Mirdametinib

1 INDICATIONS AND USAGE GOMEKLI is indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection [see Clinical Studies (14) ]. GOMEKLI is a kinase inhibitor indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of GOMEKLI is 2 mg/m 2 orally twice daily, with or without food, for the first 21 days of each 28-day cycle. Continue treatment with GOMEKLI until disease progression or unacceptable toxicity. ( 2 ) 2.1 Recommended Evaluation and Testing Before Initiating GOMEKLI Prior to administration of GOMEKLI: conduct comprehensive ophthalmic assessment [see Warnings and Precautions (5.1) ]. assess ejection fraction (EF) by echocardiogram [see Warnings and Precautions (5.2) ]. 2.2 GOMEKLI Dosage Form Overview GOMEKLI is available in 2 dosage forms: capsules or tablets for oral suspension. GOMEKLI capsules: must be swallowed whole, do not open, break or chew capsules. GOMEKLI tablets for oral suspension: can be swallowed whole or can be dispersed in drinking water and administered orally as a liquid [see Dosage and Administration (2.4) ]. 2.3 Recommended Dosage The recommended dosage of GOMEKLI is 2 mg/m 2 orally twice daily (approximately every 12 hours) with or without food for the first 21 days of each 28-day cycle. The maximum dose is 4 mg twice daily. Continue treatment with GOMEKLI until disease progression or unacceptable toxicity. The recommended dose of GOMEKLI is based on body surface area (BSA) as shown in Table 1. Table 1: Recommended Dosage for GOMEKLI Body Surface Area (m 2 ) * Recommended Dosage for Capsules or Tablets for Oral Suspension 0.40 to 0.69 1 mg twice daily 0.70 to 1.04 2 mg twice daily 1.05 to 1.49 3 mg twice daily ≥1.50 4 mg twice daily * The recommended dosage for patients with a BSA less than 0.40 m 2 has not been established. Missed dose: If the patient misses a dose of GOMEKLI, do not take an additional dose. Take the next scheduled dose at the prescribed time. Vomiting: If vomiting occurs after GOMEKLI administration, do not take an additional dose. Take the next scheduled dose at the prescribed time. 2.4 GOMEKLI Preparation and Administration Instructions GOMEKLI Capsules Swallow GOMEKLI capsules whole with or without food. If more than one capsule is required for a dose, swallow one capsule at a time. Do not open, break or chew capsules. Do not administer to patients who are unable to swallow a whole capsule [see GOMEKLI Tablets for Oral Suspension]. GOMEKLI Tablets for Oral Suspension GOMEKLI tablets for oral suspension can be swallowed whole with or without food. If more than one tablet is required for a dose, swallow one tablet at a time. For patients who are not able to swallow whole tablets, prepare GOMEKLI tablets for oral suspension dispersed in drinking water and administer orally as a liquid [see Instructions for Use ]. Preparation and Administration Add the prescribed number of tablets to a dosing cup containing approximately 5 mL to 10 mL of drinking water. Gently swirl the water and tablets until the tablets are fully dispersed and an oral suspension is obtained. It takes approximately two to four minutes to fully disperse the tablets. Once the tablets are dispersed, the oral suspension will appear white and cloudy. Administer the oral suspension immediately after preparation from a dosing cup or oral syringe. After administration of the prepared suspension, add approximately 5 mL to 10 mL of drinking water to the dosing cup and gently swirl to resuspend any remaining particles. Administer the suspension to ensure the full dose is taken. Discard the oral suspension if not administered within 30 minutes after preparation. 2.5 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 2 . Table 2: Recommended Dose Reductions for GOMEKLI for Adverse Reactions Body Surface Area (m 2 ) Reduced Dose * Morning Evening 0.40 to 0.69 1 mg once daily 0.70 to 1.04 2 mg 1 mg 1.05 to 1.49 2 mg 2 mg ≥1.50 3 mg 3 mg * Permanently discontinue GOMEKLI in patients unable to tolerate GOMEKLI after one dose reduction. The recommended dosage modifications for adverse reactions are provided in Table 3 . Table 3: Recommended Dosage Modifications and Management of Adverse Reactions for GOMEKLI Adverse Reaction Severity Dosage Modification Ocular Toxicity [see Warnings and Precautions (5.1) ] Grade ≤ 2 Continue GOMEKLI at current dose level. Consider ophthalmologic examinations every 2 to 4 weeks until resolution to ≤Grade 1 or baseline. Grade ≥ 3 Withhold GOMEKLI until ≤Grade 1 or baseline. If recovery occurs ≤14 days, resume GOMEKLI at the next lower dose. If recovery occurs in >14 days, consider permanent discontinuation of GOMEKLI. Symptomatic Retinal Pigment Epithelium Detachment (RPED) Withhold GOMEKLI until ≤Grade 1 or baseline. Resume GOMEKLI at the same dose. Retinal Vein Occlusion (RVO) Permanently discontinue GOMEKLI. Left Ventricular Dysfunction [see Warnings and Precautions (5.2) ] Asymptomatic, absolute decrease in LVEF of 10% or greater from baseline and is less than the lower limit of normal Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Any absolute decrease in LVEF 20% or greater from baseline Permanently discontinue GOMEKLI. Adverse Reaction Severity Dosage Modification Dermatologic Adverse Reactions [see Warnings and Precautions (5.3) ] Intolerable Grade 2 or Grade 3 Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Grade 3 or 4 Dermatitis Acneiform or Non-Acneiform Rash Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Other Adverse Reactions [see Adverse Reactions (6.1) ] Intolerable Grade 2 or Grade 3 Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Grade 4 Consider permanent discontinuation of GOMEKLI. * Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v. 5.0).

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Ocular Toxicity [see Warnings and Precautions (5.1) ] Left Ventricular Dysfunction [see Warnings and Precautions (5.2) ] Dermatologic Adverse Reactions [see Warnings and Precautions (5.3) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.4) ] Adults: The most common adverse reactions (>25%) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase. ( 6.1 ) Pediatric patients: The most common adverse reactions (>25%) were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact SpringWorks Therapeutics Inc. at 1-888-400-7989 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 described in the WARNINGS AND PRECAUTIONS reflects exposure to GOMEKLI in 133 patients (75 adults and 58 pediatric patients) in the ReNeu study [see Clinical Studies (14) ] (n=114) and Study NF-106 (n=19) [NCT-02096471]. Patients received GOMEKLI 2 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Among 133 patients who received GOMEKLI, 62% were exposed for one year or longer, 38% were exposed for 2 years or longer, and 12% were exposed for 3 years or longer. Neurofibromatosis Type 1-Associated Plexiform Neurofibromas The safety of GOMEKLI was evaluated in the ReNeu study [see Clinical Studies (14) ] . Eligible patients were 2 years of age and older with neurofibromatosis type 1 (NF1) who had symptomatic plexiform neurofibromas (PN). Patients were excluded for abnormal left ventricular ejection fraction (LVEF), uncontrolled hypertension, alanine transaminase (ALT) value of >2 × upper limit of normal (ULN), any current or history of retinal vein occlusion (RVO) or retinal pigment epithelium detachment (RPED), intraocular pressure >21 mmHg (or upper limit of normal adjusted by age), and history of glaucoma. Patients received GOMEKLI 2 mg/m2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Adult Patients The median age of adult patients (age ≥18) who received GOMEKLI was 35 years (range: 18-69); 64% were female; 85% were White, 9% were Black or African American, 3.4% were Asian, 3.4% were other races or race not reported; and 1.7% were Hispanic or Latino. For adult patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 0.4 to 46 months). Serious adverse reactions occurred in 17% of adult patients who received GOMEKLI. Serious adverse reactions occurring in ≥1% of patients were COVID-19 (3.4%), nephrolithiasis (3.4%), and in 1 patient each: acute kidney injury, abdominal pain, ischemic colitis, urinary tract infection, retinal vein occlusion, scoliosis, squamous cell carcinoma of skin, cerebrovascular accident and chronic obstructive pulmonary disease. One fatal adverse reaction occurred in an adult patient (1.7%) who received GOMEKLI, due to COVID-19. Permanent discontinuation of GOMEKLI due to an adverse reaction occurred in 22% of adult patients. Adverse reactions which resulted in permanent discontinuation of GOMEKLI in ≥1% of adult patients were rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, RVO, dizziness, and vomiting. Dosage interruptions of GOMEKLI due to an adverse reaction occurred in 31% of adult patients. Adverse reactions which required dosage interruption in ≥5% of patients included left ventricular dysfunction and COVID-19. Dose reductions of GOMEKLI due to an adverse reaction occurred in 17% of adult patients. Adverse reactions which required dose reductions in ≥5% of patients included rash. The most common adverse reactions (>25%) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase. Pediatric Patients The median age of pediatric patients (age ≤17 years) who received GOMEKLI was 10 years (range: 2 to 17); 54% were female; 66% were White, 20% were Black or African American, 9% were other races or race not reported, 3.6% were Asian, 1.8% were American Indian or Alaska Native; and 14% were Hispanic or Latino. For pediatric patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 1.6 to 40 months). Serious adverse reactions occurred in 14% of pediatric patients who received GOMEKLI. Serious adverse reactions in ≥1% of patients included viral gastrointestinal infections (3.6%) and in 1 patient each: diplopia, musculoskeletal pain, seizure, fall, femoral neck fracture, dehydration and hypertension. Permanent discontinuation of GOMEKLI due to an adverse reaction occurred in 9% of pediatric patients. Adverse reactions that required permanent discontinuation of GOMEKLI in ≥1% of patients were urticaria, rash, abdominal pain, constipation, and diarrhea. Dosage interruptions of GOMEKLI due to an adverse reaction occurred in 30% of pediatric patients. Adverse reactions which required dosage interruption in ≥5% of patients included COVID-19. Dose reductions of GOMEKLI due to an adverse reaction occurred in 13% of pediatric patients. Adverse reactions which required dosage reduction in ≥3% of pediatric patients were rash and decreased neutrophil count. The most common adverse reactions (>25%) were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase. Table 4: Adverse Reactions (≥20%) in Adult and Pediatric Patients with NF1- Associated PN Who Received GOMEKLI in ReNeu Adult N=58 Pediatric N=56 Total N=114 All Grades (%) Grade 3 or 4 a (%) All Grades (%) Grade 3 or 4 a (%) All Grades (%) Grade 3 or 4 a (%) Skin and Subcutaneous Tissue Disorders Rash b 90 10 73 3.6 82 7 Gastrointestinal Disorders Diarrhea c 59 0 55 5 57 2.6 Nausea 52 0 27 0 40 0 Vomiting 38 0 39 0 39 0 Abdominal Pain d 24 3.4 39 3.6 32 3.5 Stomatitis e 5 0 20 0 12 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain f 41 5 41 1.8 41 3.5 General Disorders and Administration Site Conditions Fatigue 29 1.7 13 0 21 0.9 Pyrexia 7 0 20 0 13 0 Infections and Infestations COVID-19 g 22 5 25 0 24 2.6 Paronychia 1.7 0 32 0 17 0 Upper Respiratory Tract Infection 0 0 23 0 11 0 Nervous System Disorders Headache h 14 1.7 34 1.8 24 1.8 Peripheral Neuropathy i 21 0 3.6 0 12 0 Cardiac Disorders Left Ventricular Dysfunction 16 0 27 1.8 21 0.9 Respiratory, Thoracic and Mediastinal Disorders Cough j 9 0 21 0 15 0 a All reactions were Grade 3 except one fatal case of COVID-19 in an adult. b Rash includes dermatitis acneiform, eczema, maculo-papular rash, pustular rash, dermatitis, erythematous rash, palmar-plantar erythrodysaesthesia syndrome, exfoliative rash, skin exfoliation, pruritic rash, papule, papular rash and macular rash. c Diarrhea includes frequent bowel movements. d Abdominal pain includes upper abdominal pain, gastrointestinal pain and abdominal discomfort. e Stomatitis includes mouth ulceration, aphthous ulcer. f Musculoskeletal pain includes non-cardiac chest pain, back pain, pain in extremity, neck pain, musculoskeletal chest pain, myalgia, arthralgia, and bone pain. g Includes one fatal case in an adult. h Headache includes migraine. i Peripheral neuropathy includes paresthesia, hypoesthesia, neuralgia, peripheral sensory neuropathy. j Cough includes upper-airway cough syndrome. Clinically relevant adverse reactions that occurred in <20% of patients include: Skin and Subcutaneous Tissue Disorders : alopecia, hair color changes Gastrointestinal Disorders : constipation Eye Disorders : retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED) and blurred vision Table 5 summarizes the laboratory abnormalities in ReNeu. Table 5: Select Laboratory Abnormalities (≥15%) that Worsened from Baseline in Adult and Pediatric Patients with NF1-Associated PN Who Received GOMEKLI in ReNeu Adult a Pediatric b Total c Laboratory Abnormality d,e All Grades (%) Grade 3 or 4 d (%) All Grades (%) Grade 3 or 4 d (%) All Grades (%) Grade 3 or 4 d (%) Chemistry Increased Creatine Phosphokinase 55 3.6 59 5 57 4.5 Increased Triglycerides 29 0 45 0 37 0 Decreased Glucose 5 0 36 1.8 21 0.9 Decreased Calcium f 23 0 20 0 21 0 Increased Creatinine 13 0 30 0 21 0 Increased Cholesterol 23 0 16 0 20 0 Increased Alkaline Phosphatase 13 0 29 0 21 0 Decreased Bicarbonate 11 0 21 0 16 0 Increased Alanine Aminotransferase (ALT) 9 0 21 0 15 0 Increased Aspartate Aminotransferase (AST) 18 0 9 0 13 0 Hematology Decreased Hemoglobin 21 0 29 0 25 0 Decreased Leukocytes 7 0 40 0 23 0 Decreased Neutrophils 7 0 31 11 19 5 Increased Lymphocytes 7 0 27 0 17 0 Decreased Lymphocytes 16 0 1.8 0 9 0 a The denominator used to calculate the rate was 56 based on the number of patients with a baseline value and at least one post-treatment value. b The denominator used to calculate the rate varied from 55 to 56 based on the number of patients with a baseline value and at least one post-treatment value. c The denominator used to calculate the rate varied from 111 to 112 based on the number of patients with a baseline value and at least one post-treatment value. d Graded per NCI-CTCAE version 5.0. e No Grade 5 laboratory abnormalities were reported in the ReNeu study. f Calcium corrected for albumin (mmol/L).

12.3 Pharmacokinetics GOMEKLI pharmacokinetic parameters are summarized in Table 6. Table 6: Pharmacokinetic Parameters and Characteristics of Mirdametinib General Information Steady-state [mean (%CV)] Cmax Adult patients (≥18 years): 188 (52%) ng/mL Pediatric patients (2 to17 years): 191 (62%) ng/mL AUC Adult patients (≥18 years): 431 (43%) ng·h/mL Pediatric patients (2 to 17 years): 459 (46%) ng·h/mL Time to steady-state Approximately 6 days Accumulation ratio (AUC) [mean] 1.1 to 1.9 Absorption Tmax [median (min, max)] Tablet: 0.8 (0.4-3) hours post-dose Capsule: 1.1 (0-4) hours post-dose Absolute bioavailability No data are available in humans Food effect [GMR% (90% CI)] (high-fat, high-calorie meal) Cmax 57% (54%, 61%) AUCinf 93% (90%, 96%) Distribution Human plasma protein binding Greater than 99% Apparent volume of distribution [mean (%CV)] 255 L (13%) Elimination Apparent systemic clearance [mean (%CV)] 6.3 L/h (13%) Terminal elimination half-life [mean (%CV)] 28 h (12%) Metabolism Primary pathway Metabolism involves glucuronidation and oxidation via UGT (primarily UGT1A6 and UGT2B7) and CES enzymes. Excretion Radioactivity In urine: 68% In feces: 27% Unchanged mirdametinib In urine and feces: 9% In urine: 0.7% Abbreviations: AUC: area under the plasma concentration-time curve; AUCinf: AUC from dosing extrapolated to infinity; CI: confidence interval; CES: carboxyl esterase enzyme; Cmax: maximum plasma concentration; CV: coefficient of variation; GMR: geometric least squares mean ratio; UGT: uridine diphosphate (UDP)- glycosyltransferase Specific Populations Effects of Age, Sex, and Race No clinically significant differences in mirdametinib pharmacokinetics were observed based on age (2 to 86 years), sex, and race (11% African American or Black, 12% Asian, 72% White). The effects of moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease (ESRD) on mirdametinib pharmacokinetics are unknown. Drug Interaction Studies No clinical DDI studies have been conducted. The effect of concomitant strong CYP3A4 inducers (that also co-induce UGTs, P-gp, and CES enzymes) on mirdametinib PK is currently unknown. In Vitro Studies CYP Enzymes : Mirdametinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Mirdametinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4. Transporter Systems : Mirdametinib does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters. Mirdametinib is a substrate of BCRP and P-gp transporters.