Gavreto

Indications and Usage, Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer – Accelerated Approval text removed (1.1) (8/2023) Indications and Usage, RET -Mutant Medullary Thyroid Cancer –Indication Removed (1.2) (7/2023) Dosage and Administration ( 2.1 ) (7/2023) Dosage and Administration, Dose Modification for Use with CYP3A and/or P-glycoprotein (P-gp) Inhibitors ( 2.4 ) (6/2023) Dosage and Administration, Dose Modification for Use with CYP3A Inducers ( 2.5 ) (6/2023)

1 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).

2 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 …

3 DOSAGE FORMS AND STRENGTHS Capsules: 100 mg, light blue, opaque, hard hydroxypropyl methylcellulose (HPMC) capsule printed with "BLU-667" on the capsule shell body and "100 mg" on the capsule shell cap. Capsules: 100 mg. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections, Including Opportunistic Infections [see Warnings and Precautions (5.1) ] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2) ] Hypertension [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Hemorrhagic Events [see Warnings and Precautions (5.5) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ] Risk of Impaired Wound Healing [see Warnings and Precautions (5.7) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.8) ] The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 or FDA at 1-800-FDA-1088 or 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 in the WARNINGS AND PRECAUTIONS reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 540 patients in ARROW [see Clinical Studies (14) ]. Among 540 patients who received GAVRETO, 71% were exposed for 6 months or longer and 57% were exposed for greater than one year. The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin. In addition to the 540 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to GAVRETO as a single agent in a randomized, open-label study, AcceleRET-Lung (NCT04222972), which enrolled 223 patients with RET-fusion positive locally advanced unresectable or metastatic NSCLC. RET Fusion-Positive Non-Small Cell Lung Cancer The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 281 patients with metastatic rearranged during transfection ( RET fusion-positive) non-small cell lung cancer (NSCLC) in ARROW [see Clinical Studies (14.1) ]. Among the 281 patients who received GAVRETO, 72% were exposed for 6 months or longer and 56% were exposed for ≥1 year. The median age was 60 years (range: 26 to 87 years); 54% were female, 46% were White, 46% were Asian, and 4% were Hispanic/Latino. Serious adverse reactions occurred in 65% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, anemia, pneumonitis, pyrexia, sepsis, urinary tract infection, coronavirus infection, pleural effusion, dyspnea, musculoskeletal pain, pulmonary embolism, and seizure. Fatal adverse reactions occurred in 7% of patients; fatal adverse reactions which occurred in > 1 patient included pneumonia (n=8), sepsis (n=3) and COVID (n=3). Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received GAVRE …

7 DRUG INTERACTIONS Strong or moderate CYP3A inhibitors and/or P-gp inhibitors : Avoid coadministration. If coadministration cannot be avoided, reduce the dose of GAVRETO. ( 2.4 , 7.1 , 12.3 ) Strong or moderate CYP3A inducers : Avoid coadministration. If coadministration cannot be avoided, increase the dose of GAVRETO. ( 2.5 , 7.1 , 12.3 ) 7.1 Effects of Other Drugs on GAVRETO Strong or Moderate CYP3A and/or P-gp Inhibitors Concomitant use with a strong or moderate CYP3A inhibitor and/or a P-gp inhibitor increases pralsetinib exposure [ Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to GAVRETO. Avoid coadministration of GAVRETO with a strong or moderate CYP3A and/or P-gp inhibitor. If coadministration with any of the above inhibitors cannot be avoided, reduce the GAVRETO dose [see Dosage and Administration (2.4) ]. Strong or Moderate CYP3A Inducers Concomitant use with a strong CYP3A inducer decreases pralsetinib exposure [see Clinical Pharmacology (12.3) ] , which may decrease efficacy of GAVRETO. Avoid concomitant use of GAVRETO with strong or moderate CYP3A inducers. If coadministration of GAVRETO with strong or moderate CYP3A inducers cannot be avoided, increase the GAVRETO dose [see Dosage and Administration (2.5) ].

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) Pediatric Use : Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing GAVRETO if abnormalities occur. ( 8.4 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ]. There are no available data on GAVRETO use in pregnant women to inform drug-associated risk. 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 (see Data ). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal development study, once daily oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in 100% post-implantation loss at dose levels ≥ 20 mg/kg (approximately 1.8 times the human exposure based on area under the curve [AUC] at the clinical dose of 400 mg). Post-implantation loss also occurred at the 10 mg/kg dose level (approximately 0.6 times the human exposure based on AUC at the clinical dose of 400 mg). Once daily oral administration of pralsetinib at dose levels ≥ 5 mg/kg (approximately 0.2 times the human AUC at the clinical dose of 400 mg) resulted in an increase in visceral malformations and variations (absent or small kidney and ureter, absent uterine horn, malpositioned kidney or testis, retroesophageal aortic arch) and skeletal malformations and variations (vertebral and rib anomalies and reduced ossification). 8.2 Lactation Risk Summary There are no data on the presence of pralsetinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with GAVRETO and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, GAVRETO can cause embryolethality and malformations at doses resulting in exposures below the human exposure at the clinical dose of 400 mg daily [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating GAVRETO [see Use in Specific Populations (8.1) ]. Contraception GAVRETO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Females Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. GAVRETO may render hormonal contraceptives ineffective. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose. Infertility Based on histopathological findings in the reproductive tissues of male and female rats and a dedicated fertility study in which animals of both sexes were treated and mated to each other, GAVRETO may impair fertility [see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use The safety and effectiveness of GAVRETO have been established in pediatric patients aged 12 years and older for RET fusion-positive thyroid cancer. Use of GAVRETO in this age group is supported by evidence from an adequate and well-controlled study of GAVRETO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of pralsetinib, that the exposure of pralsetinib is expected to be similar between adults and pediatric patients age 12 years and older, and that the …

12.1 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 .

11 DESCRIPTION Pralsetinib is an oral receptor tyrosine kinase inhibitor. The chemical name for pralsetinib is ( cis )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1 H -pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide. The molecular formula for pralsetinib is C 27 H 32 FN 9 O 2 , and the molecular weight is 533.61 g/mol. Pralsetinib has the following structure: The solubility of pralsetinib in aqueous media decreases over the range pH 1.99 to pH 7.64 from 0.880 mg/mL to < 0.001 mg/mL, indicating a decrease in solubility with increasing pH. GAVRETO (pralsetinib) is supplied for oral use as immediate release hydroxypropyl methylcellulose (HPMC) hard capsules containing 100 mg pralsetinib. The capsules also contain inactive ingredients: citric acid, hydroxypropyl methylcellulose (HPMC), magnesium stearate, microcrystalline cellulose (MCC), pregelatinized starch and sodium bicarbonate. The capsule shell consists of FD&C Blue #1 (Brilliant Blue FCF), hypromellose and titanium dioxide. The white printing ink contains butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, strong ammonia solution and titanium dioxide. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING GAVRETO (pralsetinib) 100 mg, light blue, opaque, immediate release, hydroxypropyl methylcellulose (HPMC) hard capsule printed with "BLU-667" on the capsule shell body and "100 mg" on the capsule shell cap are supplied as follows: Bottles of 60 capsules (NDC 50242-210-60). Bottles of 90 capsules (NDC 50242-210-90). Bottles of 120 capsules (NDC 50242-210-12). Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Protect from moisture.