Futibatinib

1) ] . 1) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). LYTGOBI is a kinase inhibitor indicated for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.

1 ) This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

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2 DOSAGE AND ADMINISTRATION Confirm the presence of an FGFR2 gene fusion or other rearrangement prior to initiation of treatment with LYTGOBI. 1 ) Recommended dose is 20 mg orally (five 4 mg tablets or one 16 mg tablet and one 4 mg tablet) once daily until disease progression or unacceptable toxicity occurs.

2 ) Swallow tablet whole, with or without food. 1) ]. An FDA-approved test for detection of FGFR2 gene fusions or other rearrangements in patients with unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma for selecting patients for treatment with LYTGOBI is not available.

2 Recommended Dosage The recommended dosage of LYTGOBI is 20 mg (five 4 mg tablets or one 16 mg and one 4 mg tablet) taken orally once daily until disease progression or unacceptable toxicity occurs. 3) ] . Swallow tablets whole. Do not crush, chew, split, or dissolve tablets.

If the patient misses a dose of LYTGOBI for more than 12 hours or if vomiting occurs, resume dosing with the next scheduled dose. 3 Dosage Modification for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 1 .

Table 1:

Recommended Dose Reductions for LYTGOBI for Adverse Reactions Dose Reduction Recommended Dosage First dose reduction 16 mg (four 4 mg tablets or one 16 mg tablet) orally once daily Second dose reduction Permanently discontinue LYTGOBI if unable to tolerate 12 mg orally once daily.

12 mg (three 4 mg tablets) orally once daily Recommended dosage modifications for adverse reactions are provided in Table 2 . 03). 1) ] Not applicable Continue LYTGOBI at the current dose and continue periodic ophthalmic evaluation: If resolving within 14 days, continue LYTGOBI at the current dose.

If not resolving within 14 days, withhold LYTGOBI until resolving; then resume LYTGOBI at previous or a lower dose. 5 - ≤7 mg/dL Continue LYTGOBI at the current dose and initiate phosphate lowering therapy. Monitor serum phosphate weekly.

Serum phosphate >7 - ≤10 mg/dL Initiate or adjust phosphate lowering therapy. Monitor serum phosphate weekly and Dose reduce LYTGOBI to next lower dose - If the serum phosphate resolves to ≤7 mg/dL within 2 weeks after dose reduction, continue at this reduced dose.

- If serum phosphate is not ≤7 mg/dL within 2 weeks, further reduce LYTGOBI to the next lower dose. - If serum phosphate is not ≤7 mg/dL within 2 weeks after the second dose reduction, withhold LYTGOBI until serum phosphate is ≤7 mg/dL and resume at the dose prior to suspending.

Serum phosphate >10 mg/dL Initiate or adjust phosphate lowering therapy and monitor serum phosphate weekly and Withhold LYTGOBI until phosphate is ≤7 mg/dL and resume LYTGOBI at the next lower dose. - Permanently discontinue LYTGOBI if serum phosphate is not ≤7 mg/dL within 2 weeks following 2 dose interruptions and reductions.

Other Adverse Reactions Grade 3 a Withhold LYTGOBI until toxicity resolves to Grade 1 or baseline, then resume LYTGOBI - for hematological toxicities resolving within 1 week, at the dose prior to suspending. - for other adverse reactions, at next lower dose.

Grade 4 a Permanently discontinue LYTGOBI

2) ] Most common (≥20%) adverse reactions were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye, nausea, decreased appetite, urinary tract infection, palmar-plantar erythrodysesthesia syndrome, and vomiting.

1 ) Most common laboratory abnormalities (≥20%) were increased phosphate, increased creatinine, decreased hemoglobin, increased glucose, increased calcium, decreased sodium, decreased phosphate, increased alanine aminotransferase, increased alkaline phosphatase, decreased lymphocytes, increased aspartate aminotransferase, decreased platelets, increased activated partial thromboplastin time, decreased leukocytes, decreased albumin, decreased neutrophils, increased creatine kinase, increased bilirubin, decreased glucose, increased prothrombin international normalized ratio, and decreased potassium.

1 ) To report SUSPECTED ADVERSE REACTIONS, contact Taiho Oncology Inc. gov/medwatch . 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to LYTGOBI as a single agent at 20 mg orally once daily in 318 patients including 145 patients with cholangiocarcinoma and 173 patients with other advanced solid tumors.

Among 318 patients who received LYTGOBI, 37% were exposed for 6 months or longer and 13% were exposed for greater than 12 months. 1) ] . Patients were treated with LYTGOBI 20 mg orally once daily until disease progression or unacceptable toxicity.

5 - 25 months). Serious adverse reactions occurred in 39% of patients receiving LYTGOBI. 9%). 9% of patients who received LYTGOBI. Adverse reactions requiring permanent discontinuation of LYTGOBI in one patient each were esophagitis, oral dysesthesia, bile duct obstruction, dizziness, and anemia.

Dosage interruptions due to an adverse reaction occurred in 66% of patients who received LYTGOBI. Adverse reactions requiring dosage interruption in ≥5% of patients included hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, increased alanine aminotransferase, increased aspartate aminotransferase, and fatigue.

Dose reductions due to an adverse reaction occurred in 58% of patients who received LYTGOBI. Adverse reactions requiring dosage reductions in ≥2% of patients who received LYTGOBI included hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, fatigue, increased alanine aminotransferase, increased aspartate aminotransferase, nail toxicity, and stomatitis.

The most common (≥20%) adverse reactions were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye, nausea, decreased appetite, urinary tract infection, palmar-plantar erythrodysesthesia syndrome, and vomiting.

The most common laboratory abnormalities (≥20%) were increased phosphate, increased creatinine, decreased hemoglobin, increased glucose, increased calcium, decreased sodium, decreased phosphate, increased alanine aminotransferase, increased alkaline phosphatase, decreased lymphocyte, increased aspartate aminotransferase, decreased platelets, increased activated partial thromboplastin time, decreased leukocytes, decreased albumin, decreased neutrophils, increased creatine kinase, increased bilirubin, decreased glucose, increased prothrombin international normalized ratio, and decreased potassium.

Table 3 summarizes the adverse reactions in TAS-120-101. Table 4 summarizes laboratory abnormalities in TAS-120-101. 03. b Includes nail toxicity, nail disorder, nail discoloration, nail dystrophy, nail hypertrophy, nail infection, nail pigmentation, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia.

c Includes diarrhea, colitis, and gastroenteritis. d Includes stomatitis, glossitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, and tongue ulceration. e Includes abdominal pain, abdominal discomfort, abdominal pain upper, gastrointestinal pain, and hepatic pain.

f Includes vomiting and hematemesis. g Includes fatigue and asthenia. h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.

i Includes arthralgia and arthritis. j Includes dry eye, keratitis, lacrimation increased, photokeratitis, punctate keratitis, and ulcerative keratitis. k Includes dysgeusia, ageusia, and taste disorder. l Includes urinary tract infection, cystitis, and dysuria.

8%). 03. b Percentages are based on patients with data at both baseline and at least one post-baseline data value. 03 does not define grades for increased phosphate. Laboratory value shift table categories were used to assess increased phosphorus levels (Grades ≥3 defined as >7 mg/dL).

d Graded based on comparison to upper limit of normal. 1 Increased potassium 16 2 Coagulation Increased activated partial thromboplastin time 36 8 Increased prothrombin international normalized ratio 25 0

4 CONTRAINDICATIONS None. None ( 4 )

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.

2 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. 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).

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.

5). If this is not possible, based on careful monitoring of tolerability, a futibatinib dose reduction to the next lower level should be considered. 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.

Table 1:

Recommended futibatinib dose reduction levels Dose Dose reduction levels First Second20 mg taken orally once daily 16 mg taken orally once daily 12 mg taken orally once daily 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. 0 mg/dL within 2 weeks following 2 dose reductions Dose modifications for serous retinal detachment are provided in Table 3.

Table 3:

Dose modifications for serous retinal detachment Adverse reaction Futibatinib dose modification Asymptomatic • Continue futibatinib at current dose. Monitoring should be performed as described in section

0%). 4%). 4%), all other adverse reactions were single occurrence. 8 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. 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 System organ class Frequency Adverse reactions Metabolism and nutrition disorders Very common Hyperphosphatemia Decreased appetite Hyponatraemia Hypophosphataemia Very common DysgeusiaNervous system disorders Common Migraine Very common Dry eyeEye disorders Common Serous retinal detachmenta Gastrointestinal disorders Very common Stomatitis Diarrhoea Nausea Constipation Dry mouth Vomiting Abdominal pain Common Intestinal obstruction Skin and subcutaneous tissue disorders Very common Palmar-plantar erythrodysaesthesia syndrome Nail disordersb Dry skin Alopecia Musculoskeletal and connective tissue disorders Very common Myalgia Arthralgia General disorders and administration site conditions Very common Fatigue Investigations Very common Liver transaminases increased 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 paronychia.

6% patients had Grade 3 events, defined as serum phosphate > 7 mg/dL and ≤ 10 mg/dL irrespective of clinical symptoms. 0 days). None of the reactions were Grade 4 or 5 in severity, serious, or led to discontinuation of futibatinib. 9 % of patients.

Hyperphosphatemia was manageable with dietary phosphate restriction and/or administration of phosphate lowering therapy and /or dose modification. 4. 2 % of patients treated with futibatinib. Reactions were all Grade 1 or 2 in severity.

1 % of patients. None of the reactions led to discontinuation of futibatinib. Serous retinal detachment was generally manageable. 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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

1.

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. 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).

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.

5). If this is not possible, based on careful monitoring of tolerability, a futibatinib dose reduction to the next lower level should be considered. 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.

Table 1:

Recommended futibatinib dose reduction levels Dose Dose reduction levels 20 mg taken orally once daily First Second 16 mg taken orally once daily 12 mg taken orally once daily 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. 0 mg/dL within 2 weeks following 2 dose reductions 4 Dose modifications for serous retinal detachment are provided in Table 3.

Table 3:

Dose modifications for serous retinal detachment Adverse reaction Futibatinib dose modification Asymptomatic • Continue futibatinib at current dose. Monitoring should be performed as described in section

0%). 4%). 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. 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 System organ class Frequency Adverse reactions Metabolism and nutrition disorders Very common Hyperphosphatemia Decreased appetite Hyponatraemia Hypophosphataemia Nervous system disorders Very common Dysgeusia Common Migraine Eye disorders Very common Dry eye Common Serous retinal detachmenta Gastrointestinal disorders Very common Stomatitis Diarrhoea Nausea Constipation Dry mouth Vomiting Abdominal pain Common Intestinal obstruction Skin and subcutaneous tissue disorders Very common Palmar-plantar erythrodysaesthesia syndrome Nail disordersb Dry skin Alopecia Musculoskeletal and connective tissue disorders Very common Myalgia Arthralgia General disorders and administration site conditions Very common Fatigue Investigations Very common Liver transaminases increased a Includes serous retinal detachment, detachment of retinal pigment epithelium, subretinal fluid, chorioretinopathy, macular oedema, and maculopathy.

See below “Serous retinal detachment”. 6% patients had Grade 3 events, defined as serum phosphate > 7 mg/dL and ≤ 10 mg/dL irrespective of clinical symptoms. 0 days). None of the reactions were Grade 4 or 5 in severity, serious, or led to discontinuation of futibatinib.

9 % of patients. Hyperphosphatemia was manageable with dietary phosphate restriction and/or administration of phosphate lowering therapy and /or dose modification. 4. 2 % of patients treated with futibatinib. Reactions were all Grade 1 or 2 in severity.

1 % of patients. None of the reactions led to discontinuation of futibatinib. Serous retinal detachment was generally manageable. 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 national reporting system listed in Appendix V.

1.