Futibatinib

1 INDICATIONS AND USAGE LYTGOBI is 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 [see Dosage and Administration (2.1) ] . This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.1) ] . 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 , 2.1 ) 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). ( 1 )

12.1 Mechanism of Action Futibatinib is a small molecule kinase inhibitor of FGFR 1, 2, 3, and 4 with IC 50 values of less than 4 nM. Futibatinib covalently binds FGFR. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. Futibatinib inhibited FGFR phosphorylation and downstream signaling and decreased cell viability in cancer cell lines with FGFR alterations including FGFR fusions/rearrangements, amplifications, and mutations. Futibatinib demonstrated anti-tumor activity in mouse and rat xenograft models of human tumors with activating FGFR genetic alterations.

2 DOSAGE AND ADMINISTRATION Confirm the presence of an FGFR2 gene fusion or other rearrangement prior to initiation of treatment with LYTGOBI. ( 2.1 ) 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. ( 2.2 ) Swallow tablet whole, with or without food. ( 2.2 ) 2.1 Patient Selection Select patients for the treatment of unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma with LYTGOBI based on the presence of an FGFR2 gene fusion or rearrangement [see Clinical Studies (14.1) ]. 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. 2.2 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. Take LYTGOBI with or without food at approximately the same time each day [see Clinical Pharmacology (12.3) ] . 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. 2.3 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 . Table 2: Recommended Dosage Modifications for LYTGOBI Adverse Reactions Adverse Reaction Severity LYTGOBI Dosage Modifications a Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03). Retinal Pigment Epithelial Detachment (RPED) [see Warnings and Precautions (5.1) ] 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. Hyperphosphatemia [see Warnings and Precautions (5.2) ] Serum phosphate ≥5.5 - ≤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

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Ocular Toxicity [see Warnings and Precautions (5.1) ] Hyperphosphatemia and Soft Tissue Mineralization [see Warnings and Precautions (5.2) ] 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. ( 6.1 ) 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Taiho Oncology Inc. at 1-844-878-2446 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch . 6.1 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. Previously Treated, Unresectable Locally Advanced or Metastatic Intrahepatic Cholangiocarcinoma The safety of LYTGOBI was evaluated in Study TAS-120-101, which included 103 patients with previously treated, unresectable locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusions or other gene rearrangements [see Clinical Studies (14.1) ] . Patients were treated with LYTGOBI 20 mg orally once daily until disease progression or unacceptable toxicity. The median duration of treatment was 9 months (range: 0.5 - 25 months). Serious adverse reactions occurred in 39% of patients receiving LYTGOBI. Serious adverse reactions in ≥2% of patients who received LYTGOBI included pyrexia (3.9%), gastrointestinal hemorrhage (3.9%), ascites (2.9%), musculoskeletal pain (2.9%), and bile duct obstruction (2.9%). Permanent discontinuation due to an adverse reaction occurred in 4.9% 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, decr

5 WARNINGS AND PRECAUTIONS Ocular Toxicity: LYTGOBI can cause retinal pigment epithelial detachment (RPED). Perform a comprehensive ophthalmological examination including optical coherence tomography (OCT) prior to initiation of therapy, every 2 months for the first 6 months, and every 3 months thereafter and urgently at any time for visual symptoms. ( 2.3 , 5.1 ) Hyperphosphatemia and Soft Tissue Mineralization: Increases in phosphate levels can cause hyperphosphatemia leading to soft tissue mineralization, calcinosis, nonuremic calciphylaxis and vascular calcification. Monitor for hyperphosphatemia and withhold, reduce the dose, or permanently discontinue based on duration and severity of hyperphosphatemia. ( 2.3 , 5.2 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Ocular Toxicity Retinal Pigment Epithelial Detachment (RPED) LYTGOBI can cause RPED, which may cause symptoms such as blurred vision. Among 318 patients who received LYTGOBI across clinical trials [see Adverse Reactions (6.1) ] where ophthalmologic monitoring did not routinely include optical coherence tomography (OCT), RPED occurred in 9% of patients. The median time to first onset of RPED was 40 days. RPED led to dose interruption of LYTGOBI in 1.3% of patients, dose reduction in 1.6% of patients, and permanent discontinuation in 0.3% of patients. Perform a comprehensive ophthalmological examination, including OCT of the macula, prior to initiation of therapy, every 2 months for the first 6 months, and every 3 months thereafter. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of LYTGOBI. Withhold or reduce the dose of LYTGOBI as recommended [see Dosage and Administration (2.3) ]. Dry Eye/Corneal Keratitis Among 318 patients who received LYTGOBI across clinical trials [see Adverse Reactions (6.1) ] , dry eye occurred in 15% of patients. Treat patients with ocular demulcents as needed. 5.2 Hyperphosphatemia and Soft Tissue Mineralization LYTGOBI can cause hyperphosphatemia leading to soft tissue mineralization, calcinosis, nonuremic calciphylaxis, and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of LYTGOBI [see Clinical Pharmacology (12.2) ] . Among 318 patients who received LYTGOBI across clinical trials [see Adverse Reactions (6.1) ] , hyperphosphatemia was reported in 88% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 5 days (range 3-117). Phosphate binders were received by 77% of patients who received LYTGOBI. Monitor for hyperphosphatemia throughout treatment. Initiate a low phosphate diet and phosphate lowering therapy when serum phosphate level is ≥5.5 mg/dL. For serum phosphate levels >7 mg/dL, initiate or intensify phosphate lowering therapy and dose reduce, withhold, or permanently discontinue LYTGOBI based on duration and severity of hyperphosphatemia [see Dosage and Administration (2.3) ] . 5.3 Embryo-Fetal Toxicity Based on findings in an animal study and its mechanism of action, LYTGOBI can cause fetal harm when administered to a pregnant woman. Oral administration of futibatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure at the clinical dose of 20 mg based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with LYTGOBI and for 1 week after the last dose of LYTGOBI. Advise males with female partners of reproductive potential to use effective contraception during treatment with LYTGOBI and for 1 week after the last dose [see Use in Specif

4 CONTRAINDICATIONS None. None ( 4 )