set off a wave of research. FGFR mutations, which are seen in patients with iCCA, have generated particular interest; the authors note that prior to the approval of pemigatinib, the first targeted therapy approved by FDA, only 15% to 25% of patients with CCA were “fit enough to receive second-line chemotherapy.”

The authors describe how “dysregulated FGFR signaling promotes the malignant transformation of cells,” leading to changes in FGFR genes that have affected many types of solid tumors—these alterations appear in urothelial, breast, endometrial and squamous cell carcinoma in addition to CCA. In the case of CCA, most alterations involve FGFR2 (6.1%), and among those with iCCA, the prevalence can be as high as 15%. This is especially true in younger patients, the authors noted.

In their discussion of the pharmacokinetics and pharmacodynamics of the drugs, the authors noted that earlier generation multi-kinase inhibitors, such as ponatinib, were aimed at multiple targets—including FGFR—but there was a downside. “These agents have less specificity in inhibiting aberrant FGFR signaling and more off-target effects,” the authors wrote. By contrast, “clinical trials of selective FGFR inhibitors, acting primarily on phosphorylation of the FGFR tyrosine kinase domain, demonstrated more potent inhibition of FGFR.”

Overcoming resistance. Patients who respond to FGFR inhibitors “eventually develop drug resistance and experience tumor progression after an initial period of disease regression or stabilization.” However, as the authors discuss, research is ongoing to understand these mechanisms and how they can be overcome. One focus appears to be on mutations that affect the ATP binding site, also called gatekeeper mutations, that can eventually limit the ability of the FGFR inhibitors to do their job. Thus, future approaches could address this target or other resistance mechanisms. The more patients who are treated with FGFR inhibitors, the authors wrote, the more scientists will learn more about these processes.

“Future analysis of clinically annotated genomic data from clinical trials and real-world patients will likely reveal more granular underpinnings of primary resistance mechanisms and help develop treatment regimens targeting multiple signaling pathways, leading to improved tumor response and patient outcome,” the authors wrote.

Future approaches. The authors also addressed management of toxicities, including possible benefits of plant-based diets. They concluded with a look forward to next steps, which will build on the overall response rate (ORR) of 35.5% seen with pemigatinib (vs 34% with infigratinib) and doubling of median progression-free survival that the authors said justifies “the euphoria” surrounding FGFR targeted therapies.

“Currently, several major approaches are being investigated to build upon this success that includes: (1) trials investigating FGFR inhibitors in treatment naïve patients, (2) combining FGFR-directed therapies with other agents active in CCA, (3) designing and testing novel FGFR inhibitors, and (4) novel sequencing strategies,” they wrote.

Such trials could change the treatment paradigm of chemotherapy in front-line treatment for CCA, although the authors cited the small share of patients carrying FGFR2 alterations as a barrier to this shift. And, they wrote, studies involving FGFR inhibition in urothelial cancer raise the possibility of pairing this mechanism with PD-1 inhibition.

“The development of FGFR inhibitors is a significant advancement in the therapeutic paradigm of advanced CCA,” the authors concluded. “Ongoing research utilizing FGFR inhibitors in treatment-naïve patients, elucidation of resistance mechanisms to harness future trials, and exploration of combination strategies will transform the treatment landscape of CCA.”

Reference

Chakrabarti S, Finnes HD, Mahipal A. Fibroblast growth factor receptor (FGFR) inhibitors in cholangiocarcinoma: current status, insight on resistance mechanisms and toxicity management. Expert Opin Drug Metab Toxicol. Published online February 12, 2022. doi:10.1080/17425255.2022.2039118