pralsetinib 100 MG Oral Capsule [Gavreto]

INDICATIONS AND USAGE GAVRETO is a kinase inhibitor indicated for treatment of: Adult patients with metastatic rearranged during transfection (RET ) fusion-positive non-small cell lung cancer as detected by an FDA approved test (NSCLC). ( 1.1 ) Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). 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 confirmatory trial(s). ( 1.2 ) 1.1 Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer GAVRETO is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. 1.2 RET Fusion-Positive Thyroid Cancer GAVRETO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.2) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

DOSAGE AND ADMINISTRATION Select patients for treatment with GAVRETO based on the presence of a RET gene fusion. ( 2.1 , 14 ) The recommended dosage in adults and pediatric patients 12 years and older is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO). ( 2.2 ) 2.1 Patient Selection Select patients for treatment with GAVRETO based on the presence of a RET gene fusion (NSCLC or thyroid cancer) [see Clinical Studies (14) ] . Information on FDA-approved tests for RET gene fusion (NSCLC) is available at http://www.fda.gov/CompanionDiagnostics. An FDA-approved test for the detection of RET gene fusion (thyroid cancer) is not currently available. 2.2 Recommended Dosage The recommended dosage of GAVRETO is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO ) [see Clinical Pharmacology (12.3) ] . Continue treatment until disease progression or until unacceptable toxicity. If a dose of GAVRETO is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for GAVRETO the next day. Do not take an additional dose if vomiting occurs after GAVRETO but continue with the next dose as scheduled. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reductions and dosage modifications for adverse reactions are provided in Table 1 and Table 2 . Table 1: Recommended Dose Reductions for GAVRETO for Adverse Reactions Dose Reduction Recommended Dosage First 300 mg once daily Second 200 mg once daily Third 100 mg once daily Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily. The recommended dosage modifications for adverse reactions are provided in Table 2 . Table 2: Recommended Dosage Modifications for GAVRETO for Adverse Reactions Adverse Reactions Severity Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 Dosage Modification Serious Infections, Including Opportunistic Infections [see Warnings and Precautions (5.1) ] Grade 2 or 3 Withhold GAVRETO until resolution. Resume at a reduced dose ( Table 1 ). Grade 4 Permanently discontinue GAVRETO. ILD/Pneumonitis [see Warnings and Precautions (5.2) ] Grade 1 or 2 Withhold GAVRETO until resolution. Resume by reducing the dose as shown in Table 1 . Permanently discontinue GAVRETO for recurrent ILD/pneumonitis. Grade 4 Permanently discontinue GAVRETO. Hypertension [see Warnings and Precautions (5.3) ] Grade 3 Withhold GAVRETO for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled. Grade 4 Discontinue GAVRETO. Hepatotoxicity [see Warnings and Precautions (5.4) ] Grade 3 or 4 Withhold GAVRETO and monitor AST/ALT once weekly until resolution to Grade 1 or baseline. Resume at reduced dose ( Table 1 ). For recurrent events at Grade 3 or higher, discontinue GAVRETO. Hemorrhagic Events [see Warnings and Precautions (5.5) ] Grade 3 or 4 Withhold GAVRETO until recovery to baseline or Grade 0 or 1. Discontinue GAVRETO for severe or life-threatening hemorrhagic events. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 or 4 Withhold GAVRETO until improvement to ≤ Grade 2. Resume at reduced dose ( Table 1 ). Permanently discontinue for recurrent Grade 4 adverse reactions. 2.4 Dose Modification for Use with CYP3A and/or P-glycoprotein (P-gp) Inhibitors Avoid coadministration of GAVRETO with any of the following: Strong CYP3A inhibitors Moderate CYP3A inhibitors P-gp inhibitors Combined P-gp and strong CYP3A inhibitors Combined P-gp and moderate CYP3A inhibitors If coadministration with any of the above inhibitors cannot be avoided, reduce the current dose of GAVRETO as recommended in Table 3 . After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume GAVRETO at the dose taken prior to initiating the inhibitor [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Table 3: Recommended Dosage Modifications for GAVRETO for Coadministration with CYP3A and/or P-gp Inhibitors Current GAVRETO Dosage Recommended GAVRETO Dosage when Coadministered with: Combined P-gp and Strong CYP3A Inhibitors Strong CYP3A Inhibitors; Moderate CYP3A Inhibitors; P-gp Inhibitors; Combined P-gp and Moderate CYP3A Inhibitors 400 mg orally once daily 200 mg orally once daily 300 mg orally once daily 300 mg orally once daily 200 mg orally once daily 200 mg orally once daily 200 mg orally once daily 100 mg orally once daily 100 mg orally once daily 2.5 Dose Modification for Use with CYP3A Inducers Avoid coadministration of GAVRETO with any of the following: Strong CYP3A inducers Moderate CYP3A inducers If coadministration with any of the above inducers cannot be avoided, increase the starting dose of GAVRETO as recommended in Table 4 starting on Day 7 of coadministration of GAVRETO with the inducer. After the inducer has been discontinued for at least 14 days, resume GAVRETO at the dose taken prior to initiating the inducer [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Table 4: Recommended Dosage Modifications for GAVRETO for Coadministration with CYP3A Inducers Current GAVRETO Dosage Recommended GAVRETO Dosage when Coadministered with: Strong CYP3A Inducers Moderate CYP3A Inducers 400 mg orally once daily 800 mg orally once daily 600 mg orally once daily 300 mg orally once daily 600 mg orally once daily 500 mg orally once daily 200 mg orally once daily 400 mg orally once daily 300 mg orally once daily

WARNINGS AND PRECAUTIONS Serious Infections, Including Opportunistic Infections: Monitor for signs and symptoms of infection and treat appropriately. Withhold, reduce the dose, or permanently discontinue GAVRETO based on severity. ( 2.3 , 5.1 ) Interstitial Lung Disease (ILD)/Pneumonitis: Withhold GAVRETO for Grade 1 or 2 reactions until resolution and then resume at a reduced dose. Permanently discontinue for recurrent ILD/pneumonitis. Permanently discontinue for Grade 3 or 4 reactions. ( 2.3 , 5.2 ) Hypertension : Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating GAVRETO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. ( 2.3 , 5.3 ) Hepatotoxicity : Monitor ALT and AST prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. ( 2.3 , 5.4 ) Hemorrhagic Events : Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage. ( 2.3 , 5.5 ) Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. ( 2.3 , 5.6 ) Risk of Impaired Wound Healing: Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established. ( 5.7 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception. ( 5.8 , 8.1 , 8.3 ) 5.1 Serious Infections, Including Opportunistic Infections GAVRETO may increase the risk for serious infections, including fatal and opportunistic infections. In the AcceleRET-Lung trial [see Adverse Reactions (6.1) ] , infections occurred in 72% of patients who received GAVRETO, including 18% with Grade 3, 3.7% with Grade 4, and 7% with fatal outcomes. Among the patients who received chemotherapy/immunotherapy, infections occurred in 52%, including 10% with Grade 3. Infections in the GAVRETO arm included pneumonia, urinary tract infection, opportunistic infections (such as pneumocystis jirovecii pneumonia, and fungal infections) and others. Monitor patients for signs and symptoms of infection and treat appropriately. Withhold, reduce the dose, or permanently discontinue GAVRETO based on severity [see Dosage and Administration (2.3) ] . 5.2 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, and fatal interstitial lung disease (ILD) / pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue GAVRETO based on severity of confirmed ILD [see Dosage and Administration (2.3) ] . 5.3 Hypertension Hypertension occurred in 35% of patients, including Grade 3 hypertension in 18% of patients [see Adverse Reactions (6.1) ] . Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue GAVRETO based on the severity [see Dosage and Administration (2.3) ] . 5.4 Hepatotoxicity Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO. Increased AST occurred in 49% of patients, including Grade 3 or 4 in 7% and increased ALT occurred in 37% of patients, including Grade 3 or 4 in 4.8% [see Adverse Reactions (6.1) ]. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and for increased ALT was 24 days (range: 7 days to 3.7 years). Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity [see Dosage and Administration (2.3) ] . 5.5 Hemorrhagic Events Serious, including fatal, hemorrhagic events can occur with GAVRETO. Grade ≥ 3 hemorrhagic events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event. Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.3) ] . 5.6 Tumor Lysis Syndrome Cases of tumor lysis syndrome (TLS) have been reported in patients with medullary thyroid carcinoma receiving GAVRETO [see Adverse Reactions (6.1) ] . Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated. 5.7 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, GAVRETO has the potential to adversely affect wound healing. Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established. 5.8 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6- RET ) and mutations ( RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC 50s ) less than 0.5 nM. In purified enzyme assays, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRB, and FGFR1 at higher concentrations that were still clinically achievable at C max . In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively. Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to uncontrolled cell proliferation. Pralsetinib exhibited anti-tumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations including KIF5B- RET , CCDC6- RET , RET M918T, RET C634W, RET V804E, RET V804L and RET V804M. In addition, pralsetinib prolonged survival in mice implanted intracranially with tumor models expressing KIF5B- RET or CCDC6- RET .