Augtyro Drug Information

Patient Selection NSCLC

Select patients for the treatment of locally advanced or metastatic NSCLC with AUGTYRO based on the presence of ROS1 rearrangement(s) in tumor specimens. An FDA-approved test to detect ROS1 rearrangements for selecting patients for treatment with AUGTYRO is not currently available. Solid Tumors Select patients for the treatment of solid tumors with AUGTYRO based on the presence of NTRK1/2/3 rearrangements in tumor specimens.

Important Information Prior to Initiating AUGTYRO Prior to initiating AUGTYRO, discontinue strong and moderate CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor.

Recommended Evaluation and Testing Before Initiating AUGTYRO Prior to initiation of AUGTYRO, evaluate: • liver function tests including bilirubin • uric acid level

Recommended Dosage

The recommended dosage of AUGTYRO for adult and pediatric patients 12 years of age and older is 160 mg taken orally once daily with or without food for 14 days, then increase to 160 mg twice daily and continue until disease progression or unacceptable toxicity.

Dosage Modifications for Adverse Reactions

The recommended dosage reductions of AUGTYRO for the management of adverse reactions are provided in Table 1. Table 2: Recommended Interstitial Lung Disease (ILD)/Pneumonitis

Administration Take AUGTYRO at approximately the same time each day with or without food. Swallow AUGTYRO capsules whole. Do not open, chew, crush, or dissolve the capsule prior to swallowing.

Do not take any AUGTYRO capsules that are broken, cracked, or damaged. If a dose of AUGTYRO is missed or if vomiting occurs at any time after taking a dose, skip the dose and resume AUGTYRO at its regularly scheduled time.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates reported 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 WARNINGS AND PRECAUTIONS and below reflects exposure to AUGTYRO in 426 patients with ROS1 -positive NSCLC (n=320), NTRK1/2/3 -positive solid tumors (n=104), or other solid tumors (n=2) in TRIDENT-1. Patients received AUGTYRO at a dose of 160 mg orally once daily for the first 14 days, then increased to 160 mg orally twice daily until disease progression or unacceptable toxicity.

Eligible patients had an ECOG status of ≤1. Patients with a history of ILD, drug-related pneumonitis, significant, uncontrolled, active cardiovascular disease, or prolonged QTc interval were excluded from enrollment in this trial. Forty-eight percent of patients were exposed to AUGTYRO for at least 6 months, and 28% were exposed for greater than 1 year.

Serious adverse reactions occurred in 35% of patients who received AUGTYRO. Fatal adverse reactions occurred in 3.5% of patients who received AUGTYRO, including pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation. Permanent discontinuation of AUGTYRO due to an adverse reaction occurred in 7% of patients.

There were no specific adverse reactions that accounted for ≥1% of permanent discontinuations. Dosage interruptions of AUGTYRO due to an adverse reaction occurred in 50% of patients. Adverse reactions that required dosage interruption in ≥2% of patients were dizziness, dyspnea, muscular weakness, ataxia, pneumonia, peripheral neuropathy, anemia, and vomiting.

Dose reductions of AUGTYRO due to an adverse reaction occurred in 38% of patients. Adverse reactions that required dosage reductions in ≥2% of patients included dizziness, ataxia, muscular weakness, peripheral neuropathy, and cognitive impairment. The most common (≥20%) adverse reactions that occurred in patients receiving AUGTYRO were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness and nausea.

Table 3 summarizes the adverse reactions that occurred in TRIDENT-1. Table 4 summarizes the laboratory abnormalities in TRIDENT-1. Table 4: Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with ROS1-Positive NSCLC or NTRK-Positive Solid Tumors Who Received AUGTYRO in TRIDENT-1

Effects of Other Drugs on AUGTYRO Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO.

P-gp Inhibitors Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO.

Effects of AUGTYRO on Other Drugs Certain CYP3A4 Substrates

Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling. Repotrectinib is a CYP3A4 inducer.

Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates. Contraceptives Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives. Avoid concomitant use of AUGTYRO with hormonal contraceptives.

Advise females of reproductive potential to use an effective nonhormonal contraceptive.

Pregnancy Risk Summary Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman. There are no available data on AUGTYRO use in pregnant women. Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA (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 respectively. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.

Animal Data In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg. No embryolethality was observed.

Pediatric Use The safety and effectiveness of AUGTYRO in pediatric patients with ROS1 -positive NSCLC have not been established. The safety and effectiveness of AUGTYRO have not been established in pediatric patients younger than 12 years of age with solid tumors who have an NTRK gene fusion. The safety and effectiveness of AUGTYRO for the treatment of locally advanced or metastatic NTRK -positive solid tumors have been established in pediatric patients 12 years of age or older.

Use of AUGTYRO in this age group is supported by evidence from an adequate and well-controlled study in adult patients with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. This includes data demonstrating that the exposure of repotrectinib in pediatric patients 12 years of age and older is expected to result in similar safety and efficacy to that of adults, and that the course of locally advanced or metastatic NTRK -positive solid tumors is sufficiently similar in adults and pediatric patients 12 years of age or older to allow extrapolation of data in adult to pediatric patients 12 years of age or older. Juvenile Animal Data Daily oral administration of repotrectinib to juvenile rats for 8 weeks starting on postnatal day 12 (approximately equal to a human pediatric age of a newborn) resulted in toxicities similar to those observed in adult rats, though juvenile animals showed decreased body weight gain at doses ≥1 mg/kg (approximately ≥0.04 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID) and decreased femur lengths at 3 mg/kg (approximately 0.1 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID).

Decreased body weight gain and decreased femur lengths persisted following 4 weeks of recovery.