Sequencing FGFR2 Inhibitors in Previously Treated Cholangiocarcinoma

Following the FDA approval of lirafugratinib (Lyrfigtu) for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma, there are currently 3 FGFR2 inhibitors now approved in the disease. The practical question has shifted from whether to use one to which to use first. No head-to-head data exist to settle it, leaving clinicians to weigh cross-trial efficacy numbers, the potential to overcome resistance mutations, and differences in tolerability.

In an interview with CancerNetwork® about the 2026 Chicago Cholangiocarcinoma Symposium, Chih-Yi “Andy” Liao, MD, described the 2 camps he has observed among oncologists. Some favor futibatinib (Lytgobi) first, since its progression-free and overall survival figures looked modestly better than those from the phase 2 FIGHT-202 study (NCT02924376) of pemigatinib (Pemazyre) before lirafugratinib was approved. Others start with pemigatinib and hold futibatinib in reserve for its potential activity against tumors that have progressed on another FGFR inhibitor, reflecting what Liao described as oncologists’ preference for keeping a backup plan.

Liao noted that lirafugratinib occupies a similar position, having been designed to overcome resistance mutations, and said he could envision using pemigatinib first and lirafugratinib upon progression. He also addressed tolerability, explaining that while all 3 agents produce FGFR2-class adverse effects such as hyperphosphatemia, the degree differs between them, and that his patients have described lirafugratinib as the hardest to tolerate. Liao framed the decision as a balance between benefits and toxicities.

Liao is an associate professor of Medicine, associate director of Gastrointestinal Oncology, and co-director of the Neuroendocrine Tumor program at University of Chicago School of Medicine.

Transcript:

CancerNetwork: If a patient comes to you with this indication, previously treated, what are you giving first among pemigatinib, futibatinib, and lirafugratinib? Do you have a ranking or a sense of when you would give one over another?

Liao: In terms of efficacy, before lirafugratinib was approved, the progression-free and overall survival numbers for futibatinib technically looked a little better than the phase 2 FIGHT-202 study [NCT02924376] with pemigatinib. A lot of oncologists I’ve seen are using futibatinib first. But I’ve also seen the other camp, where they use pemigatinib first, because futibatinib has potential activity to overcome some of these resistance mutations for tumors that have progressed on other FGFR inhibitors. Oncologists always like to have a backup plan, right? I’ve seen oncologists use pemigatinib first and futibatinib second because it may be active after pemigatinib.

Lirafugratinib is kind of the same situation, where it was designed with this in mind to overcome these resistance mutations, so perhaps after progression, let’s say on pemigatinib, it would still be active. These data were presented previously at ASCO. I could potentially see using pemigatinib first and, upon progression, using lirafugratinib.

Now, [in terms of adverse effects], these drugs are also slightly different. They all cause FGFR2-class [adverse] effects, like hyperphosphatemia, [ocular] toxicity, [nail] toxicity, and things like that, but the degree is different. From my patients’ personal, subjective experiences, lirafugratinib is probably the hardest to tolerate, but that’s just what former patients have told me. It’s always a balance between the benefits and the toxicities.

Reference

FDA approves lirafugratinib for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma. News release. FDA. September 23, 2026. Accessed September 28, 2026. https://tinyurl.com/mst6kcav