Taletrectinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]
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Overview
Taletrectinib is a kinase inhibitor that is FDA approved for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).. Common adverse reactions include diarrhea, nausea, vomiting, dizziness, rash, constipation, and fatigue (>20%)..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
FDA-labeled Indicatons
IBTROZI® (taletrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).
Dosage
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.
Dosage Modifications for Adverse Reactions The recommended dosage reductions for the management of adverse reactions are provided in the Table on right.
Dosee reduction table
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Taletrectinib in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Taletrectinib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Taletrectinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Taletrectinib in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Taletrectinib in pediatric patients.
Contraindications
None.
Warnings
Hepatotoxicity
- IBTROZI can cause hepatotoxicity, including drug-induced liver injury and fatal adverse reactions.
- In the pooled safety population, 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.
- 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.
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.
- In the pooled safety population, 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.
- Withhold, then resume at the same or reduced dose, or permanently discontinue IBTROZI based on severity.
Hyperuricemia
- IBTROZI can cause hyperuricemia.
- In the pooled safety population, 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.
Myalgia with Creatine Phosphokinase Elevation
- IBTROZI can cause myalgia with or without creatine phosphokinase (CPK) elevation.
- In the pooled safety population, 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.
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, 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.
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.
Adverse Reactions
Clinical Trials Experience
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.
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.
- Patients received IBTROZI as a single agent at 600 mg orally once daily until disease progression or unacceptable toxicity. Among patients who received IBTROZI, 68% were exposed for 6 months or longer and 47% were exposed for greater than one year.
- The median age of patients who received IBTROZI was 56 years (range: 26 to 83); 56% female; 76% Asian, 15% White, 0.6% Black or African American, 8% unknown or other races; and 1.8% were of Hispanic or Latino ethnicity.
- Serious adverse reactions occurred in 31% of patients who received IBTROZI.
- Serious adverse reactions in ≥2% of patients included pneumonia (7%), pleural effusion (4.7%), and hepatotoxicity (2.4%).
- Fatal adverse reactions occurred in 18 (5%) patients who received IBTROZI, including pneumonia (2.4%), multiple organ dysfunction syndrome (0.6%), hepatotoxicity (0.6%), cardiac arrest (0.6%), cardiac failure (0.3%), cardiopulmonary failure (0.3%), respiratory failure (0.3%), and death not otherwise specified (0.3%).
- 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.
Postmarketing Experience
There is limited information regarding Taletrectinib Postmarketing Experience in the drug label.
Drug Interactions
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.
Strong and Moderate CYP3A Inducers
- Avoid concomitant use with strong or moderate CYP3A inducers.
- 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.
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.
Use in Specific Populations
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 2% to 4% and 15% to 20%, 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, taletrectinib was administered orally to pregnant rats during the period of organogenesis from gestation day 6 to 17 at doses of 10, 30, and 100 mg/kg/day.
- 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).
- In an embryo-fetal development study, taletrectinib was administered orally to pregnant rabbits during the period of organogenesis from gestation day 6 to 19 at doses of 15, 30, and 90 mg/kg/day. 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).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Taletrectinib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Taletrectinib during labor and delivery.
Nursing Mothers
Risk Summary
There are no data on the presence of taletrectinib or its metabolites in human milk or their effects on a breastfed child or on milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with IBTROZI and for 3 weeks after the last dose.
Pediatric Use
The safety and effectiveness of IBTROZI in pediatric patients has not been established.
Geriatic 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.
Gender
There is no FDA guidance on the use of Taletrectinib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Taletrectinib with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Taletrectinib in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Taletrectinib in patients with hepatic impairment.
Females of Reproductive Potential and Males
IBTROZI can cause fetal harm when administered to a pregnant woman.
- Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating IBTROZI [see Use in Specific Populations (8.1)].
- Contraception
Females Advise females of reproductive potential to use effective contraception during treatment with IBTROZI and for 3 weeks after the last dose.
Males 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.
- Infertility
Based on findings in animals, IBTROZI may impair fertility in males and females. The effects on animal fertility were reversible.
Immunocompromised Patients
There is no FDA guidance one the use of Taletrectinib in patients who are immunocompromised.
Administration and Monitoring
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.
Monitoring
There is limited information regarding Taletrectinib Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Taletrectinib and IV administrations.
Overdosage
There is limited information regarding Taletrectinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Taletrectinib Pharmacology in the drug label.
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.
Structure
IBTROZI (taletrectinib) capsules contain taletrectinib adipate, a kinase inhibitor for oral use. The molecular formula for taletrectinib adipate is C23H24FN5O•C6H10O4 and the molecular weight is 551.61 g/mol. The chemical name is 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo [1,2b]pyridazin-6-amine monoadipate. The chemical structure of taletrectinib adipate is as follows:
Pharmacodynamics
Exposure-response relationship
- Higher taletrectinib exposure is associated with an increased risk of Grade ≥3 increased AST/ALT.
- Taletrectinib exposure-response relationships for efficacy and the time course of pharmacodynamic response have not been fully characterized.
Cardiac Electrophysiology
- The largest mean increase in the QTc interval was 12.8 msec (upper confidence interval of 15.4 msec) at the mean steady-state maximum concentration (Cmax,ss) after administration of IBTROZI 600 mg once daily.
- The increase in the QTc internal was concentration-dependent [see Warnings and Precautions (5.3)]. At plasma concentrations achieved with administration of IBTROZI 600 mg once daily with high fat food, the predicted increase in the QTc interval is 20.5 (16.3, 24.7) msec.
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.
- Absorption
Taletrectinib time to maximum plasma concentration (Tmax) is 2 to 6 hours.
- Effect of Food
Both taletrectinib AUC and Cmax increased by 1.5-fold following administration with high-fat food (1000 calories, 50% fat).
- Distribution
The estimated apparent (oral) volume of distribution is 9,820 L. Taletrectinib in vitro plasma protein binding is concentration-dependent and decreases with increasing taletrectinib concentrations (from 96% at 100 ng/mL to 93% at 10,000 ng/mL). The blood-to-plasma ratio is 1.3 to 1.4 in vitro.
- Elimination
Taletrectinib effective half-life is approximately 66 hours with an apparent (oral) clearance of 63 L/h (36%).
- Metabolism
Taletrectinib is eliminated by CYP450 and non-CYP450 (i.e., sulfation and acetylation) metabolism. CYP3A and, to a lesser extent, CYP2C8 and CYP2C9 are the CYP450 enzymes involved in taletrectinib metabolism.
- Excretion
Following a single oral dose of radiolabeled taletrectinib 200 mg, 75% of the dose was recovered in feces (15% as unchanged) and 11% in urine (2.9% as unchanged).
- Specific Populations
No clinically significant differences in the pharmacokinetics of taletrectinib were observed based on age (18 to 80 years), sex, mild to moderate renal impairment (eGFR 30 to 89 mL/min), or mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST >ULN). The effect of moderate (total bilirubin >1.5 to 3 times ULN with any AST) or severe (total bilirubin >3 x ULN with any AST) hepatic impairment, severe renal impairment (eGFR<30 mL/min), or dialysis on taletrectinib pharmacokinetics is unknown. A 30% increase in taletrectinib exposure (AUC) was observed in Asian patients compared to White patients. No clinically significant differences in the AUC were observed between White and Black patients.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- Carcinogenicity studies with taletrectinib were not conducted.
Mutagenesis
- Taletrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and additional mutagenicity tests.
- Taletrectinib was not clastogenic or aneugenic in the in vivo micronucleus study in rats in bone marrow and liver.
Impairment of Fertility
- In a fertility and early embryonic development study in rats, male animals were treated with taletrectinib at doses of 4, 25, or 60 mg/kg/day orally for 70 days before mating and during 13 days of the mating period.
- Female rats, paired with treated males, were administered taletrectinib at doses of 4, 25, or 100 mg/kg/day orally for 14 to 21 days before mating, during the mating period and up to gestational Day 6.
- No effects on mating or fertility in males or females were observed at doses below or equal to the human exposure based on AUC at the recommended dose.
- Sperm morphological abnormalities were observed in males at exposures as low as 0.03 times the human exposure based on AUC at the recommended dose.
- In repeat-dose toxicity studies up to 12 weeks in duration with oral administration of taletrectinib in rats, adverse effects in reproductive organs included epithelial vacuolation of the seminal vesicle in male rats and endometrial glandular epithelium vacuolation in the uterus with cervix in female rats at exposures 4 times the human exposure based on AUC at the recommended dose for both male and female rats.
- Findings in the reproductive organs were reversible.
Clinical Studies
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.
ROS1 TKI-Pretreated
- TRUST-I: Among the 66 patients with ROS1 TKI-pretreated NSCLC, the median age was 51 years (range: 31 to 77); 61% were female; 100% were Asian; 74% never smoked; and 71% had ECOG performance status of 1. At baseline, 97% of patients had metastatic disease, 42% of patients had CNS metastases by BICR; 92% had adenocarcinoma; 35% of patients had prior platinum-based chemotherapy for advanced disease and 100% had prior treatment with crizotinib.
- TRUST-II: Among 47 patients with ROS1 TKI-pretreated NSCLC, the median age was 55 years (range: 27 to 79); 57% were female; 47% were Asian; 34% were White; 2.1% were Black or African American, 17% were of unknown or other races; 2.1% were Hispanic or Latino; 62% never smoked; and 55% had ECOG performance status of 1. At baseline, 98% of patients had metastatic disease; 57% of patients had CNS metastases by BICR; 98% had adenocarcinoma; 40% of patients had prior platinum-based chemotherapy for advanced disease, 79% had prior treatment with crizotinib, and 21% had prior treatment with entrectinib.
How Supplied
IBTROZI is supplied as 200 mg, Size 0 white opaque hard capsules imprinted with “TAL” and “200” in blue ink as follows:
Add supply table
Storage
Store IBTROZI at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F).
Images
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Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (Patient Information).
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.
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.
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.
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.
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.
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.
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.
- 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.
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.
Lactation
- Advise women not to breastfeed during treatment with IBTROZI and for 3 weeks after the last dose.
Drug Interactions
- Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.
- Advise patients to avoid grapefruit or grapefruit juice while taking IBTROZI.
Administration
- Advise patients to swallow IBTROZI capsules on an empty stomach, at least 2 hours before or 2 hours after food intake.
- Advise patients that if a dose of IBTROZI is missed or if vomiting occurs, resume IBTROZI at its regularly scheduled time the next day.
Precautions with Alcohol
Alcohol-Taletrectinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
IBTROZI® [ib-TRO-zee]
Look-Alike Drug Names
There is limited information regarding Taletrectinib Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.