Lytgobi 4 mg film-coated tablets

Lytgobi monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy.

Lytgobi therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with biliary tract cancer.

Presence of FGFR2 gene fusions or rearrangements should be confirmed by an appropriate diagnostic test prior to initiation of Lytgobi therapy.

Posology

The recommended starting dose is 20 mg futibatinib taken orally once daily. If a dose of futibatinib is missed by more than 12 hours or vomiting occurs after taking a dose, an additional dose should not be taken, and treatment should be resumed with the next scheduled dose. Treatment should be continued until disease progression or unacceptable toxicity. In all patients, dietary restrictions that limit phosphate intake are recommended as part of hyperphosphatemia management.

A phosphate-lowering therapy should be initiated when serum phosphate level is ≥ 5.5 mg/dL. If the serum phosphate level is > 7 mg/dL, the dose of futibatinib should be modified based on the duration and severity of hyperphosphatemia (see Table 2). Prolonged hyperphosphatemia can cause soft tissue mineralization, including cutaneous calcification, vascular calcification, and myocardial calcification (see section 4.4).

If Lytgobi treatment is stopped or serum phosphate level falls below normal range, phosphate-lowering therapy and diet should be discontinued. Severe hypophosphatemia may present with confusion, seizures, focal neurologic findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis, and hemolytic anemia.

Dose adjustment due to drug interaction

Concomitant use of futibatinib with strong CYP3A/P-gp inhibitors

Co-administration of futibatinib with strong CYP3A4/P-gp inhibitors, such as itraconazole, should be avoided (see sections 4.4 and 4.5). If this is not possible, based on careful monitoring of tolerability, a futibatinib dose reduction to the next lower level should be considered.

Concomitant use of futibatinib with strong or moderate CYP3A/P-gp inducers

Co-administration of futibatinib with strong or moderate CYP3A4/P-gp inducers, such as rifampicin, should be avoided (see sections 4.4 and 4.5). If this is not possible, gradually increasing the futibatinib dose based on careful monitoring of tolerability should be considered.

Management of toxicities

Dose modifications or interruption of dosing should be considered for the management of toxicities.

The recommended dose reduction levels are provided in Table 1.

Treatment should be permanently discontinued if patient is unable to tolerate 12 mg futibatinib once daily.

Dose modifications for hyperphosphatemia are provided in Table 2.

Dose modifications for serous retinal detachment are provided in Table 3.

Dose modifications for other adverse reactions are provided in Table 4.

Special populations

Elderly

No specific dose adjustment is required for elderly patients (≥ 65 years) (see section 5.1).

Renal impairment

Dose adjustment is not required for patients with mild and moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). There are no data in patients with severe renal impairment (CLcr < 30 mL/min) or for patients with end-stage renal disease receiving intermittent haemodialysis and therefore no dosing recommendation can be made (see section 5.2).

Hepatic impairment

No dose adjustment is required when administering futibatinib to patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment. However, there is no safety data in patients with severe hepatic impairment. (see section 5.2).

Paediatric population

The safety and efficacy of futibatinib in children less than 18 years of age have not been established.

No data are available.

Method of administration

Lytgobi is for oral use. The tablets should be taken with or without food at about the same time each day. The tablets should be swallowed whole to ensure that the full dose is administered.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hyperphosphatemia

Hyperphosphatemia is a pharmacodynamic effect expected with futibatinib administration (see section 5.1). Prolonged hyperphosphatemia may cause soft tissue mineralization, including cutaneous calcification, vascular calcification, and myocardial calcification, anaemia, hyperparathyroidism, and hypocalcemia that may cause muscle cramps, QT interval prolongation, and arrythmias (see section 4.2).

Recommendations for management of hyperphosphatemia include dietary phosphate restriction, administration of phosphate-lowering therapy, and dose modification when required (see section 4.2).

Phosphate-lowering therapy was used by 83.4 % of patients during treatment with futibatinib (see section 4.8).

Serous retinal detachment

Futibatinib can cause serous retinal detachment, which may present with symptoms such as blurred vision, visual floaters, or photopsia (see section 4.8). This can moderately influence the ability to drive and use machines (see section 4.7).

Ophthalmological examination should be performed prior to initiation of therapy, 6 weeks thereafter, and urgently at any time for visual symptoms. For serous retinal detachment reactions, the dose modification guidelines should be followed (see section 4.2).

During the conduct of the clinical study, there was no routine monitoring, including optical coherence tomography (OCT), to detect asymptomatic serous retinal detachment; therefore, the incidence of asymptomatic serous retinal detachment with futibatinib is unknown.

Careful consideration should be taken with patients that have clinically significant medical eye disorders, such as retinal disorders, including but not limited to, central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, and previous retinal detachment.

Dry eye

Futibatinib can cause dry eye (see section 4.8). Patients should use ocular demulcents, in order to prevent or treat dry eye, as needed.

Embryo-foetal toxicity

Based on the mechanism of action and findings in an animal study (see section 5.3), futibatinib can cause foetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus. An effective method of contraception should be used in women of childbearing potential and in men with women partners of childbearing potential during treatment with Lytgobi and for 1 week following completion of therapy, barrier methods should be applied as a second form of contraception to avoid pregnancy (see section 4.6). A pregnancy test should be performed before treatment initiation to exclude pregnancy.

Combination with strong CYP3A/P-gp inhibitors

Concomitant use of strong CYP3A/P-gp inhibitors should be avoided because it may increase futibatinib plasma concentration (see sections 4.2 and 4.5).

Combination with strong or moderate CYP3A/P-gp inducers

Concomitant use of strong or moderate CYP3A/P-gp inducers should be avoided because it may decrease futibatinib plasma concentration (see sections 4.2 and 4.5).

Lactose

Lytgobi contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

Lytgobi contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Effects of other medicinal products on futibatinib

CYP3A/P-gp inhibitors

Co-administrations of multiple doses of 200 mg itraconazole, a strong CYP3A/P-gp inhibitor, increased futibatinib Cmax by 51% and AUC by 41% following a single oral dose of 20 mg futibatinib.

Therefore, the concomitant use of strong CYP3A/P-gp inhibitors (e.g. clarithromycin, itraconazole) may increase futibatinib plasma concentration and should be avoided. If this is not possible, a reduction in the futibatinib dose to the next lower dose level based on tolerability observed should be considered (see sections 4.2 and 4.4).

CYP3A/P-gp inducers

Co-administrations of multiple doses of 600 mg rifampin, a strong CYP3A/P-gp inducer, decreased futibatinib Cmax by 53% and AUC by 64% following a single oral dose of 20 mg futibatinib.

Therefore, the concomitant use of strong and moderate CYP3A/P-gp inducers (e.g. carbamazepine, phenytoin, phenobarbital, efavirenz, rifampin) may decrease futibatinib plasma concentration and should be avoided. If this is not possible, gradually increasing the futibatinib dose based on careful monitoring of tolerability should be considered (see sections 4.2 and 4.4).

Proton pump inhibitors

Futibatinib geometric mean ratios for Cmax and AUC were 108 % and 105 %, respectively, when coadministered in healthy subjects with lansoprazole (a proton pump inhibitor) relative to futibatinib alone. Co-administrations of a proton pump inhibitor (lansoprazole) did not result in a clinically important change in futibatinib exposure.

Effects of futibatinib on other medicinal products

Effect of futibatinib on CYP3A substrate

Midazolam (a CYP3A sensitive substrate) geometric mean ratios for Cmax and AUC were 95 % and 91 %, respectively, when co-administered in healthy subjects with futibatinib relative to midazolam alone. Co-administrations of futibatinib had no clinically significant impact on midazolam exposure.

Effect of futibatinib on P-gp and BCRP substrates

In vitro, futibatinib is an inhibitor of P-gp and BCRP. Co-administration of futibatinib with P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g, rosuvastatin) substrates may increase their exposure.

Effect of futibatinib on CYP1A2 substrates

In vitro studies indicate that futibatinib has the potential to induce CYP1A2. Co-administration of futibatinib with CYP1A2 sensitive substrates (e.g, olanzapine, theophylline) may decrease their exposure and therefore may affect their activity.

Hormonal contraceptives

It is currently unknown whether futibatinib may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should add a barrier method during Lytgobi treatment and for at least 1 week after the last dose (see section 4.6).

Women of childbearing potential/Contraception in males and females

An effective method of contraception should be used in women of childbearing potential and in men with women partners of childbearing potential during treatment with Lytgobi and for 1 week following completion of therapy. Since the effect of futibatinib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception to avoid pregnancy.

Pregnancy

There are no available data from the use of futibatinib in pregnant women. Studies in animals have shown embryo-foetal toxicity (see section 5.3). Lytgobi should not be used during pregnancy unless the potential benefit for the women justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether futibatinib or its metabolites are excreted in human milk. A risk to the breastfed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Lytgobi and for 1 week after the last dose.

Fertility

There are no data on the effect of futibatinib on human fertility. Animal fertility studies have not been conducted with futibatinib (see section 5.3). Based on the pharmacology of futibatinib, impairment of male and female fertility cannot be excluded.

Futibatinib has moderate influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or operating machines in case they experience fatigue or visual disturbances during the treatment with Lytgobi (see section 4.4).

Summary of the safety profile

The most common (≥20%) adverse reactions were hyperphosphatemia (89.7%), nail disorders (44.1%), constipation (37.2%), alopecia (35.2%), diarrhoea (33.8%), dry mouth (31.0%), fatigue (31.0%), nausea (28.3%), dry skin (27.6%), increased AST (26.9%), abdominal pain (24.8%), stomatitis (24.8%), vomiting (23.4%), palmar-plantar erythrodysaesthesia syndrome (22.8%), arthralgia (21.4%), and decreased appetite (20.0%).

The most common serious adverse reactions were intestinal obstruction (1.4%) and migraine (1.4%).

Permanent discontinuation due to adverse reactions was reported in 7.6% of patients; the most common adverse reaction led to dose discontinuation was stomatitis (1.4%), all other adverse reactions were single occurrence.

Tabulated list of adverse reactions

Table 5 summarises the adverse reactions occurring in 145 patients treated in the indicated population of Study TAS-120-101. Median duration of exposure of futibatinib was 8.87 months (min: 0.5, max: 31.7). Adverse reactions are listed according to MedDRA system organ class (SOC). Frequency categories are very common (≥ 1/10) and common (≥ 1/100 to < 1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5: Adverse reactions observed in the indicated population in TAS-120-101 study (N=145) - frequency reported by incidence of treatment emergent events

^a Includes serous retinal detachment, detachment of retinal pigment epithelium, subretinal fluid, chorioretinopathy, macular oedema, and maculopathy. See below “Serous retinal detachment”.

^b Includes nail toxicity, nail bed tenderness, nail disorder, nail discolouration, nail dystrophy, nail hypertrophy, nail infection, nail pigmentation, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis and paronuchia.

Description of selected adverse reactions

Hyperphosphatemia

Hyperphosphatemia was reported in 89.7% of patients treated with futibatinib and 27.6% patients had Grade 3 events, defined as serum phosphate > 7 mg/dL and ≤ 10 mg/dL irrespective of clinical symptoms. The median time to onset of hyperphosphatemia of any grade was 6.0 days (range: 3.0 to 117.0 days).

None of the reactions were Grade 4 or 5 in severity, serious, or led to discontinuation of futibatinib. Dose interruption occurred in 18.6 % patients and reduction in 17.9 % of patients. Hyperphosphatemia was manageable with dietary phosphate restriction and/or administration of phosphate lowering therapy and /or dose modification.

Recommendations for management of hyperphosphatemia are provided in sections 4.2 and 4.4.

Serous retinal detachment

Serous retinal detachment occurred in 6.2 % of patients treated with futibatinib. Reactions were all Grade 1 or 2 in severity. Dose interruption occurred in 2.1 % of patients and reduction in 2.1 % of patients. None of the reactions led to discontinuation of futibatinib. Serous retinal detachment was generally manageable.

Recommendations for management of serous retinal detachment are provided in sections 4.2 and 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no information on overdose of futibatinib.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01 EN04

Mechanism of action

Constitutive fibroblast growth factor receptor (FGFR) signalling can support the proliferation and survival of malignant cells. Futibatinib is a tyrosine kinase inhibitor that irreversibly inhibits FGFR 1, 2, 3, and 4 by covalent binding. Futibatinib exhibited in vitro inhibitory activity against FGFR2 resistance mutations (N550H, V565I, E566G, K660M).

Pharmacodynamic effects

Serum phosphate

Futibatinib increased serum phosphate level as a consequence of FGFR inhibition. Phosphatelowering therapy and dose modifications are recommended to manage hyperphosphatemia: see sections 4.2, 4.4 and 4.8.

Clinical efficacy and safety

TAS-120-101 a multicentre, open-label, single-arm study evaluated the efficacy and safety of futibatinib in previously treated patients with unresectable locally advanced or metastatic intrahepatic cholangiocarcinoma. Patients with prior FGFR-directed therapy were excluded. The efficacy population consists of 103 patients that had progressed on or after at least 1 prior gemcitabine and platinum-based chemotherapy and had FGFR2 fusion (77.7%) or rearrangement (22.3%), as determined by tests performed at central or local laboratories. Patients received futibatinib orally once daily at a dose of 20 mg until disease progression or unacceptable toxicity. The primary efficacy outcome measure was objective response rate (ORR) as determined by an independent review committee (IRC) according to RECIST v1.1, with duration of response (DoR) as a key secondary endpoint.

The median age was 58 years (range: 22 to 79 years), 22.3% were ≥65 years, 56.3% were female, 49.5% were Caucasian. All (100 %) patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (46.6 %) or 1 (53.4 %). All patients had at least 1 prior line of systemic therapy, 30.1% had 2 prior lines of therapy, and 23.3% had 3 or more prior lines of therapy. All patients had received prior platinum-based therapy including 91% with prior gemcitabine/ cisplatin.

Efficacy results are summarized in Table 6. The median time to response was 2.5 months (range 0.7 – 7.4 months).

In addition to the primary analysis presented here, an interim analysis was conducted without plans to stop the study. Results from both analyses were consistent. The primary analysis for DoR included censoring for new anti-cancer treatment, progressive disease or death after two or more missed tumour assessments, or at least 21 days after treatment discontinuation.

Elderly patients

In the clinical study of futibatinib, 22.3% of patients were 65 years and older. No difference in efficacy was detected between these patients and in patients < 65 years of age.

Paediatric population

The Medicines and Healthcare products Regulatory Agency has waived the obligation to submit the results of studies with Lytgobi in all subsets of the paediatric population in the treatment of cholangiocarcinoma. See section 4.2 for information in paediatric use.

Conditional approval

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The Medicines and Healthcare products Regulatory Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

The pharmacokinetics of futibatinib were evaluated in patients with advanced cancer administered 20 mg once daily unless otherwise specified.

Futibatinib exhibits linear pharmacokinetics over the dose range of 4 to 24 mg. Steady-state was reached after the first dose with a geometric mean accumulation ratio of 1.03. The geometric mean steady-state AUCss was 790 ng·h/mL (44.7% gCV) and Cmax,ss was 144 ng/mL (50.3% gCV) at the recommended dosage of 20 mg once daily.

Absorption

Median time to achieve peak plasma concentration (tmax) was 2 (range: 1.2 to 22.8) hours.

No clinically meaningful differences in futibatinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (900 calories to 1000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects.

Distribution

Futibatinib is approximately 95% bound to human plasma proteins, predominantly to albumin and α1-acid glycoprotein. The estimated apparent volume of distribution was 66.1 L (17.5%).

Biotransformation

Futibatinib is predominantly metabolised by CYP3A (40-50%) as well as glutathione conjugation (50-60%) in vitro. Following oral administration of a single 20 mg radiolabelled futibatinib dose in healthy adult male subjects, the main drug-related moiety in plasma was unchanged futibatinib (59.19% of the total sample radioactivity) in a human [14C] mass balance study in healthy adult male subjects, followed by one inactive metabolite, a cysteinylglycine conjugate TAS-06-22952 (at >10% of dose).

Elimination

The mean elimination half-life (t1/2) of futibatinib was 2.94 (26.5% CV) hours and the geometric mean apparent clearance (CL/F) was 19.8 L/h (23.0%).

Excretion

Following a single oral dose of 20 mg radiolabelled futibatinib in healthy adult male subjects, approximately 64% of the dose was recovered in faeces and 6% in urine. Futibatinib excretion in unchanged form was negligible in either urine or faeces.

Drug-drug interactions

Effect of futibatinib on CYP enzymes

In vitro studies indicate that futibatinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, and does not induce CYP2B6 or CYP3A4 at clinically relevant concentrations.

Effect of futibatinib on drug transporters

In vitro studies indicated that futibatinib inhibited P-gp and BCRP, but didn't inhibit OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1 or MATE2K at clinically relevant concentrations. Futibatinib is a substrate of P-gp and BCRP in vitro. Inhibition of BCRP is not expected to result in clinically relevant changes in the exposure of futibatinib.

Special populations

No clinically meaningful differences in the systemic exposure (less than 25% difference in AUC) of futibatinib were observed based on age (18 - 82 years), sex, race/ethnicity, body weight (36 - 152 kg), mild to moderate renal impairment, or hepatic impairment. The effect of severe renal impairment andrenal dialysis in end-stage renal disease on futibatinib exposure is unknown (see section 4.2).

Hepatic impairment

Compared to subjects with normal hepatic function, systemic exposure following a single dose of futibatinib was similar in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment (see section 4.2).

Exposure-response relationship

Dose-dependent increase in blood phosphate levels was observed following once daily futibatinib 4 mg to 24 mg dose range.

No statistically significant exposure-efficacy relationships observed for ORR within the exposure range produced by futibatinib 20 mg once daily regimen.

Repeat-dose toxicity

The main toxicological findings following repeat-dose administration of futibatinib in both rats and dogs were related to the pharmacological activity of futibatinib as an irreversible inhibitor of FGFR, including increased inorganic phosphorus and calcium in plasma, ectopic mineralization in various organs and tissues, lesions in bone/cartilage at futibatinib exposures lower than the human exposure at the clinical dose of 20 mg. Corneal lesions were found only in rats. These effects were reversible with the exception of ectopic mineralization.

Genotoxicity

Futibatinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. It was positive in the in vitro chromosome aberration test in cultured Chinese hamster lung cell (CHL/IU), but negative in the bone marrow micronucleus assay in rat and didn't induce DNA damage in comet assay in rats. Thus, futibatinib is overall non-genotoxic.

Carcinogenicity

Carcinogenicity studies with futibatinib have not been conducted.

Impairment of fertility

Dedicated fertility studies with futibatinib have not been conducted. In repeat dose toxicity studies, oral administration of futibatinib did not result in any dose-related findings likely to result in impaired fertility in male or female reproductive organs.

Developmental toxicity

Oral administration of futibatinib to pregnant rats during the period of organogenesis resulted in 100% post-implantation loss at 10 mg/kg per day (approximately 3.15 times the human exposure by AUC at the recommended clinical dose). At 0.5 mg/kg per day (approximately 0.15 times the human exposure by AUC at the recommended clinical dose), reduced mean foetal body weight, an increase in foetal skeletal and visceral malformations including major blood vessel variations were observed.

Tablet core

Mannitol (E421)

Maize starch

Lactose monohydrate

Sodium laurilsulfate

Cellulose, microcrystalline

Crospovidone

Hydroxypropylcellulose (E463)

Magnesium stearate

Film-coating

Hypromellose (E464)

Macrogols

Titanium dioxide (E171)

Lustering agent

Magnesium stearate

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

PVC/PCTFE laminated blisters with aluminium foil backing with one tablet per cavity. Each blister contains a 7-day supply of film-coated tablets sealed inside a folding cardboard wallet in the following three dose packs:

• 20 mg daily dose: Each wallet contains 35 tablets (5 tablets once daily).

• 16 mg daily dose: Each wallet contains 28 tablets (4 tablets once daily).

• 12 mg daily dose: Each wallet contains 21 tablets (3 tablets once daily).

Not all pack sizes may be marketed.

No special requirements for disposal.