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Lirafugratinib (Lyrfigtu)

Previously treated FGFR2 fusion or rearrangement-positive cholangiocarcinoma

Also known as RLY-4008
Regulatory submission
NDA submitted January 2026
Last updated
158 sources

Product information and disease descriptionPlace of product in therapyApproaches to treatmentCurrent treatment options and standard of care

Limitations of current therapies

21 evidence topics · 25 sources

Summary: limitations of current treatment for previously treated FGFR2 fusion-positive cholangiocarcinoma

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final analysis, and infigratinib an objective response rate of 23.1%; the United States approval of infigratinib was withdrawn in May 2024 after the confirmatory PROOF 301 trial randomized 48 of approximately 300 planned participants and closed for poor accrual.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.

Acquired resistance to FGFR inhibition and next-generation agents

“Cholangiocarcinoma is a rare, aggressive cancer often driven by FGFR2 fusions, which are targetable with inhibitors such as pemigatinib and futibatinib. However, resistance frequently develops due to acquired FGFR2 mutations.” (opens the source at this quote in a new tab)

“Among 51 patients included in the efficacy evaluable set, the objective response rate was 6·3% (95% CI 0·2-30·2; one confirmed partial response) in cohort A1, 30·0% (6·7-65·3; three confirmed partial responses) in cohort A2, 23·1% (5·0-53·8; three confirmed partial responses) in cohort B, and 0% in cohort C.” (opens the source at this quote in a new tab)

Landscape of clinical resistance mechanisms to FGFR inhibitors

“Overall, 49 of 82 patients (60%) had one or more detectable secondary FGFR2 kinase domain mutations upon acquired resistance. N550 molecular brake and V565 gatekeeper mutations were most common, representing 63% and 47% of all FGFR2 kinase domain mutations, respectively.” (opens the source at this quote in a new tab)

“Interestingly, disruption of the cysteine residue covalently bound by futibatinib (FGFR2 C492) was rare, observed in 1 of 42 patients treated with this drug.” (opens the source at this quote in a new tab)

“While reversible ATP-competitive FGFR inhibitors provide benefit to most patients with FGFR2 fusion–positive ICC, with approximately 80% showing stable disease or partial response, progression is typically observed within less than 1 year.” (opens the source at this quote in a new tab)

Acquired resistance to reversible FGFR inhibitors: polyclonal FGFR2 kinase domain mutations

“Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression.” (opens the source at this quote in a new tab)

“Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intra-lesional heterogeneity, with different FGFR2 mutations in individual resistant clones.” (opens the source at this quote in a new tab)

“The p.V564F gatekeeper mutation, which was common to all three patients, confers resistance by inducing a steric clash with BGJ398 in its FGFR2 binding pocket (Figure 2A).” (opens the source at this quote in a new tab)

Acquired resistance to pemigatinib: FGFR2 kinase domain mutations at progression

“Strikingly, every patient analyzed had at least 1 acquired mutation in FGFR2.” (opens the source at this quote in a new tab)

“Polyclonal resistance, involving multiple acquired FGFR2 mutations, was observed in 3 patients.” (opens the source at this quote in a new tab)

“Interestingly, no gatekeeper (FGFR2 p.V564) mutations were identified in this study as has been reported with other FGFR inhibitors (28,29).” (opens the source at this quote in a new tab)

“There is a need for FGFR inhibitors whose potency is not affected by these kinase domain mutations, including the gatekeeper mutations.” (opens the source at this quote in a new tab)

Acquired resistance to futibatinib

“Acquired resistance to futibatinib was frequently polyclonal and driven by an array of mutations within the relevant FGFR kinase domain, predominantly V565L, V565F, and N550K variants.” (opens the source at this quote in a new tab)

“In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients).” (opens the source at this quote in a new tab)

Acquired resistance to futibatinib: frequency of kinase domain, RAS, and BRAF mutations at progression

“Among FGFR inhibitor-naive patients with cholangiocarcinoma, FGFR2 kinase domain mutations were identified in 62% (23/37) of patients, and among those who harbored at least one FGFR2 variant, the frequency of polyclonal resistance was 87%, and the mean number of variants was 3.6 (Table 3).” (opens the source at this quote in a new tab)

“Patients with a partial response exhibited the highest rate (100%, 11/11) and number of kinase domain mutations (mean 3.6), while those with progressive disease as their best overall response harbored the lowest rate (14%, 1/7) and number (mean 2.0).” (opens the source at this quote in a new tab)

“Substitutions affecting V565 were seen in 74% (20/27) of all patients with clinical benefit, including 86% (18/21) and 50% (2/4) of FGFR inhibitor-naive and -exposed patients, respectively, with cholangiocarcinoma.” (opens the source at this quote in a new tab)

“In the 43 patients with cholangiocarcinoma with post-progression ctDNA samples, RAS mutations were detected at progression in 33% (14/43) and BRAF mutations in 21% (9/43)” (opens the source at this quote in a new tab)

“Compared with mechanisms of acquired resistance to reversible FGFR inhibitors reported in previously published case series and case reports, RAS mutations, gatekeeper mutations, and polyclonality appear to emerge more frequently with futibatinib.” (opens the source at this quote in a new tab)

“Consequently, treatment selection following progression on FGFR inhibitors may require a tailored approach accounting for FGFR2 kinase domain mutations and alternative signaling pathways.” (opens the source at this quote in a new tab)

Off-target MAPK pathway resistance to FGFR inhibitors

“On retrospective analysis of 17 patients with repeat sequencing following FGFRi treatment, 11 (64.7%) had new FGFR2 mutations detected, 9 (52.9%) had new alterations in MAPK pathway genes, 7 of these patients developing new alterations in both FGFR2 and MAPK pathway.” (opens the source at this quote in a new tab)

“These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi.” (opens the source at this quote in a new tab)

Limited evidence for a second FGFR inhibitor after progression

“A major challenge to the efficacy of FGFRi is the development of acquired resistance, frequently mediated by secondary on-target mutations within the FGFR kinase domain, such as gatekeeper mutations, that interfere with drug binding [11].” (opens the source at this quote in a new tab)

“Evidence supporting FGFRi second use after disease progression on first FGFRi remains limited to some case report or case series [13,14].” (opens the source at this quote in a new tab)

Hyperphosphatemia as an FGFR1-mediated class toxicity of pan-FGFR inhibitors

“Hyperphosphatemia is attributed to the inhibition of FGFR1, which then increases phosphate reabsorption in the kidney” (opens the source at this quote in a new tab)

“In addition, diarrhea is reported in 15% to 36% of patients (all CTCAE grades), owing to inhibition of FGFR4” (opens the source at this quote in a new tab)

“The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs.” (opens the source at this quote in a new tab)

Pemigatinib label: retinal pigment epithelial detachment and hyperphosphatemia

“Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%.” (opens the source at this quote in a new tab)

“PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis.” (opens the source at this quote in a new tab)

“hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE.” (opens the source at this quote in a new tab)

Pemigatinib: nail toxicity, stomatitis, and serous retinal detachment in FIGHT-202

“Among other clinically notable adverse events, nail toxicities (all related Medical Dictionary for Regulatory Activities [MedDRA] preferred terms combined; appendix p 17) were experienced by 62 (42%) of 146 patients (three [2%] grade ≥3) and occurred with a median time to onset of 6・0 months (95% CI 4・8–8・8). Five (3%) of 146 patients had dose reductions and six (4%) had dose interruptions because of nail toxicities.” (opens the source at this quote in a new tab)

“Adverse events related to serous retinal detachment due to subretinal fluid accumulation (all related MedDRA preferred terms combined; appendix p 17) occurred in six (4%) of 146 patients; all events were grade 1 or 2, except for one grade 3 event that was classified as of rhegmatogenous origin and unrelated to treatment.” (opens the source at this quote in a new tab)

“62 (42%) patients had dose interruptions due to adverse events, most frequently (at least four patients) stomatitis (n=11), palmar-plantar erythrodysaesthesia syndrome (n=8), arthralgia (n=7), fatigue (n=6), and abdominal pain (n=4).” (opens the source at this quote in a new tab)

Futibatinib label: retinal pigment epithelial detachment, hyperphosphatemia, and dose reductions

“Among 318 patients who received LYTGOBI across clinical trials [see Adverse Reactions (6.1)] where ophthalmologic monitoring did not routinely include optical coherence tomography (OCT), RPED occurred in 9% of patients.” (opens the source at this quote in a new tab)

“hyperphosphatemia was reported in 88% of patients based on laboratory values above the upper limit of normal.” (opens the source at this quote in a new tab)

“Phosphate binders were received by 77% of patients who received LYTGOBI.” (opens the source at this quote in a new tab)

“Dose reductions due to an adverse reaction occurred in 58% of patients who received LYTGOBI.” (opens the source at this quote in a new tab)

Infigratinib: withdrawal of US approval

“On May 28, 2021, FDA approved NDA 214622 for TRUSELTIQ (infigratinib phosphate) Capsules, 25 mg and 100 mg, for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma (advanced bile duct cancer or advanced cholangiocarcinoma) with a fibroblast growth factor receptor 2 fusion or other rearrangement as detected by an FDA-approved test, under the Agency's accelerated approval regulations, 21 CFR part 314, subpart H” (opens the source at this quote in a new tab)

“In its letter requesting withdrawal of approval, Helsinn stated that it is voluntarily requesting withdrawal due to difficulties in recruiting and enrolling study subjects for the required confirmatory clinical trial in first line cholangiocarcinoma (a new indication under investigation for TRUSELTIQ), and the determination that, as a result, continued distribution of TRUSELTIQ in second line cholangiocarcinoma (the accelerated approval indication) is not commercially reasonable.” (opens the source at this quote in a new tab)

“Approval is withdrawn as of May 16, 2024.” (opens the source at this quote in a new tab)

Infigratinib: early termination of the confirmatory PROOF 301 trial

“Over 40 months, 1127 patients were pre-screened at 120 sites, and 48 patients were randomly allocated to the study in a 2 : 1 ratio (29 to infigratinib, 19 to chemotherapy). With a target accrual of ∼300 patients, this study was terminated early due to poor accrual.” (opens the source at this quote in a new tab)

“This study illustrates the challenges of powering confirmatory studies in biomarker-selected subpopulations of rare tumors and highlights the need for regulatory collaboration to develop pragmatic frameworks for assessing novel therapies in ultra-rare malignancies.” (opens the source at this quote in a new tab)

Single-group design and slow enrollment of confirmatory randomized trials of FGFR inhibitors

“The limitations of the current study include the single-group design and the relatively small sample size.” (opens the source at this quote in a new tab)

“However, enrollment in these trials is occurring slowly, and other research strategies may be considered for assessing benefit in the interim.” (opens the source at this quote in a new tab)

Downgraded strength of the second-line chemotherapy recommendation

“Furthermore, FOLFOX treatment showed a limited survival benefit compared with active symptom control (6.2 months for FOLFOX versus 5.3 months for active symptom control).” (opens the source at this quote in a new tab)

“Moreover, because the ABC-06 trial is the only positive phase III trial for the second-line treatment of BTC, the LoE was also downgraded from ‘I’ to ‘II’.” (opens the source at this quote in a new tab)

Proposed explanations for the divergent NIFTY and NALIRICC results

“Treatment discontinuation due to toxicity, without disease progression, was more common in the NALIRICC trial compared to the NIFTY trial.” (opens the source at this quote in a new tab)

“As the efficacy of cytotoxic chemotherapy is often limited by early discontinuation, this might be one of the potential reasons why the ORR improvement did not translate into better survival outcomes.” (opens the source at this quote in a new tab)

“This study is limited by its unplanned nature, which may introduce biases, resulting in a lower level of evidence compared to a single randomized trial.” (opens the source at this quote in a new tab)

NALIRICC: tolerability, crossover to irinotecan, and single-country design

“This trial does not support the use of nanoliposomal irinotecan plus fluorouracil and leucovorin as a second-line treatment in patients with biliary tract cancer after progression on gemcitabine-based therapy.” (opens the source at this quote in a new tab)

“High use of subsequent therapy and crossover to irinotecan-based therapy in the control group pose a challenge to the interpretation of the overall survival data.” (opens the source at this quote in a new tab)

“NALIRICC was exclusively conducted in a single country, involving a homogeneous patient population, which might pose a limitation to the generalisability of the study’s findings to more diverse populations.” (opens the source at this quote in a new tab)

“Because molecular biomarker analysis was not mandatory for this study, we are not in a position to delineate the correlation between genetic variants and efficacy outcomes.” (opens the source at this quote in a new tab)

Internal validity and generalizability limitations of the NIFTY trial

“As this result implies that the HRs for progression-free survival might not be representative for the entire study period, further validation should be done in a large, phase 3 trial.” (opens the source at this quote in a new tab)

“Because this trial was done in a single country and all patients were of east Asian ethnicity, its findings might have limited generalisability.” (opens the source at this quote in a new tab)

Survival remains approximately one year despite recent advances

“Although recent advances have improved clinical outcomes in patients with advanced BTC, median overall survival remains around 1 year, underscoring the need for further therapeutic innovation.” (opens the source at this quote in a new tab)

“Several targeted agents have demonstrated clinically meaningful efficacy in phase 2-3 trials and are recommended as subsequent-line therapy for biomarker-selected disease, including FGFR2 gene rearrangements, IDH1 mutations, and HER2 amplification.” (opens the source at this quote in a new tab)

“Despite incremental advancements, a breakthrough in advanced BTC treatment remains elusive.” (opens the source at this quote in a new tab)