Registered purpose of the trial

“This is a Phase 1/2, open-label, FIH study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDy), and antineoplastic activity of RLY-4008, a potent and highly selective FGFR2 inhibitor, in patients with unresectable or metastatic cholangiocarcinoma (CCA) and other solid tumors.” (opens the source at this quote in a new tab)

Objectives of the dose escalation stated in the trial-in-progress abstract

“a first-in-human (FIH) precision oncology study of RLY-4008 in advanced solid tumor pts with FGFR2 alterations with primary objectives to define the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) and adverse event (AE) profile of RLY-4008 and key secondary objectives to assess FGFR2 genotype in blood and tumor tissue, pharmacokinetics (PK), and anti-tumor activity.” (opens the source at this quote in a new tab)

Registrational intent of the phase 2 cholangiocarcinoma cohort

“Phase 2 of ReFocus continues across solid tumors and with registrational intent in FGFRi-naïve, FGFR2 f/r CCA.” (opens the source at this quote in a new tab)

“RLY-4008 is currently being evaluated in a global phase 1/2 clinical trial (ReFocus) in patients with FGFR2-altered CCA and multiple other solid tumors including a single arm, potentially registration-enabling cohort for FGFRi-naïve FGFR2-fusion CCA.” (opens the source at this quote in a new tab)

Regulatory advice on the sequence of indications

“We also met with the U.S. Food and Drug Administration, or the FDA, in 2024 regarding the lirafugratinib regulatory path, at which meeting the FDA suggested that we first file a NDA in CCA followed by a tumor agnostic supplemental NDA for FGFR2 fusions with data from more patients and more follow up.” (opens the source at this quote in a new tab)

Study dates and enrollment: registry record

Milestone	Registry record
Study start (actual)	“2020-09-02”
Primary completion (actual)	“2025-09-05”
Study completion (actual)	“2025-09-05”
Enrollment (actual)	“490”

Registered sites

“This study has 48 locations” (opens the source at this quote in a new tab)

Start of enrollment

“US enrollment began SEP2020 and Europe/Asia start-up is underway.” (opens the source at this quote in a new tab)

Initiation of the expansion cohorts

“The expansion cohorts were initiated in December 2021 and now consist of seven different cohorts based on FGFR2 alteration and tumor type.” (opens the source at this quote in a new tab)

Completion of enrollment in the pivotal cohort and closure of enrollment

“Enrollment is complete in the pivotal expansion cohort in patients with FGFR2-fusion CCA who have not previously received an FGFR inhibitor” (opens the source at this quote in a new tab)

“In 2024, we closed enrollment for the ReFocus Trial to allow the relevant data to mature and inform our future clinical development decisions.” (opens the source at this quote in a new tab)

Data cut-off dates of the reported analyses

“As of 01AUG22, 38 pts with FGFR2 f/r, FGFRi naïve CCA were efficacy evaluable.” (opens the source at this quote in a new tab)

“As of 30 Jan 23, 116 pts (82 f/r, 27 mutation, 6 amplification) received RLY-4008 at doses of 20-200 mg/day, including 91 with CCA.” (opens the source at this quote in a new tab)

“As of 09May23, 98 pts with solid tumors other than CCA (21 tumor types) were enrolled and treated at the RP2D.” (opens the source at this quote in a new tab)

“As of 27SEP2024, the primary efficacy analysis of IRC-assessed data (n=114) and the secondary analysis of investigator-assessed data (n=116) set was done.” (opens the source at this quote in a new tab)

Registered design details

Design feature	Registry record
Primary purpose	“Treatment”
Allocation	“Non-Randomized”
Interventional model	“Parallel Assignment”
Masking	“None (Open Label)”

Four-part structure and expansion groups

“The study consists of 4 parts: a dose escalation (Part 1), a dose expansion (Part 2), and an extension (Part 3) and a rollover (Part 4).” (opens the source at this quote in a new tab)
“Group 1: CCA patients w/ an FGFR2 fusion previously treated w/ an FGFRi treatment” (opens the source at this quote in a new tab)
“Group 2: CCA patients w/ an FGFR2 fusion w/ prior chemotherapy but no prior FGFRi treatment” (opens the source at this quote in a new tab)
“Group 3: Non-CCA patients w/ an FGFR2 fusion and no prior FGFRi” (opens the source at this quote in a new tab)
“Group 4: Non-CCA patients w/ an FGFR2 amplification and no prior FGFRi treatment” (opens the source at this quote in a new tab)
“Group 5: Non-CCA patients w/ an FGFR2 mutation and no prior FGFRi treatment” (opens the source at this quote in a new tab)
“Group 6: CCA patients w/ an FGFR2 fusion with no prior chemotherapy and no prior FGFRi treatment” (opens the source at this quote in a new tab)
“Group 7: CCA patients w/ an FGFR2 mutation or amplification and no prior FGFRi treatment” (opens the source at this quote in a new tab)

Seamless phase 1/2 design and dose-escalation method

“Here, we present updated dose escalation results from ReFocus (NCT04526106), a seamless Phase I/II, open label study evaluating the safety and preliminary efficacy of RLY-4008 in patients (pts) with advanced, FGFR2-altered solid tumors.” (opens the source at this quote in a new tab)
“Adult pts received RLY-4008 BID, QD, QD discontinuous on a 4-week (wk) cycle following a Bayesian Optimal Interval design.” (opens the source at this quote in a new tab)

Composition of the pivotal cohort

“Part 1 Cohort 2 + Part 2 Group 2A + Part 3 Group 2A Extension” (opens the source at this quote in a new tab)

Design of the pivotal cohort as described by the FDA

“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)

Determination of FGFR2 status

“FGFR2 f/r status was determined by local testing.” (opens the source at this quote in a new tab)

“FGFR2 alteration will be confirmed retrospectively by central laboratory assessment.” (opens the source at this quote in a new tab)

Key inclusion criteria: registry record

Criterion	Quoted registry text
Diagnosis	“Histologically or cytologically confirmed unresectable or metastatic solid tumor”
FGFR2 alteration	“Documented FGFR2 gene fusion, mutation, or amplification per local testing of blood and/or tumor”
Measurable disease	“Patient must have measurable disease per RECIST v1.1”
Performance status	“Patient has ECOG performance status of 0-1”
Prior therapy	“Patient must have disease that is refractory to standard therapy, disease that has not adequately responded to standard therapy, disease for which standard or curative therapy does not exist, or the patient must be intolerant to or have declined standard therapy”
Part 3 extension (pivotal)	“CCA patients with an FGFR2 fusion with prior chemotherapy but not previously treated with an FGFRi”

Key exclusion criteria: registry record

“Ongoing, clinically significant FGFRi-induced retinal detachment or an ongoing clinically significant corneal or retinal disorder” (opens the source at this quote in a new tab)
“Patient does not have adequate organ function (defined in protocol)” (opens the source at this quote in a new tab)
“Clinically significant, uncontrolled cardiovascular disease” (opens the source at this quote in a new tab)
“CNS metastases or primary CNS tumor that is associated with progressive neurologic symptoms” (opens the source at this quote in a new tab)

Eligibility criteria reported for the pivotal analysis

“Histologically or cytologically confirmed diagnosis of unresectable or metastatic CCA or other solid tumors per RECIST v1.1 that were refractory to or inadequately responded to standard therapy, or for which no standard therapy exists or was declined” (opens the source at this quote in a new tab)
“Documented FGFR2 genomic alteration (fusion, mutation, or amplification) per local assessment of blood and/or tumor tissue” (opens the source at this quote in a new tab)

Eligibility during dose escalation

“This is a global, multi-center, FIH dose escalation/expansion study of RLY-4008 (NCT04526106) in adult pts who have unresectable or metastatic solid tumors with FGFR2 alteration per local assessment, ECOG performance status 0-2, measurable or evaluable disease per RECIST 1.1, and who are refractory, intolerant, or declined standard therapy including pan-FGFRi.” (opens the source at this quote in a new tab)

FGFR2 rearrangement testing and qualifying breakpoints in the pivotal cohort

“The presence of FGFR2 fusions or other rearrangements was determined in 112 (97%) enrolled patients using next-generation sequencing (NGS) testing. Qualifying in-frame fusions and other FGFR2 rearrangements were predicted to have a breakpoint within intron 17/exon 18 of the FGFR2 gene leaving the FGFR2 kinase domain intact.” (opens the prescribing information at this quote)

Postmarketing commitment for a companion diagnostic

“Conduct adequate analytical and clinical validation studies to support revisions to the labeling of lirafugratinib to specify the use of an FDA-authorized in vitro companion diagnostic device to accurately and reliably identify patients using blood and/or tissue samples who have FGFR2 fusions and other rearrangements and for whom lirafugratinib therapy is indicated.” (opens the source at this quote in a new tab)

Dosing in the pivotal cohort

“Patients received lirafugratinib 70 mg once daily until disease progression or unacceptable toxicity.” (opens the source at this quote in a new tab)

Registered arms

Arm	Registry description
“Part 1: Dose Escalation”	“Multiple doses of RLY-4008 for oral administration.”
“Part 2: Dose Expansion”	“Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.”
“Part 3: Extension”	“Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.”
“Part 4: Rollover”	“Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.”

Doses and schedules explored during dose escalation

“The dose escalation portion of the study enrolled 116 patients with advanced, FGFR2-altered solid tumors, the majority of whom have CCA (n=91), and investigated 15 doses, ranging from 20mg to 100mg, across three dose schedules – once daily (QD), once daily intermittent and twice daily.” (opens the source at this quote in a new tab)

Selection of the recommended phase 2 dose

“RLY-4008 had favorable PK with doses ≥40 mg QD providing FGFR2 occupancy ≥90%. 70 mg QD was the RP2D based on PK, safety, anti-tumor activity and exposure-dependent tumor regressions in FGFRi-naïve CCA f/r pts.” (opens the source at this quote in a new tab)

Intrapatient dose escalation during phase 1

“initially at 30 mg once daily and subsequently at 50 and 70 mg once daily (per protocol, which permitted intrapatient dose escalation based on tolerability)” (opens the source at this quote in a new tab)

Registered primary outcome measures

Outcome measure	Time frame
“Part 1 and Part 4: Number of patients with adverse events and serious adverse events”	“Every cycle (4-week cycles) until study discontinuation, approximately 24 months”
“Part 1: Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-4008”	“Cycle 1 (4-week cycle) of treatment for MTD and at the end of every cycle (4-week cycles) for RP2D until study discontinuation, approximately 24 months”
“Part 2 and Part 3: Objective Response Rate (ORR) assessed by Independent Review Committee per RECIST v1.1”	“Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months”

Registered secondary outcome measures for Parts 2 and 3

Outcome measure	Time frame
“Part 2 and Part 3: Duration of response (DOR) assessed by Investigator and Independent Review Committee per RECIST v1.1”	“Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months”
“Part 2 and Part 3: Progression-free survival (PFS) assessed by Investigator and Independent Review Committee per RECIST v1.1”	“Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months”
“Part 2 and Part 3: Disease control rate (DCR) assessed by Investigator and Independent Review Committee per RECIST v1.1”	“Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months”
“Part 2 and Part 3:Overall survival (OS)”	“Up to approximately 36 months.”
“Part 2 and Part 3:Change from baseline in quality of life as assessed by EORTC QLQ-C30”	“Approximately every 4 weeks during treatment, approximately 24 months”
“Part 2 and Part 3: Number of patients with dose reductions”	“Every 28-day cycle until end of treatment, approximately 24 months.”
“Part 2 and Part 3: Correlation between FGFR2 genotype by central tissue assessment and antitumor response, as measured by ORR”	“Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months”

Endpoints of the pivotal cohort

“The primary endpoint was confirmed ORR per RECIST v1.1 by independent review committee (IRC). Key secondary endpoint was duration of response (DOR); other secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and quality of life per EORTC QLC-C30.” (opens the source at this quote in a new tab)

Assessments during dose escalation

“Treatment-related adverse events (TRAEs), PK, ctDNA and anti-tumor activity (RECIST v1.1) were assessed.” (opens the source at this quote in a new tab)

Definitions of objective response rate and disease control rate

“ORR is defined as the proportion of patients achieving a confirmed response of complete response or partial response per RECIST v1.1.” (opens the source at this quote in a new tab)
“DCR is defined as the proportion of patients with a confirmed response of complete response, partial response, or stable disease per RECIST v1.1.” (opens the source at this quote in a new tab)

Efficacy outcome measures used for approval

“The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as determined by an independent review committee according to RECIST v1.1.” (opens the source at this quote in a new tab)

Regulatory basis for ORR in single-arm studies

“When defined in this manner, ORR is a direct measure of a drug antitumor activity, which can be evaluated in a single-arm study.” (opens the source at this quote in a new tab)
“The significance of ORR is assessed by its magnitude and duration, and the percentage of CRs.” (opens the source at this quote in a new tab)
“In settings where there is no available therapy and where major tumor regressions can be presumed to be attributed to the tested drug, the FDA has sometimes accepted ORR and response duration observed in single-arm studies as substantial evidence supporting accelerated approval.” (opens the source at this quote in a new tab)
“Single-arm trials do not adequately characterize time-to-event endpoints such as overall survival, DFS (and EFS), TTP, or PFS.” (opens the source at this quote in a new tab)

Response benchmarks of earlier FGFR inhibitors against which activity was framed

“Previous, nonselective FGFRi have validated FGFR2 f/r as a target in CCA by achieving an objective response rate (ORR) of ∼20-40% with duration of response (DOR) ∼5-9 months.” (opens the source at this quote in a new tab)

“Despite achieving response rates of 23% to 42% in cholangiocarcinoma” (opens the source at this quote in a new tab)
“their clinical benefit has been limited by their incomplete target coverage due to side effects that prevent optimal dosing, and the emergence of FGFR2 resistance mutations” (opens the source at this quote in a new tab)

Planned size of the pivotal cohort

“Of the seven cohorts, the potential pivotal cohort consists of approximately 100 previously treated, FGFRi-naïve FGFR2-fusion CCA patients.” (opens the source at this quote in a new tab)

Participants enrolled by part and group

“QDC (N=58); QDD (N=41); BID (N=17)” (opens the source at this quote in a new tab)
“Group 1A (QDC): FGFR2-f/r + CCA with prior chemotherapy + prior FGFRi (N=53)” (opens the source at this quote in a new tab)
“Group 2A (QDC): FGFR2-f/r + CCA with prior chemotherapy with no prior FGFRi (N=26)” (opens the source at this quote in a new tab)
“Group 6 (QDC): FGFR2-f/r + CCA naïve to prior chemotherapy and FGFRi (N=11)” (opens the source at this quote in a new tab)
“Group 7 (QDC): FGFR2-mutant or amplified CCA with no prior FGFRi (N=42)” (opens the source at this quote in a new tab)
“Group 2A Extension (QDC): FGFR2-f/r + CCA with prior chemotherapy with no prior FGFRi (N=86)” (opens the source at this quote in a new tab)
“Group 3 (QDC): FGFR2-f/r naïve to prior FGFRi (N=46)” (opens the source at this quote in a new tab)
“Group 4 (QDC): FGFR2-amplified naïve to prior FGFRi (N=46)” (opens the source at this quote in a new tab)
“Group 5 (QDC): FGFR2-mutant naïve to prior FGFRi (N=37)” (opens the source at this quote in a new tab)
“Pivotal Cohort (N=116)” (opens the source at this quote in a new tab)

Participants treated and analyzed in the pivotal cohort

“Pivotal cohort of patients (n=116) with advanced/metastatic CCA harboring FGFR2 f/r previously treated with ≥1 systemic therapy and FGFRi-naive were treated with oral lirafugratinib 70 mg once daily until disease progression or unacceptable toxicity.” (opens the source at this quote in a new tab)
“The primary efficacy analysis excluded 2 patients as not available.” (opens the source at this quote in a new tab)

Size of the pooled safety population

“All Solid Tumors (70 mg QD Safety Population; N=385)” (opens the source at this quote in a new tab)

Confidence interval method

“Percentages based on number of patients in the analysis set for each treatment arm. Exact Clopper-Pearson used for 95% CI.” (opens the source at this quote in a new tab)

Prespecified hypothesis, response-rate threshold, and power for the pivotal cohort

No evidence found.

Primary and secondary efficacy analysis sets

“As of 27SEP2024, the primary efficacy analysis of IRC-assessed data (n=114) and the secondary analysis of investigator-assessed data (n=116) set was done. The primary efficacy analysis excluded 2 patients as not available.” (opens the source at this quote in a new tab)
“IRC and investigator assessments are based on different populations and cannot compare directly.” (opens the source at this quote in a new tab)

Safety analysis set and overall survival population

“Safety analysis set (N=116) is used for the overall survival analysis because the safety analysis set is equal to the full analysis set, which includes all enrolled patients who had received at least 1 dose of study drug.” (opens the source at this quote in a new tab)

FGFR inhibitor-pretreated participants in the non-cholangiocarcinoma and mutation groups

“Additional 27 patients who received prior FGFRi were enrolled in Groups 3 (n=10), 4 (n=3), 5 (n=8), and 7 (n=6). These patients were not included in the efficacy analyses but were included in the safety analyses.” (opens the source at this quote in a new tab)

Efficacy-evaluable population in the 2022 interim analysis

“Safety was analyzed in all dosed pts and efficacy in pts with FGFR2 f/r, FGFRi-naïve CCA with measurable disease and an opportunity for ≥2 tumor assessments to confirm response.” (opens the source at this quote in a new tab)

Duration of treatment in the pivotal and supportive cholangiocarcinoma populations

Population	Median duration of treatment, weeks (range)
FGFR inhibitor-naive, chemotherapy-pretreated FGFR2 fusion or rearrangement cholangiocarcinoma (pivotal cohort, N=114)	“41 (4, 138)”
FGFR inhibitor-pretreated, chemotherapy-pretreated FGFR2 fusion or rearrangement cholangiocarcinoma (Group 1A, N=53)	“27 (2, 96)”
FGFR inhibitor-naive, chemotherapy-naive FGFR2 fusion or rearrangement cholangiocarcinoma (Group 6, N=11)	“36 (16, 55)”

Extent of exposure in the prescribing information safety populations

“Among the 385 patients who received LYRFIGTU, 48% were exposed for 6 months or longer and 19% were exposed for greater than 12 months.” (opens the prescribing information at this quote)
“Among the 116 patients who received LYRFIGTU, 73% were exposed for 6 months or longer and 37% were exposed for greater than 12 months.” (opens the prescribing information at this quote)

Discontinuations during dose escalation

“Overall, median treatment duration was 24 wks (range <1-108 wks). 105 pts discontinued (PD (81%), AE (3%), other (7%)).” (opens the source at this quote in a new tab)

Treatment status at the 2022 interim analysis

“Most pts received the recommended phase 2 dose (RP2D); most (68%) remain on treatment with median duration of 6 months (<0.1 - 18.5 months).” (opens the source at this quote in a new tab)

Reasons for discontinuation and follow-up status in the pivotal cohort

No evidence found.

Baseline characteristics of the pivotal cohort, primary efficacy analysis set (N=114), n (%) unless stated

Characteristic	Pivotal cohort (N=114)
Median age, years (range)	“57 (29, 81)”
Male	“44 (38.6)”
Female	“70 (61.4)”
Asian	“26 (22.8)”
Black or African American	“2 (1.8)”
White	“62 (54.4)”
Other or multiple races	“1 (0.9)”
Race not reported or unknown	“23 (20.2)”
North America	“47 (41.2)”
Europe	“40 (35.1)”
Asia-Pacific	“27 (23.7)”
ECOG performance status 0	“57 (50.0)”
ECOG performance status 1	“57 (50.0)”
Median prior lines of systemic therapy (range)	“1 (1-5)”
One prior line of systemic therapy	“72 (63.2)”
Two prior lines	“31 (27.2)”
Three prior lines	“5 (4.4)”
Four prior lines	“4 (3.5)”
Five prior lines	“2 (1.8)”
Prior chemotherapy	“114 (100)”
Gemcitabine-platinum without immune checkpoint inhibitor	“66 (57.9)”
Gemcitabine-platinum with immune checkpoint inhibitor	“38 (33.3)”
Fluoropyrimidine-based chemotherapy	“37 (32.5)”
Other chemotherapy	“5 (4.4)”
Prior immune checkpoint inhibitor	“42 (36.8)”
Immune checkpoint inhibitor without gemcitabine-platinum	“4 (3.5)”

Age and sex of the pivotal cohort as reported in the abstract

“Median age 57 years with 61.4% female.” (opens the source at this quote in a new tab)

Baseline characteristics as reported in the prescribing information (N=116)

“The median age was 57 years (range 29- 81), 61% female, 55% White, 22% Asian, 1.7% Black or African American, 0.9% were other and 20% were unknown race or not reported; 5% Hispanic or Latino, 78% not Hispanic or Latino, and 16% were ethnicity unknown or not reported; 50% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 50% had ECOG of 1, and 96% had intrahepatic cholangiocarcinoma. Ninety percent (90%) of patients had in-frame FGFR2 gene fusions; the most commonly identified FGFR2 fusion partner was BICC1 (n=30, 26%).” (opens the prescribing information at this quote)
“All patients had received at least one prior line of platinum-based systemic therapy, 28% had 2 prior lines of therapy, and 10% had 3 or more prior lines of therapy; 58% received prior gemcitabine/cisplatin without immunochemotherapy.” (opens the prescribing information at this quote)

Prior therapy in the dose-escalation population

“50% had prior FGFRi, and median lines of prior therapies was 3 (1-15).” (opens the source at this quote in a new tab)

Prior therapy in the non-cholangiocarcinoma cohorts

“Across these arms of the study, enrolled patients had received a median of approximately three prior lines of therapy, with the vast majority (94%) having received prior chemotherapy/ADC and nearly half (45%) having received prior targeted therapies.” (opens the source at this quote in a new tab)

Primary endpoint and secondary efficacy endpoints by independent review committee, pivotal cohort

Endpoint	Pivotal cohort (N=114)
Complete response, n (%)	“3 (2.6)”
Partial response, n (%)	“50 (43.9)”
Stable disease, n (%)	“57 (50.0)”
Progressive disease, n (%)	“3 (2.6)”
Not evaluable, n (%)	“1 (0.9)”
Objective response rate, n (%) [95% CI]	“53 (46.5) [37.1, 56.1]”
Disease control rate, n (%) [95% CI]	“110 (96.5) [91.3, 99.0]”
Median duration of response, months [95% CI]	“11.8 [7.5, 13.0]”
Median progression-free survival, months [95% CI]	“11.3 [9.2, 14.8]”
Median overall survival, months [95% CI] (safety analysis set, N=116)	“22.8 [18.1, 27.2]”

Duration of response, landmark rates, and disease control as reported in the abstract

“IRC-assessed ORR was 47%, and median DOR was 11.8 months (mos) (95% CI, 7.5-13.0), where 76.2% of responses lasted >6 mos. Median PFS was 11.3 mos (95% CI, 9.2, 14.8), with 12-month rate of 49.2%. Median OS was 22.8 mos (95% CI, 17.3-27.2), with 12-month rate of 74.6%. DCR was 96.5%.” (opens the source at this quote in a new tab)

Best overall response by independent review committee and by investigator

Best overall response	Independent review committee, primary efficacy analysis set	Investigator, secondary efficacy analysis set
Complete response, n (%)	“3 (2.6)”	“0”
Partial response, n (%)	“50 (43.9)”	“61 (52.6)”
Stable disease, n (%)	“57 (50.0)”	“51 (44.0)”
Progressive disease, n (%)	“3 (2.6)”	“3 (2.6)”
Not evaluable, n (%)	“1 (0.9)”	“1 (0.9)”
Objective response rate, n (%)	“53 (46.5)”	“61 (52.6)”
Objective response rate, 95% CI	“37.1, 56.1”	“43.1, 61.9”
Disease control rate, n (%)	“110 (96.5)”	“112 (96.6)”
Disease control rate, 95% CI	“91.3, 99.0”	“91.4, 99.1”

Duration of response by independent review committee: events and censoring

Measure	Pivotal cohort responders
Median duration of response, months (95% CI)	“11.8 (7.5, 13.0)”
Number of patients with events	“25”
Number of patients censored	“28”

Objective response rate and duration of response as stated by the FDA

“ORR was 46% (95% CI: 36, 55) and median DOR was 11.8 months (95% CI: 7.5, 13.0).” (opens the source at this quote in a new tab)

Efficacy results in the prescribing information (N=116)

Efficacy parameter	Lirafugratinib (N=116)
Median duration of response, months (95% CI)	“11.8 (7.5, 13.0)”
Duration of response of 6 months or longer, n (%)	“33 (62)”
Duration of response of 12 months or longer, n (%)	“11 (21)”

Time to response

“The median time to response was 1.9 months (range 1.1, 10.9 months).” (opens the prescribing information at this quote)

Objective response rate and progression-free survival as stated by the sponsor at approval

“In the Phase 1/2 ReFocus trial (NCT04526106), Lyrfigtu demonstrated a confirmed objective response rate (ORR) of 46% and a median duration of response of 11.8 months in patients with the proposed indication. Median progression-free survival was 11.3 months (95% CI, 9.2, 14.8), with a 12-month rate of 49.2%.” (opens the source at this quote in a new tab)
“Beyond the confirmed ORR of 45.7% which speaks for itself, I’ve witnessed, first-hand, many of my own patients who were able to regain meaningful quality of life and precious time with their loved ones, owing to the robust tumor shrinkage they achieved on this treatment.” (opens the source at this quote in a new tab)

Overall survival confidence interval as stated by the sponsor at NDA submission

“Median OS was 22.8 mos (95% CI, 18.1-27.2), with 12-month rate of 74.6%.” (opens the source at this quote in a new tab)

Supportive cohorts: FGFR inhibitor-pretreated and chemotherapy-naive FGFR2 fusion or rearrangement cholangiocarcinoma, independent review committee

Endpoint	FGFR inhibitor-pretreated, chemotherapy-pretreated (Group 1A, N=53)	FGFR inhibitor-naive, chemotherapy-naive (Group 6, N=11)
Complete response, n (%)	“0”	“1 (9.1)”
Partial response, n (%)	“12 (22.6)”	“6 (54.5)”
Stable disease, n (%)	“29 (54.7)”	“4 (36.4)”
Progressive disease, n (%)	“10 (18.9)”	“0”
Not evaluable, n (%)	“2 (3.8)”	“0”
Objective response rate, n (%) [95% CI]	“12 (22.6) [12.3, 36.2]”	“7 (63.6) [30.8, 89.1]”
Disease control rate, n (%) [95% CI]	“41 (77.4) [63.8, 87.7]”	“11 (100) [71.5, 100]”
Median duration of response, months [95% CI]	“5.6 [3.8, NE]”	“9.2 [5.6, NE]”
Median progression-free survival, months [95% CI]	“5.6 [3.7, 7.4]”	“11.0 [3.7, NE]”
Median overall survival, months [95% CI]	“10.9 [6.6, 18.2]”	“NE [12.6, NE]”

Interim analysis at the recommended phase 2 dose, investigator-assessed (data cut-off August 1, 2022)

Endpoint	70 mg once daily (N=17)	All dose levels (N=38)
Objective response rate, n (% [95% CI])	“15 (88.2 [63.6 - 98.5])”	“24 (63.2 [46.0 - 78.2])”
Confirmed objective response rate, n (% [95% CI])	“14 (82.4 [56.6 - 96.2])”	“22 (57.9 [40.8 - 73.7])”
Response ongoing, n/N (%)	“15/15 (100.0)”	“19/24 (79.2)”
Disease control rate, n (%)	“17 (100.0)”	“36 (94.7)”
Remaining on treatment, n (%)	“15 (88.2)”	“26 (68.4)”

Tumor resection with curative intent after response

“One pt treated at the RP2D had a near-complete response and subsequent tumor resection with curative intent.” (opens the source at this quote in a new tab)

Dose escalation: FGFR inhibitor-naive and FGFR inhibitor-pretreated FGFR2 fusion or rearrangement cholangiocarcinoma, all doses

Endpoint	FGFR inhibitor-naive (N=25)	Prior FGFR inhibitor (N=50)
Objective response rate, n (% [95% CI])	“13 (52% [31.3%-72.2%])”	“7 (14% [5.8%-26.7%])”
Median duration of response, months (range)	“8.2 (1.9-18.6)”	“5.6 (1.9-7.4)”
Duration of response longer than 24 weeks	“10/13 (77%)”	“4/7 (57%)”
Response ongoing	“6/13 (46%)”	“2/7 (29%)”
Disease control rate, n (%)	“22 (88%)”	“40 (80%)”

Dose escalation: response at and above the recommended phase 2 dose

“Among the 91 CCA patients in the dose escalation portion of the study, 25 had FGFR2 fusions and had not previously received an FGFR inhibitor (FGFRi-naïve FGFR2-fusion CCA).” (opens the source at this quote in a new tab)
“Eleven of these patients were treated at or above the pivotal dose of 70mg QD” (opens the source at this quote in a new tab)
“Eight of the 11 patients (including all 4 patients receiving the pivotal dose) had a partial response (73% overall response rate (ORR)), and an additional three patients experienced a best response of stable disease” (opens the source at this quote in a new tab)
“In patients treated at or above the pivotal dose of 70mg QD (n=14), the ORR was 21 percent, and in patients treated at doses below the 70mg QD pivotal dose (n=36), the ORR was 11 percent” (opens the source at this quote in a new tab)

Dose escalation: tumor reductions across doses and FGFR2 alterations

“Anti-tumor activity was observed in CCA and solid tumors across doses and FGFR2 alterations with radiographic tumor reductions in 74 (64%), SD/PR in 83 (72%), including 4/4 (100%) FGFRi-naïve CCA f/r pts at RP2D achieving confirmed PR.” (opens the source at this quote in a new tab)

Non-cholangiocarcinoma solid tumors with FGFR2 fusion or rearrangement (Group 3)

“In the phase 1/2 ReFocus Trial (RLY-4008-101; NCT04526106),46 subjects (Group 3) with non-cholangiocarcinoma solid tumors harboring FGFR2 fusion/rearrangements (f/r) received lirafugratinib 70 mg once daily. The ORR was 33.3% (95% CI 19.6 - 49.5). However, this sample size was insufficient to support regulatory approval of lirafugratinib for a tissue agnostic indication.” (opens the source at this quote in a new tab)

“In the Phase 1/2 ReFocus study, data from 42 non-CCA solid tumor patients with FGFR2 fusion/rearrangement (13 tumor types) showed meaningful antitumor activity of lirafugratinib.” (opens the source at this quote in a new tab)

Non-cholangiocarcinoma solid tumors: initial analysis by FGFR2 alteration (data cut-off May 9, 2023)

“Twenty had f/r with an ORR of 40% (8/20, 7 confirmed/5 ongoing) and DOR from 8-50+ weeks. Twenty-seven had amplification with an ORR of 33% (9/27, 7 confirmed/5 ongoing) and DOR from 8-32+ weeks. Pts with breast (n=7), lung (n=3), and pancreatic (n=5) cancer with FGFR2 f/r or amplification had confirmed ORRs of 43%, 67%, and 40%, respectively. Response varied by mutation with ORR 14.3% (2 [N549K; C382R]/14; both confirmed, 1 ongoing) with DOR each of 40+ weeks.” (opens the source at this quote in a new tab)

Non-cholangiocarcinoma solid tumors: sponsor-reported analysis (data cut-off August 23, 2023)

“Nine of 26 patients experienced a partial response (PR) (35% overall response rate (ORR))” (opens the source at this quote in a new tab)
“Four of the 10 HR+/HER2- patients achieved PRs (40% ORR)” (opens the source at this quote in a new tab)
“Eight of 34 patients experienced a PR (24% ORR)” (opens the source at this quote in a new tab)
“In addition, three of the 24 patients with FGFR2 mutations achieved a PR (breast, gastric and ameloblastic tumors).” (opens the source at this quote in a new tab)

FGFR2 mutation- or amplification-positive cholangiocarcinoma (Group 7)

No evidence found.

Baseline FGFR2 resistance mutations in FGFR inhibitor-pretreated cholangiocarcinoma

“28/46 ct-DNA-evaluable pts with CCA with prior FGFRi had ≥1 baseline resistance mutation, most commonly at FGFR2 N549X (23/46) or V564X (17/46).” (opens the source at this quote in a new tab)

Mechanisms of acquired resistance: circulating tumor DNA analysis of 28 participants

“Polyclonal FGFR2 kinase domain mutations and receptor tyrosine kinase-mitogen activated protein kinase (RTK-MAPK) bypass alterations emerged as common lirafugratinib resistance mechanisms in the FGFR inhibitor-naive context (8/16 and 9/16 patients, respectively).” (opens the source at this quote in a new tab)
“Importantly, lirafugratinib demonstrated clinical efficacy in the FGFR inhibitor-refractory setting, with ctDNA dynamics showing resolution of multiple FGFR2 mutations and persistence or emergence of others.” (opens the source at this quote in a new tab)

Mechanisms of acquired resistance: single-institution analysis of 30 participants

“Patients with acquired lirafugratinib resistance manifested an unprecedented emergence of FGFR2 mutations in the M538 and/or L618 residues of the kinase domain, documented in 11 of 16 cases (69%). Compared with futibatinib resistance, FGFR2 molecular brake (N550) and gatekeeper (V565) mutations were rare.” (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)

Quality of life as a registered secondary endpoint

“Part 2 and Part 3:Change from baseline in quality of life as assessed by EORTC QLQ-C30” (opens the source at this quote in a new tab)

Reported quality-of-life result in the pivotal cohort

“QoL was maintained.” (opens the source at this quote in a new tab)

EORTC QLQ-C30 scores, change from baseline, and time to deterioration

No evidence found.

Treatment-related adverse event overview, n (%)

Category	All solid tumors, 70 mg once daily (N=385)	Pivotal cholangiocarcinoma cohort (N=116)
Any treatment-related adverse event	“379 (98.4)”	“116 (100)”
Grade 3 or higher treatment-related adverse event	“167 (43.4)”	“67 (57.8)”
Treatment-related adverse event leading to dose reduction	“213 (55.3)”	“88 (75.9)”
Treatment-related adverse event leading to dose interruption	“262 (68.1)”	“96 (82.8)”
Treatment-related adverse event leading to discontinuation	“10 (2.6)”	“5 (4.3)”
Treatment-related adverse event leading to death	“0”	“0”

Safety populations described in the prescribing information

“The safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to LYRFIGTU 70 mg orally once daily in 385 patients with multiple advanced solid tumors evaluated in REFOCUS including 232 patients with cholangiocarcinoma and 153 patients with other advanced solid tumors.” (opens the prescribing information at this quote)
“The safety of LYRFIGTU was evaluated in REFOCUS, which included 116 patients with cholangiocarcinoma harboring FGFR2 gene fusions and other rearrangements who were previously treated with chemotherapy or chemoimmunotherapy, but naïve to FGFR inhibitor therapy” (opens the prescribing information at this quote)

Adverse reactions in more than 15% of the pivotal cohort (N=116), prescribing information, %

Adverse reaction	All grades (%)	Grade 3 or 4 (%)
Nail toxicity	“89”	“12”
Palmar-plantar erythrodysesthesia syndrome	“82”	“33”
Stomatitis	“80”	“12”
Alopecia	“66”	“0”
Dry eye	“53”	“0”
Dry mouth	“50”	“0”
Fatigue	“43”	“3.4”
Dysgeusia	“39”	“0.9”
Retinal pigment epithelial detachment	“38”	“1.7”
Dry skin	“37”	“0”
Constipation	“37”	“0.9”
Rash	“34”	“5”
Infection	“34”	“8”
Abdominal pain	“28”	“3.4”
Blurred vision	“22”	“0.9”
Diarrhea	“22”	“0.9”
Hemorrhage	“22”	“2.6”
Musculoskeletal pain	“22”	“0”
Nausea	“21”	“1.7”
Decreased appetite	“20”	“0”
Urinary tract infection	“19”	“0.9”
Pyrexia	“18”	“0.9”
Neuropathy peripheral	“18”	“0.9”
Edema	“17”	“0”
Vomiting	“16”	“0.9”
Corneal toxicity	“16”	“0”
Nasal dryness	“15”	“0”

Ophthalmologic monitoring schedule in the pivotal cohort

“evaluated by visual acuity testing, slit-lamp examination, fundoscopy with digital imaging, and optical coherence tomography (OCT) imaging occurred at Screening, every odd-numbered cycle from C3D1 to C13D1 and every other odd- numbered cycle thereafter” (opens the prescribing information at this quote)

Select laboratory abnormalities worsening from baseline in the pivotal cohort, prescribing information, %

Laboratory abnormality	All grades (%)	Grade 3 or 4 (%)
Phosphate increased	“75”	“0”
Alanine aminotransferase increased	“53”	“7”
Creatinine increased	“52”	“0.9”
Sodium decreased	“49”	“20”
Hemoglobin decreased	“49”	“8”
Lymphocytes decreased	“47”	“7”
Blood bilirubin increased	“45”	“5”
Aspartate aminotransferase increased	“42”	“5”
Platelets decreased	“39”	“3.4”
Glucose increased	“37”	“5”
Leukocytes decreased	“31”	“2.6”
Alkaline phosphatase increased	“26”	“1.7”
Phosphate decreased	“25”	“5”
Albumin decreased	“25”	“0.9”
Neutrophils decreased	“23”	“2.6”
Bicarbonate decreased	“20”	“0”

Adverse reactions leading to permanent discontinuation in the pivotal cohort

“palmar-plantar erythrodysesthesia syndrome (3 patients), stomatitis, anaphylactic reaction, and infection (1 patient each).” (opens the prescribing information at this quote)

Dosage interruption and dose reduction for adverse reactions in the pivotal cohort, prescribing information

“Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received LYRFIGTU.” (opens the prescribing information at this quote)
“Dosage interruptions due to an adverse reaction occurred in 88% of patients who received LYRFIGTU 70 mg once daily.” (opens the prescribing information at this quote)
“Dose reductions due to an adverse reaction occurred in 81% of patients who received LYRFIGTU.” (opens the prescribing information at this quote)

On-target treatment-emergent adverse events: stomatitis, palmar-plantar erythrodysesthesia, nail toxicity, and retinal pigment epithelial detachment, n (%)

Adverse event	All solid tumors (N=385), any grade	All solid tumors (N=385), grade 3 or higher	Pivotal cohort (N=116), any grade	Pivotal cohort (N=116), grade 3 or higher
Stomatitis (includes lip ulceration and mouth ulceration)	“263 (68.3)”	“47 (12.2)”	“91 (78.4)”	“14 (12.1)”
Palmar-plantar erythrodysesthesia syndrome	“255 (66.2)”	“77 (20.0)”	“95 (81.9)”	“38 (32.8)”
Nail toxicities	“282 (73.2)”	“31 (8.1)”	“102 (87.9)”	“14 (12.1)”
Retinal pigment epithelial detachment	“113 (29.4)”	“7 (1.8)”	“43 (37.1)”	“2 (1.7)”

Monitoring of retinal pigment epithelial detachment in the trial

“RPED was monitored by optical coherence tomography.” (opens the source at this quote in a new tab)

Off-isoform treatment-emergent adverse events: hyperphosphatemia and diarrhea, n (%)

Adverse event	All solid tumors (N=385), any grade	All solid tumors (N=385), grade 3 or higher	Pivotal cohort (N=116), any grade	Pivotal cohort (N=116), grade 3 or higher
Hyperphosphatemia	“79 (20.5)”	“0”	“24 (20.7)”	“0”
Diarrhea	“72 (18.7)”	“3 (0.8)”	“25 (21.6)”	“1 (0.9)”

Management of hyperphosphatemia

“Hyperphosphatemia did not require dose reductions or discontinuations; 1 patient (0.3%) experienced a dose interruption, and no phosphate binder interventions were needed.” (opens the source at this quote in a new tab)

Treatment-related adverse events leading to dose interruption or discontinuation, n (%)

Event	All solid tumors (N=385)	Pivotal cohort (N=116)
Stomatitis leading to dose interruption	“80 (20.8)”	“25 (21.6)”
Palmar-plantar erythrodysesthesia syndrome leading to dose interruption	“138 (35.8)”	“63 (54.3)”
Stomatitis leading to discontinuation	“3 (0.8)”	“1 (0.9)”
Anaphylactic reaction leading to discontinuation	“1 (0.3)”	“1 (0.9)”
Drug hypersensitivity leading to discontinuation	“1 (0.3)”	“0”
Palmar-plantar erythrodysesthesia syndrome leading to discontinuation	“4 (1.0)”	“3 (2.6)”
Nail disorder leading to discontinuation	“1 (0.3)”	“0”

Grade 3 or higher events and dose modifications in the pivotal cohort as reported in the abstract

“Common grade ≥3 on-target, off-tumor treatment-related adverse events (TRAEs) included palmar-plantar erythrodysesthesia (32.8%) and stomatitis (12.1%). TRAEs led to dose reductions of 75.9%, dose interruption of 82.8%, and treatment discontinuation of 4.3%.” (opens the source at this quote in a new tab)

Ocular toxicity in the pooled safety population

“Among 385 patients who received LYRFIGTU, RPED occurred in 31% of patients, including Grade 3 events in 1.8%. The median time to first onset was 57 days. RPED led to dose interruption in 15% of patients and dose reduction in 10%.” (opens the source at this quote in a new tab)
“Among 385 patients who received LYRFIGTU, blurred vision occurred in 18% of patients with Grade 3 events in 1.3% of patients.” (opens the source at this quote in a new tab)
“Dry eye occurred in 38% of patients.” (opens the source at this quote in a new tab)
“Among 385 patients who received LYRFIGTU, corneal toxicity/keratitis occurred in 11% of patients.” (opens the source at this quote in a new tab)

Hyperphosphatemia in the pooled safety population

“Hyperphosphatemia occurred in 21% of patients. The median time to onset was 15 days. Hyperphosphatemia led to dose interruption in one (0.3%) patient and no permanent discontinuation.” (opens the source at this quote in a new tab)

Serious and fatal adverse reactions and most common adverse reactions

“Serious adverse reactions occurred in 32% of patients. Serious adverse reactions reported in ≥2% of patients were infection (6%), pneumonia (3.4%), fatigue (2.6%), and hemorrhage (2.6%). A fatal adverse reaction of hemorrhage occurred in one patient.” (opens the source at this quote in a new tab)
“The most common adverse reactions (≥20%) were nail toxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, alopecia, dry eye, dry mouth, fatigue, dysgeusia, retinal pigment epithelial detachment, constipation, dry skin, infection, rash, abdominal pain, hemorrhage, blurred vision, diarrhea, musculoskeletal pain, nausea, and decreased appetite.” (opens the source at this quote in a new tab)
“The most common laboratory abnormalities (≥20%) were increased phosphate, increased alanine aminotransferase, increased creatinine, decreased hemoglobin, decreased sodium, decreased lymphocytes, increased blood bilirubin, increased aspartate aminotransferase, decreased platelets, increased glucose, decreased leukocytes, increased alkaline phosphatase, decreased albumin, decreased phosphate, decreased neutrophils, decreased bicarbonate.” (opens the source at this quote in a new tab)

Safety in earlier analyses across doses

“Across all doses (N=195), the most common treatment-related AEs (TRAEs) were low-grade stomatitis (48%), PPE (46%), and dry mouth (31%). No grade 4/5 TRAEs were observed.” (opens the source at this quote in a new tab)

“Across doses, most common TRAEs were low-grade PPE (57%), stomatitis (56%), dry mouth (38%), alopecia (28%), and dry eye (22%). No grade 4/5 TRAEs were observed.” (opens the source at this quote in a new tab)

Safety in the non-cholangiocarcinoma cohorts

“Most common treatment-related adverse events (TRAEs, all grades; grade 3) were stomatitis (50%; 10%), nail toxicities (44%; 4%), and palmar-plantar erythema (45%; 5%). Typical off-isoform TRAEs for pan-FGFR inhibitors were uncommon, including hyperphosphatemia (16%; 0%) and diarrhea (9%; 1%). One percent of pts discontinued treatment because of TRAEs. No grade 4/5 TRAEs were observed.” (opens the source at this quote in a new tab)

Planned post hoc analysis of mucocutaneous adverse events after immune checkpoint inhibitors

“Lirafugratinib: An ePoster post-hoc analysis from the ReFocus trial examining prior immunotherapy exposure and mucocutaneous adverse event risks.” (opens the source at this quote in a new tab)

All-cause treatment-emergent adverse events and deaths from any cause in the pivotal cohort

No evidence found.

Summary

ReFocus is an open-label, non-randomized phase 1/2 trial without a comparator arm, and the approval rests on a single-arm cohort of 116 participants with previously treated FGFR2 fusion or rearrangement cholangiocarcinoma who had not received an FGFR inhibitor. In that cohort the objective response rate by independent review committee was 46.5% (53 of 114; 95% CI 37.1 to 56.1), with 3 complete responses (2.6%), and median duration of response was 11.8 months (95% CI 7.5 to 13.0) with 25 events and 28 of 53 responders censored at the September 27, 2024 cut-off. The FDA states an objective response rate of 46% (95% CI 36 to 55) in 116 participants and the sponsor's approval announcement cites 45.7%, consistent with a denominator of 116; the primary efficacy analysis set contains 114 participants. The FDA endpoint guidance states that single-arm trials do not adequately characterize time-to-event endpoints, so the median progression-free survival of 11.3 months and median overall survival of 22.8 months cannot be attributed to lirafugratinib without a control. The overall survival 95% CI is reported as 17.3 to 27.2 months in the published abstract and as 18.1 to 27.2 months in the presentation and the NDA announcement. No prespecified response-rate threshold, hypothesis test, or power calculation for the pivotal cohort was located; the only planned size found was approximately 100 participants.

As of September 26, 2026, the pivotal results were available as a congress abstract, a sponsor-posted slide presentation, sponsor press releases, the FDA approval notice, and prescribing information posted on the product website but not yet on Drugs@FDA or DailyMed; no peer-reviewed full publication of the pivotal cohort was located, and the registry record, completed on September 5, 2025, carries no posted results. Quality of life was a registered secondary endpoint, but the only reported result is the abstract statement that it was maintained.

Tolerability required frequent dose modification in the pivotal cohort: treatment-related adverse events led to dose reduction in 75.9% and dose interruption in 82.8% of participants, the prescribing information reports dose reduction for an adverse reaction in 81% and dosage interruption in 88%, grade 3 or higher palmar-plantar erythrodysesthesia occurred in 32.8%, and retinal pigment epithelial detachment occurred in 37.1%. The FDA required a randomized postmarketing trial comparing 70 mg once daily with a lower dosage, with trial completion scheduled for November 2031, so whether a lower dose preserves efficacy with less toxicity is not established.

Generalizability is limited. The registry lists 48 sites in 13 countries or regions, 18 of them in the United States. Enrollment required ECOG performance status 0 or 1, 63.2% of the pivotal cohort had received one prior line of therapy, 54.4% were White, 22.8% Asian, and 1.8% Black, and FGFR2 status was determined by local testing, with an FDA-authorized companion diagnostic still a postmarketing commitment due in 2029. Participants previously treated with an FGFR inhibitor had an objective response rate of 22.6% (12 of 53) and median progression-free survival of 5.6 months, and only 11 chemotherapy-naive participants were treated, so the pivotal estimates do not transfer to those groups. The earlier interim response rate of 88.2% at the recommended dose (15 of 17, investigator-assessed, August 2022) was not reproduced in the full cohort. Resistance analyses in 28 and 30 treated participants identified FGFR2 kinase domain mutations and bypass alterations at progression. The trial was sponsored first by Relay Therapeutics and then by Elevar Therapeutics after the December 2024 license.