Ibtrozi Drug Information
Generic name: TALETRECTINIB
Uses of Ibtrozi
® (taletrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC) . IBTROZI is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC).
Dosage & Administration of Ibtrozi
| First Dose Reduction | 400 mg once daily |
|---|---|
| Second Dose Reduction | 200 mg once daily |
| Permanently discontinue IBTROZI capsules in patients unable to tolerate 200 mg once daily. | |
Side Effects of Ibtrozi
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. 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 1 Based on NCI CTCAE version 5.0 a Includes enterocolitis b Includes vertigo, and vertigo positional c Includes dysesthesia, hypoesthesia, neuralgia, paresthesia, and peripheral sensory neuropathy d Includes ageusia e Includes dermatitis, dermatitis acneiform, drug eruption, eczema, eyelid rash, palmar-plantar erythrodysesthesia syndrome, rash maculo-papular, rash papular, skin exfoliation, and drug reaction with eosinophilia and systemic symptoms (DRESS) f Includes asthenia g Includes productive cough Adverse Reaction 1 IBTROZI N=337 All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Diarrhea a 64
Nausea 47 1.5 Vomiting 43 1.5 Constipation 21 0 Nervous System Disorders
Dizziness b 22
Peripheral neuropathy c 17 0.3 Dysgeusia d 15 0 Skin and Subcutaneous
Tissue Rash e 22
General Disorders Fatigue f 20 0.9 Cardiac Electrocardiogram QT prolonged 19 3.6
Metabolism and Nutritional Decreased appetite 16
Respiratory, thoracic and mediastinal disorders Cough g 16 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 Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase 1 Based on NCI CTCAE version 5.0 2 The denominator used to calculate the rate varied from 149 to 336 based on the number of patients with a baseline value and at least one post-treatment value.
Laboratory Abnormality 1 IBTROZI 2 All Grades (%) Grade 3 or 4 (%) Hematology Hemoglobin decreased 48
Lymphocytes decreased 38 4.8 Neutrophils decreased 25 5 Chemistry
AST increased 87 10 ALT increased 85 13 Creatine phosphokinase increased 53 5 Cholesterol increased 41 0 Triglycerides increased 41
Creatinine increased 39 0.3 Uric acid increased 38 0 Gamma glutamyl transferase
increased 36
Warnings & Cautions for Ibtrozi
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 .
Interstitial Lung Disease/Pneumonitis
IBTROZI can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis. In the pooled safety population, 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 .
Drug Interactions with Ibtrozi
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. 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 Safety for Ibtrozi
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).
Pediatric Use of Ibtrozi
Pediatric Use The safety and effectiveness of IBTROZI in pediatric patients has not been established.
Clinical Studies of Ibtrozi
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. Table 5: Efficacy Results in ROS1-Positive TKI-Naïve NSCLC Patients per BICR Assessment Abbreviations: CI = Confidence interval; NR = Not reached; “+” indicating ongoing response a Median DOR not included for TRUST-II given the shorter duration of follow-up. b Based on observed duration of response Efficacy Parameters ROS1 TKI-Naïve N=157 TRUST-I TRUST-II n=103 n=54 Response Rate, % (95% CI) 90% 85% Complete Response 5% 7% Partial Response 85% 78% Duration of Response (DOR) n= 93 n= 46 Median DOR (95% CI) NR (30.4, NR) -- a Range (months) 1.1, 46.9+ 1.4+, 30.4+ % with DOR b ≥12 months 72 63 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. 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. Efficacy results are summarized in Table 6. Table 6: Efficacy Results in ROS1-Positive TKI-Pretreated NSCLC Patients per BICR Assessment Abbreviations: CI = Confidence interval; “+” indicating ongoing response a Median DOR not included for TRUST-II given the shorter duration of follow-up. b Based on observed duration of response. Efficacy Parameters ROS1 TKI-Pretreated N=113 TRUST-I TRUST-II n=66 n=47 Response Rate, % (95% CI) 52% 62% Complete Response 0% 11% Partial Response 52% 51% Duration of Response (DOR) n= 34 n= 29 Median DOR (95% CI) 13.2 -- a Range (months) 1.4, 38.7+ 1.7+, 30.4+ % with DOR b ≥6 months 74 83 % with DOR b ≥12 months 44 45 Among 113 ROS1 TKI-pretreated patients, across TRUST-I and TRUST-II, 24 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 15 patients.
Among 32 patients who had re-biopsied samples tested by next-generation sequencing after failure of a prior ROS1 TKI, 15 had resistance mutations. Responses were observed in 8 of these 15 patients; all responding patients had tumors with solvent front mutation G2032R.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
Ready to save on Ibtrozi?
Compare prescription prices at over 70,000 pharmacies and start saving today—no enrollment required.
Compare Ibtrozi Prices