Lirafugratinib

Lirafugratinib (RLY-4008), discovered by Relay Therapeutics and licensed worldwide to Elevar Therapeutics in December 2024, was approved by the FDA on 23 September 2026 as Lyrfigtu capsules for adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or other rearrangement. The new drug application (NDA 220425) was received on 27 January 2026, was granted priority review, and used the Real-Time Oncology Review pilot program and the Assessment Aid. Lirafugratinib had received orphan drug designation for cholangiocarcinoma in January 2022 and breakthrough therapy designation in 2023. The application was not referred to an advisory committee. The approval letter states the application is approved for use as recommended in the agreed-upon labeling, and neither the letter nor the prescribing information contains the accelerated approval statement that appears in the labeling of pemigatinib, futibatinib, and infigratinib; the ReFocus cohort had been described in 2024 as designed to support accelerated approval. Approval rests on 116 FGFR inhibitor-naive participants in the single-arm phase 1/2 REFOCUS trial (NCT04526106), with an objective response rate of 46% (95% CI 36 to 55) and a median duration of response of 11.8 months. The FDA required a randomized trial comparing 70 mg once daily with a lower dosage and a P-gp and BCRP drug interaction trial, and accepted a commitment to validate a companion diagnostic. Elevar expects product availability in the fourth quarter of 2026. A marketing authorization application was submitted to the European Medicines Agency in September 2026, and a phase 2 tumor-agnostic study (ReFocus202, NCT07359820) began dosing in June 2026.

The prescribing information lists no contraindications and three warnings and precautions: ocular toxicity, hyperphosphatemia and soft tissue mineralization, and embryo-fetal toxicity. Among 385 participants in the REFOCUS safety population (232 with cholangiocarcinoma and 153 with other solid tumors), retinal pigment epithelial detachment occurred in 31% (grade 3 in 1.8%), with a median time to onset of 57 days, blurred vision in 18%, dry eye in 38%, corneal toxicity or keratitis in 11%, and hyperphosphatemia in 21%, with a median time to onset of 15 days and one dose interruption (0.3%). Ophthalmological examination including optical coherence tomography of the macula is required before treatment, every 2 months for the first 13 months, and every 4 months thereafter. Among the 116 participants with cholangiocarcinoma, serious adverse reactions occurred in 32% and one participant died of hemorrhage; the most frequent adverse reactions were nail toxicity (89%, grade 3 or 4 in 12%), palmar-plantar erythrodysesthesia syndrome (82%, grade 3 or 4 in 33%), stomatitis (80%, grade 3 or 4 in 12%), and alopecia (66%). Treatment-related adverse events led to dose reduction in 75.9%, dose interruption in 82.8%, and discontinuation in 4.3% of participants in the ASCO Gastrointestinal Cancers Symposium 2026 report, and the prescribing information reports permanent discontinuation for an adverse reaction in 5%, dosage interruption in 88%, and dose reduction in 81%. The FDA required a postmarketing randomized trial to characterize severe stomatitis, palmar-plantar erythrodysesthesia syndrome, retinal pigment epithelial detachment, and nail toxicities at 70 mg once daily compared with a lower dosage.

Three other FGFR inhibitors have been approved by the FDA for previously treated FGFR2 fusion- or rearrangement-positive cholangiocarcinoma, each under accelerated approval based on response rate and duration of response: pemigatinib (Pemazyre, 2020), infigratinib (Truseltiq, 2021; withdrawn 16 May 2024, with United States distribution discontinued), and futibatinib (Lytgobi, 2022). Their pivotal single-arm trials reported objective response rates of 36% (pemigatinib, N=107), 23% (infigratinib, N=108), and 42% (futibatinib, N=103), with median durations of response of 9.1, 5.0, and 9.7 months; the FIGHT-202 final analysis reported an objective response rate of 37.0% for pemigatinib. In REFOCUS, lirafugratinib produced an objective response rate of 46% (N=116) with a median duration of response of 11.8 months. The labels differ in dosing (lirafugratinib 70 mg and futibatinib 20 mg once daily continuously; pemigatinib 13.5 mg for 14 of 21 days; infigratinib 125 mg for 21 of 28 days on an empty stomach). Hyperphosphatemia was reported in 93%, 82%, and 88% of participants receiving pemigatinib, infigratinib, and futibatinib across clinical trials, with phosphate-lowering therapy or binders in 33%, 83%, and 77%, compared with 21% for lirafugratinib, consistent with its preclinical selectivity over FGFR1. Retinal pigment epithelial detachment was reported in 31% of participants receiving lirafugratinib, with monitoring that included optical coherence tomography, and in 9% to 11% of participants receiving the other agents, whose trials did not routinely include optical coherence tomography; lirafugratinib labeling requires examination every 2 months for 13 months, compared with every 2 months for 6 months for pemigatinib and futibatinib. Pemigatinib and infigratinib were approved with an FDA-approved test, whereas no FDA-authorized test is available for lirafugratinib. Preclinically, lirafugratinib retained potency against the FGFR2 V564F gatekeeper mutation, against which pan-FGFR inhibitors showed a more than 55-fold loss of potency. No head-to-head or indirect treatment comparison of lirafugratinib with another FGFR inhibitor has been published. In an institutional cohort in which the second FGFR inhibitor after progression was lirafugratinib in 12 participants and futibatinib in 10, all 3 partial responses (13.6%) occurred with lirafugratinib, and the authors state that differences in clinical activity across FGFR inhibitors may reflect confounding factors. For the comparators, a matching-adjusted indirect comparison reviewed by NICE gave hazard ratios for futibatinib compared with pemigatinib of 0.95 (95% CI 0.72 to 1.21) for overall survival and 1.07 (95% CI 0.86 to 1.30) for progression-free survival. A reported average monthly United States price of $44,000 for futibatinib was identified, and NICE reports list prices in England of £7,159.04 for a pack of 14 pemigatinib 13.5 mg tablets and £2,386.33 per pack of futibatinib; no lirafugratinib price has been published.

Cholangiocarcinoma is a malignancy of the biliary epithelium, usually an adenocarcinoma, classified by anatomic site as intrahepatic, perihilar, or distal. In the United States, perihilar disease accounts for approximately 50% to 60% of cholangiocarcinomas, distal disease for 20% to 30%, and intrahepatic disease for 10% to 20%, and cholangiocarcinoma comprises approximately 15% of primary liver tumours. Together with gallbladder and ampullary cancer, it forms biliary tract cancer, which accounts for less than 1% of all cancers worldwide.

The indication is defined by a genomic alteration. FGFR2 fusions or rearrangements occur almost exclusively in intrahepatic cholangiocarcinoma. The fusions most commonly join FGFR2 exons 1 to 17, which carry the extracellular and kinase domains, to one of many partner genes, and loss of the C-terminal negative regulatory domain encoded by exon 18 leads to constitutive kinase activity. The previously treated population is the population in which lirafugratinib was approved: adults with unresectable, locally advanced or metastatic disease after prior systemic therapy, which in REFOCUS meant prior chemotherapy or chemoimmunotherapy without a prior FGFR inhibitor.

Most established risk factors for cholangiocarcinoma share chronic inflammation of the biliary epithelium and bile stasis, including choledochal cyst, Caroli disease, primary sclerosing cholangitis, choledocholithiasis, cirrhosis, chronic hepatitis B and C, and, in endemic regions, liver fluke infection; cirrhosis, non-alcoholic fatty liver disease, and hepatitis B are more strongly associated with intrahepatic disease. In most locations the majority of cases have no identifiable risk factor. No risk factor specific to FGFR2 fusion-positive disease was identified in the cited sources; in one institutional series FGFR alterations were more frequent in participants aged 40 years or younger (20%) than in older participants (6.7%).

No registry reports the incidence of previously treated FGFR2 fusion or rearrangement-positive cholangiocarcinoma. It is estimated from the incidence of cholangiocarcinoma, the frequency of FGFR2 fusions or rearrangements, and the proportion of participants who reach later-line therapy. The American Cancer Society estimates that about 8,000 people in the United States are diagnosed with bile duct cancer each year, and notes that the true number is likely higher because some cases are misclassified. In the Surveillance, Epidemiology, and End Results program, the age-adjusted incidence of intrahepatic cholangiocarcinoma rose 148.8% between 2001 and 2017, from 0.80 to 1.99 per 100 000 person-years, while extrahepatic cholangiocarcinoma rose 7.5%.

FGFR2 fusions or rearrangements are reported in 10% to 16% of intrahepatic cholangiocarcinomas and in 9.2% of 6,802 cholangiocarcinoma samples profiled in one genomic dataset (see 2.2.1.2.2). Only part of the incident population reaches second-line treatment: ABC-06 reported that 15% to 25% receive second-line therapy, and 46% of 413 participants in a United States commercial-claims cohort with advanced biliary tract cancer initiated a second line. Relay Therapeutics estimated that FGFR2-mediated cancers of all tumour types affect approximately 11,000 late-line patients annually in the United States.

Reported frequencies of FGFR2 fusions or rearrangements in intrahepatic cholangiocarcinoma are 13.6% (9 of 66) by reverse-transcriptase polymerase chain reaction, 13% (12 of 96) by fluorescence in situ hybridization, 14% in a sequenced institutional cohort, and 13.9% in a European routine-testing cohort. Central prescreening for FIGHT-202 confirmed FGFR2 fusions or rearrangements in 107 of 1,206 participants (9%), which the investigators describe as broadly consistent with the published range of 10% to 16%. In a comprehensive genomic profiling dataset of 6,802 cholangiocarcinoma samples, 9.2% had FGFR2 rearrangements, of which 76.1% were classified as fusions and 20.7% as other rearrangements, with BICC1 the most common partner (26.7%). In the FIGHT-202 prescreening cohort analysed for clinicogenomic correlates, 74 participants (6.1%) had FGFR2 rearrangements, 15.2% in the United States, 7.4% in Europe, and 2.2% in the rest of the world, which the investigators attribute partly to inclusion of extrahepatic cholangiocarcinoma. In a multicentre Italian cohort of 312 participants with advanced intrahepatic cholangiocarcinoma, FGFR2 fusions or rearrangements occurred in 10.6%. In a surgical FISH series, FGFR2 rearrangements were found in 12/96 intrahepatic, 0/25 perihilar, and 0/31 extrahepatic tumours. Frequency varied with the biopsy site sampled (9% of primary tumour biopsies, 6% and 4% of other sites) and was enriched 2.1-fold in participants with African ancestry. The FGFR2 cohort of FIGHT-202 contained greater proportions of women and of participants younger than 65 years than the other cohorts, and in a resected cohort FGFR2 fusion was more often present in younger (53 vs. 62 years) and female (83 vs. 49%) participants, whereas a European routine-testing cohort found no association between FGFR2 fusions and age or sex.

Overall prevalence of the underlying cancer is limited by short survival: SEER estimated 116,514 people living with liver and intrahepatic bile duct cancer in the United States in 2023, and the 16-year limited-duration prevalence of cholangiocarcinoma from 2001 to 2017 was reported as 5.92, higher for extrahepatic (4.23) than intrahepatic (1.69) disease. Nearly 40% of biliary tract cancers harbour a genetic alteration that is a potential target for precision medicine.

Cholangiocarcinoma is usually diagnosed at an advanced stage. SEER reports 5-year relative survival for liver and intrahepatic bile duct cancer of 37.4% for localized, 13.4% for regional, and 3.6% for distant disease, and across 40,030 SEER cholangiocarcinoma cases diagnosed from 2001 to 2017 median overall survival from diagnosis was 8 months overall and 6 months for intrahepatic disease. In the first-line advanced setting, median overall survival was 12.9 months with durvalumab plus gemcitabine and cisplatin in the TOPAZ-1 three-year update and 12.7 months with pembrolizumab plus gemcitabine and cisplatin in KEYNOTE-966. After progression, median overall survival in ABC-06 was 6.2 months with FOLFOX plus active symptom control and 5.3 months with active symptom control alone.

FGFR2 fusion-positive disease has a comparatively favourable natural history. In an institutional series of 377 participants, FGFR genetic aberrations were associated with longer overall survival (37 versus 20 months, P < .001), which remained significant after excluding participants treated with FGFR inhibitors, and co-occurring TP53 and CDKN2A/B alterations were associated with shorter survival. Median cancer-specific survival was 123 versus 37 months with and without FGFR2 translocations in a FISH series, 5-year overall survival after resection of intrahepatic cholangiocarcinoma was 83% versus 32% by FGFR2 fusion status, and in a multicentre real-world cohort FGFR2 fusions or rearrangements retained a prognostic association with overall survival after exclusion of participants treated with targeted therapy. In the multicentre cohort, median overall survival was 26.5 months with and 17.0 months without FGFR2 fusions or rearrangements, with a hazard ratio of 0.54 (95% CI 0.30-0.95) at multivariate analysis, and after resection of intrahepatic cholangiocarcinoma 10-year overall survival was 46 vs. 22% by FGFR2 fusion status. Not every series found a difference: outcome did not differ significantly by FGFR2 fusion status in a Japanese RT-PCR series, and in a European routine-testing cohort median overall survival was 32.2 versus 13.6 months (HR = 0.81, p = 0.52). Participants with FGFR2 rearrangements may be less likely to benefit from first-line platinum chemotherapy, although time to progression did not differ by FGFR2 status in one sequenced cohort.

Cholangiocarcinoma arises predominantly from cholangiocytes and can also develop from peribiliary glands and hepatocytes. Chronic inflammation, growth factors, and bile acids in the tumour microenvironment drive carcinogenesis, and the tumours are highly desmoplastic. Genomic alterations track with anatomic subtype: FGFR2 fusions, IDH1 and IDH2 mutations, and BAP1 mutations characterize intrahepatic disease, and in one sequenced cohort the most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 fusions (14%).

FGFR2 fusions retain the extracellular and kinase domains of FGFR2 and lose the C-terminal negative regulatory region, and truncation of FGFR2 after exon 17 is oncogenic in itself. Fusion partners exhibit oligomerization capability, and fusion proteins interact in the absence of FGF ligand, so kinase activation is ligand-independent. Signalling proceeds through the MAPK (RAS, RAF, MEK, ERK) and PI3K, AKT, and mTOR pathways; expression of FGFR2 fusion kinases activated MAPK and conferred transforming ability in cell models, and patient-derived organoids were dependent on Ras-Erk signalling. Fusion partners are diverse: 56 different partners were identified among 107 participants in FIGHT-202, 42 (75%) unique to one participant, with BICC1 the most common (29%). FGFR2 fusions usually co-occur with inactivation of TP53, CDKN2A, or BAP1, and in a Japanese series of 102 cholangiocarcinomas they were mutually exclusive with KRAS and BRAF mutations. All tested FGFR2 rearrangement partners were oncogenic and sensitive to FGFR2 inhibition in vitro, which the authors interpret as indicating that the FGFR2 fusion, irrespective of partner gene, is the clinically important variable.

Diagnosis rests on cross-sectional imaging followed by histological or cytological confirmation, because no radiological pattern is specific for cholangiocarcinoma. Guidelines recommend a core biopsy for pathology and molecular profiling before non-surgical treatment, molecular analysis in advanced disease suitable for systemic treatment, and profiling when first-line systemic treatment is initiated; parallel testing by next-generation sequencing is preferred over single-gene testing, and ESMO recommends tumour next-generation sequencing in advanced cholangiocarcinoma. FGFR inhibitors are recommended for FGFR2 fusions after at least one prior line of systemic therapy.

FGFR2 fusion detection is technically demanding because partners are diverse. In 226 cases tested by three methods, detection rates were 9.7% with RNA-based sequencing, 7.1% with DNA-based sequencing, and 10.2% with FISH, and against RNA-confirmed fusions DNA-based sequencing had a sensitivity of 71.4% and FISH 95.2%. In an interlaboratory ring trial, 13 of 16 centres (81%) passed the sequencing round, and partner-agnostic methods were judged superior. FoundationOne CDx is FDA approved for detecting FGFR2 fusions or rearrangements for pemigatinib, with an adjusted positive percentage agreement of 87.1% against an externally validated assay and 100% agreement on all measures against the F1 CLIA/CAP assay, although 27 of 107 FGFR2 rearrangement-positive participants enrolled in FIGHT-202 could not be evaluated with it because of insufficient DNA; the futibatinib label states that no FDA-approved test is available, and the lirafugratinib approval letter requires validation studies to support labeling of a companion diagnostic using blood or tissue. Circulating tumour DNA detected FGFR2 rearrangements in 5.3% of cholangiocarcinoma liquid biopsies against 7.6% of tissue samples, rising to 8.4% when tumour fraction was 1% or higher, and detected 84% of tissue-confirmed FGFR2 fusions or rearrangements in one study, whose authors advise confirming fusions with unidentified partners by tissue profiling. ESMO ranks FGFR2 fusions at ESCAT level IB, with an estimated prevalence of 5%-15% of intrahepatic cholangiocarcinomas, and notes that a DNA-based test might miss a fusion whose break point region is not fully covered by the gene panel, whereas RNA-based panels identify the fusion transcript and the fusion partner. In a multicentre Italian cohort, extended molecular profiling was performed in 79.9% of participants with advanced cholangiocarcinoma, and 26 (18.7%) of the 139 participants with an ESCAT I-III alteration received a corresponding tailored treatment.

Long-term morbidity in advanced biliary tract cancer arises mainly from recurrent biliary obstruction and its management, by infection, and by functional decline after progression on first-line therapy. Active symptom control in the second-line setting is defined to include biliary drainage, antibiotics, analgesia, steroids, anti-emetics, palliative radiotherapy, and transfusion of blood products. In a single-centre series of 171 participants who received a palliative biliary stent, complications occurred in 91 (53%) and cholangitis was the most frequent, in 48 (53%) of those with complications; median survival was 75.5 days. In a United States claims cohort, 69.5% of participants had an all-cause inpatient hospitalization and 65.6% a biliary-tract-cancer-related hospitalization, with a mean stay of 7 days per visit and the largest share of inpatient visits occurring during third-line therapy. Rapid decline in performance status after first-line progression limits how many participants can be treated at all.

Robust health-related quality-of-life data in cholangiocarcinoma are sparse, which the authors of a disease primer attribute to low incidence, high lethality, limited trial enrollment until recently, and a historical lack of dedicated measurement tools. The EORTC QLQ-BIL21 was validated in 172 participants with cholangiocarcinoma and 91 with gallbladder cancer and measures eating, jaundice, tiredness, pain, and anxiety symptoms alongside the generic QLQ-C30.

In the second-line setting, the ABC-06 quality-of-life analysis found no difference between arms in time to deterioration of the global health scale (adjusted hazard ratio 0.97, 95% CI 0.48 to 1.97, P = 0.937) and found that adding FOLFOX did not worsen global, physical, social, or symptom scores, whereas the active-symptom-control arm declined across several domains including the EQ-5D utility value, which fell from 0.75 at baseline to 0.62 at month 4. In the first-line setting, neither durvalumab nor pembrolizumab added to gemcitabine and cisplatin worsened patient-reported outcomes: median time to deterioration of global health status or quality of life was 7.4 months versus 6.7 months in TOPAZ-1, and estimates were similar between arms in KEYNOTE-966.

In a United States commercially insured cohort of participants with advanced biliary tract cancer treated before immuno-oncology regimens were approved, mean per-patient-per-month all-cause costs were $18,274 overall, of which approximately 84% ($15,296) were biliary-tract-cancer-related. Costs rose with each line of therapy, from $19,589 in first line to $22,617 in second line and $33,534 in third line. Outpatient and inpatient utilization were the main cost drivers, and approximately 70% of participants had at least one inpatient visit. Earlier estimates cited in the same study were $7,743 per-patient-per-month for advanced cholangiocarcinoma-associated costs after first-line failure and $20,696 per-patient-per-month for all-cause biliary tract cancer management. In a separate claims analysis of participants receiving pemigatinib, mean per-patient-per-month medical costs were $13,444 for those with a prior cancer-of-unknown-primary diagnosis and $9,881 for those without. In a second United States claims analysis of 221 participants initiating pemigatinib, mean all-cause health care costs were $11,139 per patient per month, of which $8,889 was attributable to cholangiocarcinoma-related care, driven mainly by ambulatory visits and inpatient stays.

Cholangiocarcinoma imposes measurable work loss and indirect costs on working-age households. In a United States retrospective claims analysis of 1,065 participants with cholangiocarcinoma who had work absence and disability benefits eligibility, mean all-cause days absent per patient per month for illness were 6.0 for intrahepatic and 4.3 for extrahepatic disease, and 12.9% and 6.6% respectively had at least one cholangiocarcinoma-related short-term disability claim. Median indirect costs per patient per month from absenteeism, short-term disability, and long-term disability were $622, $635, and $690 for intrahepatic disease and $304, $589, and $465 for extrahepatic disease. A patient and advocate writing in a disease primer describes declining a first-line clinical trial because insurance would not cover the associated standard-of-care costs and she did not want to put her family in financial distress, and describes travel for trial participation as a source of financial burden.

Eligibility for lirafugratinib requires identification of an FGFR2 fusion or rearrangement, and the guideline recommendation for molecular analysis in advanced disease applies to all participants suitable for systemic treatment. The yield of testing is low relative to the number tested: in 91 biliary tract tumours profiled at one centre, potentially actionable alterations were found in 23.1% and genomically matched therapy was introduced in 7.7%, and FGFR2 fusions or rearrangements occur in approximately 9% of profiled cholangiocarcinomas. The Canadian drug agency estimated that testing costs approximately $38,000 to identify a single patient eligible for pemigatinib. NICE estimated that adding FGFR2 as a target to the NHS panel test would incur an additional cost of £34, or £340 for each additional person identified who is FGFR2-positive, and a Taiwanese cost-effectiveness model applied a genetic testing fee of NT$30,000. Tissue sufficiency also limits yield: 27 of 107 FGFR2 rearrangement-positive participants in FIGHT-202 could not be evaluated with FoundationOne CDx because of insufficient DNA, and ESMO advises that the cost-effectiveness of next-generation sequencing be assessed at the local level. Tissue-based profiling fails in up to 26.8% of metastatic biliary tract cancers, which is one reason for plasma-based testing. Among 221 participants initiating pemigatinib, those with a prior cancer-of-unknown-primary diagnosis had higher ambulatory costs ($8,584 versus $5,308 per patient per month) and shorter median overall survival (10.2 versus 30.7 months), and the authors recommend reflexive genomic testing for cancer of unknown primary. At approval, the FDA required further validation studies before a companion diagnostic for lirafugratinib is specified in labeling.

Non-targeted second-line chemotherapy provides limited benefit. In ABC-06, the only positive phase 3 second-line trial, median overall survival was 6.2 months with FOLFOX plus active symptom control versus 5.3 months with active symptom control alone, and an objective response occurred in 4 of 81 participants (5%); the Pan-Asian adaptation of the ESMO guideline downgraded the level of evidence for this recommendation. Randomized results for liposomal irinotecan are inconsistent between NIFTY and NALIRICC; in NALIRICC median overall survival was 6·9 months with liposomal irinotecan plus fluorouracil and leucovorin and 8·2 months in the control group (HR 1·08), and grade 3 or worse adverse events affected 34 (71%) of 48 and 24 (50%) of 48 participants.

Reversible FGFR inhibitors produce responses in a minority and benefit that is time-limited. Pemigatinib produced an objective response rate of 37.0% with median progression-free survival of 7.0 months and median overall survival of 17.5 months in the FIGHT-202 final analysis, and infigratinib an objective response rate of 23.1%; the United States approval of infigratinib was withdrawn in May 2024 after the confirmatory PROOF 301 trial randomized 48 of approximately 300 planned participants and closed for poor accrual. The irreversible inhibitor futibatinib produced an objective response rate of 42% with median progression-free survival of 9.0 months. The accelerated approvals of futibatinib and infigratinib rested on single-group trials, and randomized first-line trials of FGFR inhibitors have enrolled slowly.

Toxicity arises from inhibition of FGFR isoforms other than FGFR2. Hyperphosphatemia, attributed to FGFR1 inhibition, was reported from laboratory values in 93% of participants receiving pemigatinib and 88% receiving futibatinib, and 77% of futibatinib recipients received phosphate binders; diarrhea attributed to FGFR4 inhibition occurs in 15% to 36%. Retinal pigment epithelial detachment occurred in 11% with pemigatinib and 9% with futibatinib, nail toxicity in 42% of FIGHT-202 participants, and dose reductions for adverse reactions in 58% of futibatinib recipients.

Acquired resistance is common. Progression on reversible FGFR inhibitors is typically observed within 1 year, 49 of 82 participants (60%) had one or more secondary FGFR2 kinase domain mutations at acquired resistance, most often at the N550 molecular brake (63% of mutations) and the V565 gatekeeper (47%), and resistance is frequently polyclonal; new MAPK pathway alterations appeared in 9 of 17 participants with repeat sequencing. Every participant analysed at progression on pemigatinib had at least 1 acquired FGFR2 mutation, and after futibatinib FGFR2 kinase domain mutations were identified in 62% (23/37) of FGFR inhibitor-naive participants with cholangiocarcinoma, RAS mutations in 33% (14/43), and BRAF mutations in 21% (9/43). A second FGFR inhibitor produced an objective response rate of 13.6% and median progression-free survival of 3.8 months, against 47.6% and 8.5 months with the first. Median overall survival in advanced biliary tract cancer as a whole remains around 1 year.

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.

Prior FGFR inhibitor exposure is the largest reported modifier of lirafugratinib activity. In the ReFocus dose-escalation analysis, the objective response rate among participants with FGFR2 fusion or rearrangement-positive cholangiocarcinoma was 52% (13 of 25) without and 14% (7 of 50) with prior FGFR inhibitor therapy, with median duration of response of 8.2 and 5.6 months. Resistance mutations explain part of the difference: 28 of 46 pretreated participants evaluable by circulating tumour DNA had at least one baseline FGFR2 resistance mutation, and the proportion with such mutations rose from 1 of 6 without prior FGFR inhibitor to 5 of 12 after one and 6 of 7 after two or more. Acquired resistance to lirafugratinib differs from that to pan-FGFR inhibitors, with FGFR2 M538 or L618 mutations in 11 of 16 cases and receptor tyrosine kinase or MAPK bypass alterations in 9 of 16.

Co-occurring alterations modify outcome with approved FGFR inhibitors. In a real-world pemigatinib cohort, median progression-free survival was 4.79 versus 8.66 months with and without CDKN2A mutations and 5.97 versus 8.52 months with and without BAP1 mutations, without a difference in overall survival. With futibatinib, progression-free survival was shorter with CDKN2B alterations (4.8 versus 11.0 months), responses did not correlate with fusion partner, and response rates did not differ by TP53 status. With pemigatinib in FIGHT-202, participants with TP53 alterations (n = 9) had no objective responses and a median progression-free survival of 2.8 months vs 9.0 months, CDKN2A/B alterations were associated with shorter median progression-free survival (6.4 months vs 9.0 months), and response did not differ between rearrangements and predicted fusions (40.0% vs 34.8%) or between BICC1 and other partners. In an institutional series, TP53 and CDKN2A/B alterations were associated with shorter overall survival and BAP1 had no prognostic effect. By alteration type, FGFR fusions were associated with the most favourable FGFR inhibitor outcomes (objective response rate 45.9%), with median progression-free survival of 7.3 months, against 4.1 months for mutations and 2.1 months for amplifications. Within second-line chemotherapy, FOLFOX benefit in ABC-06 was independent of platinum sensitivity and the number of elevated tumour markers stratified survival. In first-line chemoimmunotherapy, the survival benefits of durvalumab in TOPAZ-1 were generally consistent across the subgroups analysed, including PD-L1 tumour area positivity of 1% or greater and of less than 1%.

Care management starts with molecular profiling at initiation of first-line systemic therapy, using a method able to detect FGFR2 fusions with unknown partners, so that an FGFR2 fusion or rearrangement is known before progression. During lirafugratinib therapy, a comprehensive ophthalmological examination including optical coherence tomography of the macula is required before initiation, every 2 months for the first 13 months, and every 4 months thereafter, with urgent evaluation for visual symptoms; retinal pigment epithelial detachment occurred in 31% of recipients (grade 3 in 1.8%) at a median of 57 days, and dry eye in 38%, treated with ocular demulcents. The corresponding schedule for pemigatinib and futibatinib is every 2 months for the first 6 months and every 3 months thereafter. Serum phosphate is monitored throughout treatment; hyperphosphatemia occurred in 21% of lirafugratinib recipients at a median of 15 days, and phosphate binders were required in 7 (1.8%), whereas the pemigatinib and futibatinib labels specify a low-phosphate diet and phosphate-lowering therapy at defined serum thresholds. Effective contraception is required during treatment and for 6 months (females) or 3 months (males with female partners) after the last dose.

Disease-directed care continues alongside targeted therapy: follow-up every 8 to 12 weeks with CT or MRI and CA 19-9 or CEA where secreted, biliary drainage for obstruction, prompt treatment of biliary sepsis, and education on stent patency. Serial circulating tumour DNA can detect emerging resistance mutations before radiologic progression.