Repotrectinib

AUGTYRO is a kinase inhibitor indicated for the treatment of • adult patients with locally advanced or metastatic ROS1- positive non-small cell lung cancer (NSCLC). • adult and pediatric patients 12 years of age and older with solid tumors that: • have a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion and • are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity. • have progressed following treatment or have no satisfactory alternative therapy. 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 the confirmatory trials.

Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. Fusion proteins that include ROS1 or TRK domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Repotrectinib exhibited anti-tumor activity in cultured cells expressing ROS1 fusions and mutations including SDC4-ROS1, SDC4-ROS1 G2032R, CD74-ROS1, CD74-ROS1 G2032R, CD74-ROS1 D2033N, and CD74-ROS1 L2026M. Repotrectinib also inhibited cell proliferation in cultured cells expressing NTRK fusions and mutations including LMNA-TRKA, LMNA-TRKA G595R, EVT6-TRKB G639R, and ETV6-TRKC G623R.

• Select patients for the treatment of locally advanced or metastatic NSCLC based on the presence of ROS1 rearrangement(s) in tumor specimens. • Select patients for treatment of locally advanced or metastatic solid tumors based on the presence of an NTRK gene fusion. • Recommended Dosage: 160 mg orally once daily for 14 days, then increase to 160 mg twice daily, with or without food.

None. None.

• Central Nervous System (CNS) Effects: Can cause CNS adverse reactions including dizziness, ataxia, and cognitive impairment. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. • Interstitial Lung Disease (ILD)/Pneumonitis: Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. • Hepatotoxicity: Monitor liver function tests every 2 weeks during the first month of treatment, and as clinically indicated thereafter. Based on severity, withhold and then resume at same or reduced dose, or permanently discontinue.

The following clinically significant adverse reactions are described elsewhere in the labeling: • Central Nervous System Adverse Reactions • Interstitial Lung Disease (ILD)/Pneumonitis • Hepatotoxicity • Myalgia with Creatine Phosphokinase Elevation • Hyperuricemia • Skeletal Fractures • Embryo-Fetal Toxicity The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.

• Strong and Moderate CYP3A Inhibitors: Avoid concomitant use. • P-gp inhibitors: Avoid concomitant use. • Strong and Moderate CYP3A Inducers: Avoid concomitant use. • Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes can cause reduced efficacy. • Hormonal contraceptives: Avoid concomitant use.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F).