Romvimza Drug Information

is indicated for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) for which surgical resection will potentially cause worsening functional limitation or severe morbidity. ROMVIMZA is a kinase inhibitor indicated for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) for which surgical resection will potentially cause worsening functional limitation or severe morbidity.

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 ROMVIMZA in 83 patients with TGCT enrolled in the double-blind portion and in 35 patients with TGCT in the open-label portion who crossed over to ROMVIMZA in MOTION, and in 135 patients with TGCT or solid tumors in other clinical trials. The safety of ROMVIMZA was evaluated in 83 adult patients with TGCT in MOTION. MOTION excluded patients with bilirubin, AST, or ALT >ULN. All patients received ROMVIMZA twice weekly until disease progression or unacceptable toxicity.

Among these patients, 82% were exposed for 6 months or longer and 30% were exposed for greater than one year. Serious adverse reactions occurred in 2.4% of patients who received ROMVIMZA. Serious adverse reactions in ≥1% included subcutaneous abscess (1.2%) and cellulitis (1.2%). Permanent discontinuation due to an adverse reaction occurred in 4.8% of patients who received ROMVIMZA. Adverse reactions leading to permanent discontinuation in one patient each included periorbital edema, neuropathy, rash, and hypertension. Dose reductions due to an adverse reaction or laboratory abnormality occurred in 39% of patients who received ROMVIMZA. Adverse reactions leading to dose reductions in ≥2% of patients receiving ROMVIMZA were rash, periorbital edema, peripheral edema, fatigue, pruritus, face edema, increased CPK, neuropathy, and hypertension.

Dose interruptions due to an adverse reaction or laboratory abnormality occurred in 40% of patients who received ROMVIMZA. Adverse reactions leading to interruptions in ≥2% of patients included rash, fatigue, peripheral edema, increased CPK, periorbital edema, face edema, pruritus, neuropathy, and hypertension. The most common (≥20%) adverse reactions, including laboratory abnormalities that occurred in patients receiving ROMVIMZA were increased AST, periorbital edema, fatigue, rash, increased cholesterol, peripheral edema, face edema, decreased neutrophils, decreased leukocytes, pruritus, and increased ALT. Table 3 and Table 4 summarize the adverse reactions and laboratory abnormalities in MOTION during the randomized phase through Week 25. Table 3: Adverse Reactions Occurring in ≥10% of Patients Receiving ROMVIMZA with a Difference Between Arms of >5% Compared to Placebo Through Week 25 in MOTION Adverse Reaction* ROMVIMZA N=83 Placebo N=39 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) *The severity of adverse reactions was assessed using CTCAE v5.0. 1 Includes multiple related terms Eye disorders Periorbital edema 1 60 3.6 21 0 Lacrimation increased 12 0 0 0 Dry eye 1 10 0 0 0 General disorders and administration site conditions Fatigue 1 59 1.2 38

Peripheral edema 1 33 1.2 8 0 Face edema 31 1.2 8

0 Skin and subcutaneous tissue disorders Rash 1 47 3.6 5 0 Pruritus 29 2.4 8 0 Vascular disorders Hypertension 17 4.8 10

Nervous system disorders Neuropathy 1 12 1.2 2.6 0 Other clinically significant

adverse reactions occurring in <10% of patients treated with ROMVIMZA include blurred vision (6%). Table 4: Laboratory Abnormalities Worsening from Baseline in ≥10% of Patients Receiving ROMVIMZA with a Difference Between Arms of >5% Compared to Placebo Through Week 25 in MOTION Laboratory Abnormality a ROMVIMZA N=83 Placebo N=39 b All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) AST – aspartate aminotransferase, ALT – alanine aminotransferase, ALP – alkaline phosphatase a The severity of adverse reactions was assessed using CTCAE v5.0. b The denominator used to calculate the rate was 83 for ROMVIMZA and 38 for placebo based on the number of patients with a baseline value and at least one post-treatment value. Chemistry AST increased 92 0 11 0 Cholesterol increased 43 0 16 0 ALT increased 24 0 16 0 Creatinine increased 17 0 2.6 0 ALP increased 14 0 8 0 Magnesium increased 13 1.2 2.6 0 Calcium decreased 13 0 2.6 0 Hematology Neutrophils decreased 31 1.2 2.6 0 Leukocytes decreased 29 0 8 0 Additional clinically significant laboratory abnormality: Increased Creatine Phosphokinase (CPK)

Effects of

ROMVIMZA on Other Drugs Table 5 describes drug interactions where concomitant use with ROMVIMZA affects another drug. Table 5: Effect of ROMVIMZA on Other Drugs P-glycoprotein (P-gp) substrates Prevention or Management Avoid concomitant use with P-gp substrates while taking ROMVIMZA. If concomitant use cannot be avoided, take ROMVIMZA at least 4 hours prior to P-gp substrates unless otherwise recommended in the substrate Prescribing Information. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of vimseltinib pharmacokinetics and it being a P-gp inhibitor in vitro.

Concomitant use of ROMVIMZA with P-gp substrates may increase exposure of these substrates; however, this has not been studied clinically. Breast Cancer Resistance Protein (BCRP) substrates Prevention or Management Avoid concomitant use with BCRP substrates while taking ROMVIMZA. Refer to the Prescribing Information of the BCRP substrate for dose modifications if concomitant use cannot be avoided. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of vimseltinib pharmacokinetics and it being a BCRP inhibitor in vitro.

Concomitant use of ROMVIMZA with BCRP substrates may increase exposure of these substrates; however, this has not been studied clinically. Organic Cation Transporter 2 (OCT2) substrates Prevention or Management Avoid concomitant use with OCT2 substrates while taking ROMVIMZA. Refer to the Prescribing Information of the OCT2 substrate for dose modifications if concomitant use cannot be avoided. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of vimseltinib pharmacokinetics and it being an OCT2 inhibitor in vitro.

Concomitant use of ROMVIMZA with OCT2 substrates may increase exposure of these substrates; however, this has not been studied clinically.

Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, ROMVIMZA can cause fetal harm when administered to a pregnant woman. There are no available data on vimseltinib use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In female rats administered vimseltinib during the period of organogenesis, fetal structural abnormalities occurred at exposures that were at least 3 times the recommended dose based on AUC ( see Data ). Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data In a rat embryo-fetal development study, pregnant female rats were dosed once daily during the period of organogenesis (gestational days 6 to 17) at doses of 2.5, 5, or 15 mg/kg/day. Structural abnormalities (skeletal variations) occurred at ≥2.5 mg/kg/day (approximately 3 times the exposure at the recommended dose based on AUC). Additional structural abnormalities (cardiac malformations) were observed at the highest dose of 15 mg/kg/day (approximately 23 times the exposure at the recommended dose based on AUC).

Pediatric Use The safety and effectiveness of ROMVIMZA in pediatric patients have not been established. Animal Toxicity Data In a 26-week repeat-dose toxicology study, rats administered vimseltinib at ≥2.5 mg/kg/day had physeal thickening and decay of the incisors and molars. Bone and tooth toxicities occurred at exposures at least 8 times the recommended dose based on AUC.