Summary: anticipated position of lirafugratinib

The FDA approved lirafugratinib on 23 September 2026 for adults with previously treated unresectable, locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or other rearrangement. Efficacy was established in 116 participants who had received prior chemotherapy or chemoimmunotherapy and no FGFR inhibitor. Its place is therefore the one guidelines assign to FGFR inhibitors: after progression on at least one prior systemic line, which in current practice is gemcitabine and cisplatin with durvalumab or pembrolizumab, as an alternative to pemigatinib and futibatinib, with FOLFOX as the non-targeted second-line standard of care. Use depends on molecular testing that identifies the fusion or rearrangement.

Lirafugratinib differs from the approved FGFR inhibitors in selectivity. In vitro it shows more than 250-fold selectivity over FGFR1 and more than 5,000-fold over FGFR4, and it retained activity against FGFR2 resistance mutations, including V565 gatekeeper variants, in preclinical models. Hyperphosphatemia was reported as an adverse reaction in 21% of lirafugratinib recipients, whereas the pemigatinib and futibatinib labels report hyperphosphatemia from laboratory values in 93% and 88%; the definitions differ and no head-to-head comparison exists. Activity after a prior FGFR inhibitor was lower (see 2.2.2.3), and FGFR inhibitor-pretreated participants are outside the population in which approval efficacy was established. In an institutional cohort, median progression-free survival was 3.8 months with a second FGFR inhibitor and 8.5 months with the first, stable disease was achieved in 13 (59.1%) participants given a second FGFR inhibitor, and all 3 partial responses with a second FGFR inhibitor occurred with lirafugratinib; the authors conclude that the utility of a second FGFR inhibitor may depend on the nature of the resistance mechanism. Resistance profiles to lirafugratinib and futibatinib differ, and three participants who progressed on lirafugratinib responded to futibatinib, which supports sequencing guided by the resistance mutation detected.

Lirafugratinib is taken orally at 70 mg once daily until progression or unacceptable toxicity, which places care in the outpatient and specialty pharmacy setting with scheduled ophthalmologic examinations. The manufacturer expects United States availability by the fourth quarter of 2026.

Approved indication and the population in which efficacy was established

“On September 23, 2026, the Food and Drug Administration approved lirafugratinib (Lyrfigtu, Elevar Therapeutics, Inc.), a kinase inhibitor, for the treatment of adults with previously treated unresectable, locally advanced or metastatic cholangiocarcinoma harboring a fibroblast growth factor receptor 2 (FGFR2) gene fusion or other rearrangement.” (opens the source at this quote in a new tab)
“Efficacy was evaluated in REFOCUS (NCT04526106), a multicenter, open-label, single-arm trial in 116 patients with unresectable or metastatic cholangiocarcinoma who were naïve to FGFR inhibitor treatment and had received prior chemotherapy or chemoimmunotherapy.” (opens the source at this quote in a new tab)

Care setting: oral once-daily outpatient therapy

“The recommended lirafugratinib dose is 70 mg orally once daily until disease progression or unacceptable toxicity.” (opens the source at this quote in a new tab)

Manufacturer and clinician statements on the position of lirafugratinib

“The FDA approval of Lyrfigtu introduces a vital second-line treatment option for patients living with CCA and their families” (opens the source at this quote in a new tab)
“Lyrfigtu is expected to be available to patients in the U.S. by Q4 2026.” (opens the source at this quote in a new tab)
“And unlike earlier pan-FGFR inhibitors, it selectively targets FGFR2 while minimizing off-isoform toxicities.” (opens the source at this quote in a new tab)
“The results also reinforce the importance of molecular testing at diagnosis so that patients can be matched to therapies most likely to benefit them.” (opens the source at this quote in a new tab)

Lirafugratinib: FGFR2 selectivity designed to spare FGFR1 and FGFR4

“Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion–positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations.” (opens the source at this quote in a new tab)
“In vitro, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations.” (opens the source at this quote in a new tab)

“Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro,” (opens the source at this quote in a new tab)

Lirafugratinib: activity against FGFR2 resistance mutations in preclinical models

“In addition, RLY-4008 has potent in vitro and in vivo activity against FGFR2 mutations that drive clinical resistance to available pan-FGFRi.” (opens the source at this quote in a new tab)
“Finally, RLY-4008 spares FGFR1 in vivo, indicating the potential to avoid FGFR1-mediated toxicities in the clinic.” (opens the source at this quote in a new tab)

“In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y.” (opens the source at this quote in a new tab)

Sequencing of irreversible FGFR inhibitors guided by resistance mutations

“After lirafugratinib progression, three patients received futibatinib and experienced prolonged disease response.” (opens the source at this quote in a new tab)
“The complementary activity of lirafugratinib and futibatinib against FGFR2 kinase domain mutations supports their sequential use when precise resistance mutations are detected in patients.” (opens the source at this quote in a new tab)

“Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors.” (opens the source at this quote in a new tab)

Outcomes with a second FGFR inhibitor in routine care and trials

“Among the 22 patients who received a second FGFRi, outcomes were inferior to firsts exposure (ORR of 13.6% vs 47.6% and median PFS of 3.8 vs 8.5 months).” (opens the source at this quote in a new tab)

Second FGFR inhibitor after progression: survival, disease control, and dependence on the resistance mechanism

“However, the median PFS during second use was 3.8 months [95%CI, 2.9–7.0] versus 8.5 months [95%CI, 5.9–12.6] during first-line therapy. Median OS dropped from 22.4 months [95%CI, 15.7–50.6] to 10.9 months [95%CI, 4.5–22.6].” (opens the source at this quote in a new tab)
“While second FGFRi was associated with lower ORR and shorter PFS, but disease control was achieved in almost 60% of patients, and a subset derived durable benefit.” (opens the source at this quote in a new tab)
“The clinical utility of using a second FGFRi may therefore depend on the nature of the resistance mechanism and the ability of subsequent inhibitors to overcome it.” (opens the source at this quote in a new tab)
“Also, the small numbers in certain tumor subgroups, particularly for rarer histology and FGFRi second use cases, limit the statistical power for subgroup comparisons.” (opens the source at this quote in a new tab)

Lirafugratinib (Lyrfigtu)

Place in treatment, anticipated use, and care setting