2.1 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 [see Clinical Studies (14.1)].

An FDA-approved test to detect ROS1 rearrangement(s) for selecting patients for treatment with IBTROZI is not currently available.

2.2 Recommended Testing and Evaluation Before Initiating IBTROZI

• Before initiating IBTROZI, evaluate liver function tests (including ALT, AST, and bilirubin), electrolytes, ECG, and uric acid [see Warnings and Precautions (5.1, 5.3, 5.4)].

2.3 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) [see Clinical Pharmacology (12.2, 12.3)] 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 [see Adverse Reactions (6.1)].

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.

2.4 Dosage Modifications for Adverse Reactions

The recommended dosage reductions for the management of adverse reactions are provided in Table 1.

The recommended dosage modifications of IBTROZI for the management of adverse reactions are provided in Table 2.

5.1 Hepatotoxicity

IBTROZI can cause hepatotoxicity, including drug-induced liver injury and fatal adverse reactions.

In the pooled safety population [see Adverse Reactions (6.1)], based on laboratory values, 88% of patients treated with IBTROZI experienced increased aspartate aminotransferase (AST), including 10% Grade 3 or 4. Increased alanine aminotransferase (ALT) occurred in 85% of patients treated with IBTROZI, including 13% Grade 3 or 4. The median time to first onset of AST or ALT elevation was 15 days (range: 3 days to 20.8 months).

Increased AST or ALT each led to dose interruption in 7% of patients. Increased AST and ALT leading to dose reduction occurred in 5% and 9% of patients, respectively. Increased AST and ALT each led to permanent discontinuation of IBTROZI in 0.3% of patients. Other liver-related adverse reactions leading to permanent discontinuation of IBTROZI were hepatotoxicity (0.6% of patients) and increased bilirubin (0.3% of patients).

Concurrent elevations in AST or ALT ≥3 times the upper limit of normal (ULN) and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in 2 (0.6%) patients treated with IBTROZI. Fatal liver events occurred in 2 (0.6%) patients.

Monitor liver function tests (AST, ALT, and bilirubin) prior to administration of IBTROZI, every 2 weeks during the first 2 months of treatment, and then monthly thereafter as clinically indicated with more frequent testing in patients who develop transaminase elevations. Withhold, then resume at reduced dose upon improvement, or permanently discontinue IBTROZI based on severity [see Dosage and Administration (2.4)].

5.2 Interstitial Lung Disease/Pneumonitis

IBTROZI can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis.

In the pooled safety population [see Adverse Reactions (6.1)], interstitial lung disease (ILD)/pneumonitis occurred in 2.3% of patients treated with IBTROZI, including Grade 3 or 4 in 1.1% of patients. The median time to first onset of ILD/pneumonitis was 3.8 months (range: 12 days to 11.8 months).

ILD/pneumonitis led to dose interruption of IBTROZI in 1.1% of patients. ILD/pneumonitis required dose reduction in 0.6% of patients and permanent discontinuation of IBTROZI in 0.6% of patients. One fatal ILD case occurred in a patient who received 400 mg once daily dose of IBTROZI.

Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold IBTROZI in patients with suspected ILD/pneumonitis. Withhold, then reduce the dose or permanently discontinue IBTROZI if Grade ≥2 ILD/pneumonitis is confirmed [see Dosage and Administration (2.4)].

5.3 QTc Interval Prolongation

IBTROZI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. IBTROZI prolongs the QTc interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)].

In the pooled safety population [see Adverse Reactions (6.1)], of the 351 patients who underwent at least one post baseline ECG assessment, 13% experienced an increase in QTcF of >60 msec compared to baseline after receiving IBTROZI and 2.6% had an increase in QTcF to >500 msec. Overall, 3.4% of patients had Grade ≥3 QTc interval prolongation. The median time from the first dose of IBTROZI to the onset of ECG QT prolongation was 22 days (range: 1 day to 38.7 months). QTc prolongation led to dose interruption and dose reduction, each in 2.8% of patients treated with IBTROZI.

Monitor ECGs and electrolytes prior to administration of IBTROZI, and then periodically thereafter as clinically indicated during treatment. Adjust the frequency of monitoring based on risk factors such as known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and concomitant medications associated with QTc interval prolongation.

Significant prolongation of the QTc interval may occur when IBTROZI is taken with food, strong and moderate CYP3A inhibitors, and/or drugs with a known potential to prolong QTc. Administer IBTROZI on an empty stomach. Avoid coadministration of IBTROZI with strong and moderate CYP3A inhibitors and/or drugs with a known potential to prolong QTc [see Dosage and Administration (2.3), Drug Interactions (7.1, 7.2)].

Withhold, then resume at the same or reduced dose, or permanently discontinue IBTROZI based on severity [see Dosage and Administration (2.4)].

5.4 Hyperuricemia

IBTROZI can cause hyperuricemia.

In the pooled safety population [see Adverse Reactions (6.1)], 14% of patients treated with IBTROZI experienced hyperuricemia reported as an adverse reaction, with 16% of these patients requiring urate-lowering medication without pre-existing gout or hyperuricemia. Hyperuricemia Grade ≥3 occurred in one patient. The median time to first onset of hyperuricemia was 2.1 months (range: 7 days to 35.8 months). Hyperuricemia leading to dose interruption occurred in 0.3% of patients.

Monitor serum uric acid levels prior to administration of IBTROZI and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold, then resume at the same or reduced dose, or permanently discontinue IBTROZI based on severity [see Dosage and Administration (2.4)].

5.5 Myalgia with Creatine Phosphokinase Elevation

IBTROZI can cause myalgia with or without creatine phosphokinase (CPK) elevation.

In the pooled safety population [see Adverse Reactions (6.1)], myalgia occurred in 10% of patients treated with IBTROZI. The median time to first onset of myalgia was 11 days (range: 2 days to 10 months).

Concurrent myalgia with increased CPK within a 7-day time period was observed in 0.9% of patients. IBTROZI was interrupted in one patient (0.3%) with myalgia, who also presented with concurrent CPK elevation.

Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during IBTROZI treatment every 2 weeks during the first month of treatment and then as clinically indicated in patients reporting unexplained muscle pain, tenderness, or weakness. Withhold, then resume at the same or reduced dose upon improvement [see Dosage and Administration (2.4)].

5.6 Skeletal Fractures

IBTROZI can increase the risk of fractures. ROS1 inhibitors as a class have been associated with skeletal fractures.

In the pooled safety population [see Adverse Reactions (6.1)], 3.4% of patients experienced fractures including 1.4% Grade 3. Some fractures occurred in the setting of an accidental fall or other predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions. Fractures involved the ribs (1.4%), spine (0.9%), femur (0.6%), humerus (0.3%), and acetabulum (0.3%). The median time to first onset of fracture was 10.7 months (range: 26 days to 29.1 months). Dose interruption occurred in 0.3% of patients.

Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of IBTROZI on healing of known fractures and risk of future fractures.

5.7 Embryo-Fetal Toxicity

Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor kinase (TRK) signaling, findings from animal studies and its mechanism of action, IBTROZI can cause fetal harm when administered to a pregnant woman.

In animal reproduction studies, oral administration of taletrectinib to pregnant rats during the period of organogenesis caused structural abnormalities. Oral administration of taletrectinib to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities. Findings in both species occurred at doses resulting in exposures below or equal to the human exposure based on AUC at the recommended dose.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IBTROZI and for 3 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IBTROZI and for 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

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 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). Among the 352 patients who received IBTROZI, 68% were exposed for at least 6 months, and 47% were exposed for greater than 1 year. 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.

7.1 Effects of Other Drugs on 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 [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)]. Withhold IBTROZI if the QTc interval is >500 msec or the change from baseline is >60 msec [see Dosage and Administration (2.4)].

IBTROZI causes QTc interval prolongation [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)]. Concomitant use of IBTROZI with other drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

IBTROZI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 352 patients who received IBTROZI 600 mg orally once daily, 88 (25%) patients were 65 years of age and older, and 14 (4%) patients were 75 years of age and older. There were no clinically meaningful differences in safety and efficacy between patients younger than 65 years of age and patients 65 years of age or older.

12.1 Mechanism of Action

Taletrectinib is an inhibitor of tyrosine kinase ROS1, including ROS1 resistance mutations. Taletrectinib also showed inhibitory effects on tropomyosin receptor kinases (TRKs) TRKA, TRKB, and TRKC.

Fusion proteins that include ROS1 domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Taletrectinib inhibited growth of cancer cells expressing ROS1 fusion genes and mutations.

In mice subcutaneously implanted with tumors harboring ROS1 fusions, including the G2032R mutation, administration of taletrectinib resulted in tumor growth inhibition. Taletrectinib had anticancer activity in an intracranial NSCLC xenograft model harboring a ROS1 fusion.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Taletrectinib pharmacokinetics (PK) were characterized at steady state for the approved recommended dosage and the PK parameters presented below are as mean (CV%), unless otherwise specified.

Taletrectinib maximum concentration (Cmax) is 476 (36%) ng/mL and systemic exposure (AUC) is 9,649 (36%) ng•h/mL. Taletrectinib Cmax and AUC increase in a dose proportional manner over the dose range of 50 mg to 1200 mg (0.08 to 2 times the approved recommended dosage). Taletrectinib accumulation is approximately 4-fold and steady state reached within 7 days.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Locally Advanced or Metastatic ROS1-Positive NSCLC

The efficacy of IBTROZI was evaluated in 270 patients with ROS1-positive locally advanced or metastatic NSCLC who received IBTROZI at a dose of 600 mg orally once daily, enrolled in two multicenter, single-arm, open-label clinical trials: TRUST-I (NCT04395677) or TRUST-II (NCT04919811). In both trials, patients were required to have histologically confirmed, locally advanced or metastatic, ROS1-positive NSCLC, ECOG performance status of 0 or 1, and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Identification of ROS1 gene fusions in tumor specimens was determined in local laboratories using next-generation sequencing (NGS), polymerase chain reaction (PCR), fluorescence in situ (FISH), or immunohistochemistry (IHC).

The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 as assessed by a blinded independent central review (BICR). Intracranial response according to modified RECIST v1.1 was assessed by BICR. Tumor assessments with imaging were performed every 6 weeks for the first 24 weeks, every 9 weeks for the following year, and every 12 weeks thereafter. The efficacy populations included 157 patients naïve to treatment with a ROS1 TKI and 113 patients who received one prior ROS1 TKI. Patients could be chemotherapy-naïve or have received prior chemotherapy for locally advanced disease.

ROS1 TKI-Naïve

TRUST-I: Among 103 patients with ROS1 TKI-naïve NSCLC treated in TRUST-I, the median age was 56 years (range: 26 to 78); 55% were female; 100% were Asian; 73% never smoked; and 81% had ECOG performance status of 1. At baseline, 91% of patients had metastatic disease; 17% of patients had CNS metastases by BICR; 96% had adenocarcinoma; and 19% of patients had prior platinum-based chemotherapy for advanced disease.

TRUST-II: Among 54 patients with ROS1 TKI-naïve NSCLC treated in TRUST-II, the median age was 57 years (range: 27 to 82); 56% were female; 65% were Asian; 22% were White; 1.9% were Black or African American; 11% were of unknown race; 1.9% were of Hispanic or Latino ethnicity; 50% never smoked; and 61% had ECOG performance status of 1. At baseline, 91% of patients had metastatic disease, 35% of patients had CNS metastases by BICR; 98% had adenocarcinoma; and 19% of patients had prior platinum-based chemotherapy for advanced disease.

Efficacy results are summarized in Table 5.

Among 157 ROS1 TKI-naïve patients across TRUST-I and TRUST-II, 15 had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months prior to study entry; responses in intracranial lesions were observed in 11 patients.

Hepatotoxicity

• Advise patients of the risk of hepatoxicity and of the need for laboratory tests to monitor liver function during treatment with IBTROZI and to immediately contact their healthcare providers if they experience symptoms of hepatotoxicity [see Warnings and Precautions (5.1)].

Interstitial Lung Disease (ILD)/Pneumonitis

• Inform patients of the risk of ILD/pneumonitis during treatment with IBTROZI and to contact their healthcare provider immediately if they experience new or worsening pulmonary symptoms indicative of ILD/pneumonitis [see Warnings and Precautions (5.2)].

QTc Interval Prolongation

• Inform patients of the risk of QT interval prolongation during treatment with IBTROZI and to advise patients to contact their healthcare provider immediately for any symptoms of QT interval prolongation [see Warnings and Precautions (5.3)].

Hyperuricemia

• Advise patients of the risk of hyperuricemia during treatment with IBTROZI and to contact their healthcare provider if they experience signs or symptoms associated with hyperuricemia [see Warnings and Precautions (5.4)].

Myalgia with Creatine Phosphokinase Elevation

• Advise patients of the risk of myalgia with creatine phosphokinase elevation during treatment with IBTROZI and to contact their healthcare provider if they experience unexplained muscle pain, tenderness, or weakness [see Warnings and Precautions (5.5)].

Skeletal Fractures

• Inform patients of the risk of bone fractures during treatment with IBTROZI and advise patients to contact their healthcare provider immediately if they experience signs or symptoms of fracture [see Warnings and Precautions (5.6)].

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.7), Use in Specific Populations (8.1, 8.3)].
• Advise females of reproductive potential to use effective contraception during treatment with IBTROZI and for 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IBTROZI and for 3 weeks after the last dose [see Use in Specific Populations (8.3)].

Photosensitivity

• Inform patients that IBTROZI can cause photosensitivity. Advise patients to minimize sun exposure while taking IBTROZI and to use sun protection, including broad-spectrum sunscreen, during treatment with IBTROZI and for at least 5 days after discontinuation [see Adverse Reactions (6.1)].

Lactation

• Advise women not to breastfeed during treatment with IBTROZI and for 3 weeks after the last dose [see Use in Specific Populations (8.2)].

Drug Interactions

• Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].
• Advise patients to avoid grapefruit or grapefruit juice while taking IBTROZI [see Dosage and Administration (2.3)].

Administration

• Advise patients to swallow IBTROZI capsules on an empty stomach, at least 2 hours before or 2 hours after food intake [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
• Advise patients that if a dose of IBTROZI is missed or if vomiting occurs, resume IBTROZI at its regularly scheduled time the next day [see Dosage and Administration (2.3)].

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Version: 1, 06/2025