Ibtrozi Drug Information

IBTROZI ® (taletrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC).

Patient Selection

Select patients for the treatment of locally advanced or metastatic NSCLC with IBTROZI based on the presence of ROS1 rearrangement(s) in tumor specimens. An FDA-approved test to detect ROS1 rearrangement(s) for selecting patients for treatment with IBTROZI is not currently available.

Recommended Testing and Evaluation Before Initiating IBTROZI

Before initiating IBTROZI, evaluate liver function tests (including ALT, AST, and bilirubin), electrolytes, ECG, and uric acid.

Recommended Dosage and Administration

The recommended dosage of IBTROZI is 600 mg orally once daily on an empty stomach (no food intake at least 2 hours before and 2 hours after taking IBTROZI) until disease progression or unacceptable toxicity. Take IBTROZI at approximately the same time each day. Swallow IBTROZI capsules whole.

Do not open, chew, crush, or dissolve the capsule prior to swallowing. Avoid food or drink containing grapefruit during treatment with IBTROZI. Minimize sun exposure and use sun protection, including broad-spectrum sunscreen, during treatment with IBTROZI and for at least 5 days after discontinuation.

Missed Dose If a dose is missed, take the next dose at its scheduled time on the following day. Vomiting If vomiting occurs at any time after taking a dose, take the next dose at its scheduled time on the following day.

Dosage Modifications for Adverse Reactions

The recommended dosage reductions for the management of adverse reactions are provided in Table 1. Table 2: Hepatotoxicity (Elevation of ALT or AST)

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 section and below reflects exposure to IBTROZI as a single agent at 600 mg orally once daily until disease progression or unacceptable toxicity in 352 patients with ROS1 -positive NSCLC (N=337) and other solid tumors (N=15). In this pooled safety population, the most common (≥20%) adverse reactions were diarrhea, nausea, vomiting, dizziness, rash, constipation, and fatigue.

The most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased ALT, increased AST, decreased neutrophils, increased creatine phosphokinase, decreased lymphocytes, increased magnesium, decreased hemoglobin, and increased triglycerides. Locally Advanced or Metastatic ROS1-Positive NSCLC The safety of IBTROZI was evaluated in the TRUST-I and TRUST-II studies. Key eligibility criteria were histologically confirmed, locally advanced or metastatic, ROS1 -positive NSCLC, ECOG performance status ≤1, and measurable disease per RECIST v1.1.

Among patients who received IBTROZI, 68% were exposed for 6 months or longer and 47% were exposed for greater than one year. Serious adverse reactions occurred in 31% of patients who received IBTROZI. Fatal adverse reactions occurred in 18 (5%) patients who received IBTROZI, including pneumonia (2.4%), multiple organ dysfunction syndrome ( %).

Permanent discontinuation of IBTROZI was required in 7% of patients due to adverse reactions. Adverse reactions resulting in permanent discontinuation of IBTROZI in ≥2 patients were pneumonia, ILD, and hepatotoxicity. Dosage interruptions of IBTROZI due to an adverse reaction occurred in 41% of patients.

Adverse reactions which required dosage interruption in ≥5% of patients included increased AST and increased ALT. Dose reductions of IBTROZI due to an adverse reaction occurred in 29% of patients. Adverse reactions that required dosage reductions in ≥5% of patients included increased ALT and increased AST.

Table 3 summarizes the adverse reactions in this population. Table 3: Adverse Reactions (≥15%) in Patients with ROS1-Positive NSCLC Who Received IBTROZI in TRUST-I and TRUST-II 0 Clinically relevant adverse reactions in <15% of patients receiving IBTROZI were pneumonia, eye disorders, myalgia, skeletal fracture, ILD/pneumonitis, dermatologic adverse reactions including drug reaction with eosinophilia and systemic symptoms (DRESS), and photosensitivity reactions. Table 4 summarizes the laboratory abnormalities.

Table 4: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ROS1-Positive NSCLC Who Received IBTROZI in TRUST-I and TRUST-II

Effects of Other Drugs on IBTROZI Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong or moderate CYP3A inhibitors. Taletrectinib is a CYP3A substrate. Concomitant use of IBTROZI with a strong or moderate CYP3A inhibitor increases taletrectinib exposure, which may increase the risk of IBTROZI adverse reactions.

Concomitant use of IBTROZI with a strong or moderate CYP3A inducer decreases taletrectinib exposure, which may reduce the effectiveness of IBTROZI. Gastric Acid Reducing Agents Avoid concomitant use with proton pump inhibitors (PPI) and H2 receptor antagonists. Administer locally acting antacids at least 2 hours before or 2 hours after taking IBTROZI.

Concomitant use of a proton pump inhibitor decreases taletrectinib exposure, which may reduce the effectiveness of IBTROZI. 7.2. Drugs That Prolong the QTc Interval Avoid concomitant use of IBTROZI with other drug(s) with a known potential to prolong the QTc interval, such as antiarrhythmic drugs. If concomitant use cannot be avoided, adjust the frequency of monitoring as recommended.

Withhold IBTROZI if the QTc interval is >500 msec or the change from baseline is >60 msec. IBTROZI causes QTc interval prolongation. Concomitant use of IBTROZI with other drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

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, IBTROZI can cause fetal harm when administered to a pregnant woman. Limited data from case reports with IBTROZI used in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, oral administration of taletrectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities at exposures that were below or equal to the human exposure based on AUC at the recommended dose ( 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.

Taletrectinib caused fetal abnormalities including abnormal ossification of the pelvis at 100 mg/kg/day (1.3 times the human exposure based on AUC at the recommended dose). Maternal lethality and increased total pregnancy loss were observed at doses ≥15 mg/kg/day (≥0.04 times the human exposure based on AUC at the recommended dose). Fetal malformations, including undeveloped or no development of eyes, nose, and mouth, ventricular malformations, thoracic vascular malformations, and skull malformations were observed at 30 mg/kg/day (0.1 times the human exposure based on AUC at the recommended dose).

Pediatric Use The safety and effectiveness of IBTROZI in pediatric patients has not been established.