Lyrfigtu (lirafugratinib)

Approved September 23, 2026, it joins pemigatinib (Pemazyre, 2020) and futibatinib (Lytgobi, 2022) as a second-line option for FGFR2-fusion cholangiocarcinoma after chemotherapy. A third drug in the class, infigratinib (Truseltiq), was approved in 2021 and withdrawn in 2024. Two 2026 resistance studies suggest lirafugratinib and futibatinib provoke different resistance mutations, which may make them usable in sequence.

In about 10 to 20% of intrahepatic cholangiocarcinomas, a piece of the FGFR2 gene is fused to an unrelated gene, and the fused protein signals the cancer cell to grow nonstop. The 2 approved FGFR drugs, pemigatinib and futibatinib, block FGFR2 but also its close relatives FGFR1 and FGFR4. Blocking FGFR1 raises blood phosphate, and blocking FGFR4 causes diarrhea, which is why dose cuts and pauses are common on those drugs. Lirafugratinib was designed with long molecular-dynamics simulations of how the 4 receptors move, and it binds a flexible loop that only FGFR2 exposes; in lab tests it is about 250 times more selective for FGFR2 than FGFR1 and about 5,000 times more than FGFR4. It binds permanently (covalently), and it was built to keep working against several FGFR2 mutations that cause resistance to the older drugs.

In the 116-patient pivotal ReFocus cohort, the most common serious (grade 3 or higher) side effects were the on-target skin and mouth effects of blocking FGFR2: hand-foot syndrome (palmar-plantar erythrodysesthesia, painful redness and peeling on the palms and soles) in 32.8% and mouth sores (stomatitis) in 12.1%. Side effects led to a dose reduction in 75.9% of patients and a pause in 82.8%, but only 4.3% stopped the drug because of them, and quality of life was maintained. The drug was designed to avoid the high phosphate and diarrhea seen with the older FGFR drugs. In the safety data behind the approval, high phosphate was still reported in 21% of patients, though almost always mild, and diarrhea was among the most common side effects. The FDA label warns about eye problems, including fluid under the retina (retinal pigment epithelial detachment, seen in 31%), so an eye exam with a retina scan is needed before starting, every 2 months for the first 13 months and every 4 months after that, and right away for any vision change. It also warns about high blood phosphate that can lead to calcium deposits in soft tissues, so phosphate is checked throughout treatment, and about harm to a developing baby: women who could become pregnant should use effective birth control during treatment and for 6 months after the last dose, and men with such partners for 3 months after the last dose.

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The approved label covers adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement. The pivotal cohort excluded anyone who had already taken an FGFR inhibitor, so the efficacy numbers in the label apply to FGFR-inhibitor-naive patients. A 2026 Annals of Oncology analysis reported responses in some patients whose cancer had become resistant to earlier FGFR drugs, but that is not the population the approval was built on.

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ReFocus (NCT04526106) is a Phase 1/2 study that started September 2, 2020 and enrolled 490 patients across cholangiocarcinoma and other FGFR2-altered cancers. Its pivotal cohort enrolled 116 adults with FGFR2 fusion or rearrangement cholangiocarcinoma who had had at least 1 prior treatment but never an FGFR inhibitor. By independent review in 114 patients, 46.5% responded (95% CI 37.1 to 56.1; 3 complete and 50 partial responses), 96.5% had their disease controlled, and responses lasted a median 11.8 months, with 76.2% lasting more than 6 months. Median progression-free survival was 11.3 months and median overall survival 22.8 months. Results were presented at the 2026 ASCO Gastrointestinal Cancers Symposium.

Relay Therapeutics in Cambridge, Massachusetts designed RLY-4008 with D. E. Shaw Research using computer simulations of protein motion, and opened the ReFocus trial in September 2020. The FDA gave it breakthrough therapy and orphan drug designations. In October 2023 Relay paused its commercial preparation for cholangiocarcinoma to focus on other programs, and on December 3, 2024 it licensed worldwide rights to Elevar Therapeutics, a Fort Lee, New Jersey subsidiary of Korea's HLB Group, for up to $500 million. Elevar filed the NDA; the FDA accepted it with priority review, announced March 30, 2026, and Elevar submitted a European application on September 15, 2026. The FDA approved it as Lyrfigtu on September 23, 2026, 2 days before its action date, using its Real-Time Oncology Review program.

Advanced cholangiocarcinoma is treated first with gemcitabine and cisplatin, usually plus an immunotherapy. After that, treatment follows the tumor's molecular profile: FGFR2 fusions (pemigatinib, futibatinib, lirafugratinib), IDH1 mutations (ivosidenib), HER2 overexpression (zanidatamab), and a few others. Every one of these depends on tumor genomic testing, which is why testing at diagnosis matters.