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Safety overview
ADVERSE REACTIONS (≥15%) IN PATIENTS WITH ROS1+ NSCLC WHO RECEIVED IBTROZI IN TRUST-I AND TRUST-II1,2
| IBTROZI (N=337) | ||||
|---|---|---|---|---|
| ADVERSE REACTIONS* | ALL GRADES (%) | GRADE 1 (%) | GRADE 2 (%) | GRADE 3 OR 4 (%) |
| GASTROINTESTINAL DISORDERS | ||||
| Diarrhea† | 64 | 50 | 11 | 2.1 |
| Nausea | 47 | 37 | 9 | 1.5 |
| Vomiting | 43 | 34 | 8 | 1.5 |
| Constipation | 21 | 18 | 3 | 0 |
| NERVOUS SYSTEM DISORDERS | ||||
| Dizziness‡ | 22 | 20 | 2.1 | 0.3 |
| Peripheral neuropathy§ | 17 | 13 | 3.6 | 0.3 |
| Dysgeusia|| | 15 | 13 | 2.1 | 0 |
| SKIN AND SUBCUTANEOUS TISSUE | ||||
| Rash¶ | 22 | 13 | 8 | 1.8 |
| GENERAL DISORDERS | ||||
| Fatigue# | 20 | 15 | 4.5 | 0.9 |
| CARDIAC | ||||
| Electrocardiogram QT prolonged | 19 | 13 | 2.7 | 3.6 |
| METABOLISM AND NUTRITIONAL | ||||
| Decreased appetite | 16 | 11 | 4.2 | 0.3 |
| RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS | ||||
| Cough** | 16 | 12 | 4.7 | 0 |
*Based on NCI CTCAE version 5.0.1
†Includes enterocolitis.1
‡Includes vertigo and vertigo positional.1
§Includes dysesthesia, hypoesthesia, neuralgia, paresthesia, and peripheral sensory neuropathy.1
IIIncludes ageusia.1
¶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).1
#Includes asthenia.1
**Includes productive cough.1
SERIOUS ADVERSE REACTIONS1
- Serious ARs occurred in 31% of patients who received IBTROZI. Serious ARs in ≥2% of patients included pneumonia (7%), pleural effusion (4.7%), and hepatotoxicity (2.4%)
- Fatal ARs 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%)
AR=adverse reaction; CTCAE=Common Terminology Criteria for Adverse Reactions; NCI=National Cancer Institute; NSCLC=non-small cell lung cancer; ROS1=ROS proto-oncogene 1.
Laboratory abnormalities
LABORATORY ABNORMALITIES* (≥20%) IN PATIENTS WITH ROS1+ NSCLC WHO RECEIVED IBTROZI IN TRUST-I AND TRUST-II1,2
| IBTROZI† | ||||
|---|---|---|---|---|
| LABORATORY ABNORMALITY‡ | ALL GRADES (%) | GRADE 1 (%) | GRADE 2 (%) | GRADE 3 OR 4 (%) |
| HEMATOLOGY | ||||
| Hemoglobin decreased | 48 | 31 | 14 | 3.6 |
| Lymphocytes decreased | 38 | 14 | 19 | 4.8 |
| Neutrophils decreased | 25 | 11 | 8 | 5 |
| CHEMISTRY | ||||
| AST increased | 87 | 57 | 20 | 10 |
| ALT increased | 85 | 51 | 21 | 13 |
| Creatine phosphokinase increased | 53 | 37 | 11 | 5 |
| Cholesterol increased | 41 | 32 | 9 | 0 |
| Triglycerides increased | 41 | 30 | 8 | 2.5 |
| Creatinine increased | 39 | 21 | 18 | 0.3 |
| Uric acid increased | 38 | 38 | 0 | 0 |
| Gamma glutamyl transferase increased | 36 | 28 | 6 | 1.8 |
| Alkaline phosphatase increased | 30 | 28 | 2 | 0 |
| Calcium decreased | 28 | 21 | 5 | 1.8 |
| Albumin decreased | 25 | 19 | 6 | 0.9 |
| Bilirubin increased | 24 | 18 | 4.5 | 0.6 |
| Potassium increased | 21 | 13 | 7 | 1.2 |
| Sodium increased | 20 | 16 | 2.4 | 0.9 |
*Laboratory abnormalities that worsened from baseline.1
†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 1 post-treatment value.1
‡Based on NCI CTCAE version 5.0.1
ALT=alanine aminotransferase; AST=aspartate aminotransferase.
Dose modification rates
Majority of patients were able to remain on treatment1
7% of patients discontinued treatment due to ARs
The ARs resulting in permanent discontinuation of IBTROZI in ≥2 patients were pneumonia, ILD, and hepatotoxicity.
29% of patients required a dose reduction due to ARs
ARs that required dosage reductions in ≥5% of patients included increased ALT and increased AST.
41% of patients required a dose interruption due to ARs
ARs that required dosage interruption in ≥5% of patients included increased AST and increased ALT.
IBTROZI has specific dose modifications for hepatotoxicity, ILD/pneumonitis, QTc interval prolongation, hyperuricemia, creatine phosphokinase elevation, and other ARs. See dose modifications for more information.
ILD=interstitial lung disease; QD=once daily; QTc=corrected QT interval.
Additional safety information
Most GI events were mild to moderate and resolved quickly1,2
Incidence of Gl events with IBTROZI was 88% (310/352)2
- The most frequently (≥10%) reported GI events were diarrhea, nausea, vomiting, and constipation, and most were mild to moderate
Grade ≥3 events2
- Overall occurrence: 6%
ONSET AND RESOLUTION OF GI EVENTS (ANY GRADE)2
| MEDIAN TIME TO ONSET | MEDIAN EVENT DURATION |
|---|---|
| 1 day (range: 1 to 35.4 months) | 2 days (range: 1 to 55.9 months) |
- 92.3% of GI events recovered* (79.9% without and 12.4% with treatment)
In TRUST-II, standard antiemetics, such as prochlorperazine, were used for treatment of vomiting. Use of prophylactic antiemetics was also permitted. Loperamide as well as other medications and supportive care according to institution protocol were used to treat diarrhea. Constipation was treated with laxatives, and prophylactic treatment of constipation was permitted. In TRUST-I, supportive care was permitted, and utilization of antiemetics or antidiarrheals was not prohibited.2,3
Dose modifications due to GI events were low2
- Interruptions: 7%
- Reductions: 4.3%
- Discontinuations: 0.6%
*Recovered means the GI event recovered to normal or baseline range.2
GI=gastrointestinal.
The majority of CNS events were mild to moderate and transient1,2
Incidence of CNS events with IBTROZI was 48.9% (172/352)2
- The most frequently (≥5%) reported CNS events were dizziness, dysgeusia, headache, hypoesthesia, and muscular weakness
Grade ≥3 events2
- Overall occurrence: 5%
ONSET AND RESOLUTION OF CNS EVENTS (ANY GRADE)2
| MEDIAN TIME TO ONSET | MEDIAN EVENT DURATION |
|---|---|
| 13.5 days (range: 1 day to 30.9 months) | 8 days (range: 1 day to 59.4 months) |
Dose modifications due to CNS events were low2
- Interruptions: 2.8%
- Reductions: 2.0%
- Discontinuations: 0.6%
CNS=central nervous system.
Incidence of hepatotoxicity with IBTROZI1
Incidence of AST elevation was 88% and ALT elevation was 85% based on laboratory values1
- Concurrent elevations in AST or ALT ≥3 times ULN and total bilirubin ≥2 times ULN, with normal alkaline phosphatase, occurred in 2 (0.6%) patients
- The median time to first onset of AST or ALT elevation was 15 days (range: 3 days to 20.8 months)
Grade ≥3 AST/ALT laboratory values1
- Increased AST: 10%
- Increased ALT: 13%
ONSET AND RESOLUTION OF AST/ALT ELEVATION EVENTS2
| MEDIAN TIME TO ONSET | MEDIAN TIME TO RESOLUTION |
|---|---|
| 16.5 days (range: 6 days to 20.7 months) | 49 days (range: 3 days to 63.9 months) |
- Fatal liver outcomes occurred in 2 (0.6%) patients1
- The majority of liver-related events were LFT abnormalities, which were transient and resolved with or without supportive management2
Dose modifications due to increased AST/ALT events were low1
- Interruptions: 7%
- Reductions: 5% (AST), 9% (ALT)
- Discontinuations: 0.3%
LFT=liver function test; ULN=upper limit of normal.
ADDITIONAL SAFETY INFORMATION1,2
| ADVERSE EVENT | INFORMATION | MEDIAN ONSET AND MEDIAN TIME TO RESOLUTION |
|---|---|---|
ILD/pneumonitis | Incidence
Dose modifications
| Onset 3.8 months (range: 12 days to 11.8 months)Resolution 1.03 months (range: 8 days to 4.9 months) |
| QTc interval prolongation | Incidence
| Onset 22 days (range: 1 day to 38.7 months)Resolution 1.41 months (range: 1 day to 24.5 months) |
| Hyperuricemia | Incidence
Dose modifications
| Onset 2.1 months (range: 7 days to 35.8 months)Resolution 1.41 months (range: 4 days to 45.5 months) |
| Myalgia with Creatine Phosphokinase Elevation | Incidence
Dose modifications
| Onset 11 days (range: 2 days to 10 months)Resolution 12 days (range: 1 day to 18.4 months) |
| Skeletal Fractures | Incidence
Dose modifications
| Onset 10.7 months (range: 26 days to 29.1 months)Resolution 6.88 months (range: 5 days to 18.9 months) |
CPK=creatine phosphokinase; QTcF=QT interval corrected by Fridericia’s formula.
INDICATION
IBTROZI™ (taletrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hepatotoxicity: Hepatotoxicity, including drug-induced liver injury and fatal adverse reactions, can occur. 88% of patients experienced increased AST, including 10% Grade 3/4. 85% of patients experienced increased ALT, including 13% Grade 3/4. Fatal liver events occurred in 0.6% of patients. 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 and dose reduction in 5% and 9% of patients, respectively. Permanent discontinuation was caused by increased AST, ALT, or bilirubin each in 0.3% and by hepatotoxicity in 0.6% of patients.
Concurrent elevations in AST or ALT ≥3 times the ULN and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in 0.6% of patients.
Monitor liver function tests (AST, ALT, and bilirubin) prior to treatment, every 2 weeks during the first 2 months, and then monthly thereafter as clinically indicated. Test more frequently if transaminase elevations occur. Advise patients to immediately report symptoms of hepatotoxicity. Based on severity and resolution, withhold, then resume at a reduced dose or permanently discontinue.
Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, or fatal ILD or pneumonitis can occur. ILD/pneumonitis occurred in 2.3% of patients, including 1.1% Grade 3/4. One fatal ILD case occurred at the 400 mg daily dose. 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 in 1.1% of patients, dose reduction in 0.6% of patients, and permanent discontinuation in 0.6% of patients.
Monitor patients for new or worsening pulmonary symptoms. Advise patients to report symptoms. If ILD/pneumonitis is suspected, immediately withhold; based on severity and resolution, resume at same or reduced dose, or permanently discontinue.
QTc Interval Prolongation: QTc interval prolongation can occur, 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 patients who received IBTROZI and underwent at least one post baseline ECG, QTcF increase of >60 msec compared to baseline and QTcF >500 msec occurred in 13% and 2.6% of patients, respectively. 3.4% of patients experienced Grade ≥3. Median time from first dose of IBTROZI to onset of ECG QT prolongation was 22 days (range: 1 day to 38.7 months). Dose interruption and dose reduction each occurred in 2.8% of patients.
Monitor ECGs and electrolytes prior to start of therapy, and then periodically thereafter as clinically indicated. Adjust frequency based on risk factors such as known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and concomitant medications.
Significant QTc interval prolongation 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 concomitant use with strong and moderate CYP3A inhibitors and/or drugs with a known potential to prolong QTc.
Advise patients to immediately report any symptoms of QT interval prolongation. Based on severity and resolution, withhold, then resume at same or reduced dose, or permanently discontinue.
Hyperuricemia: Hyperuricemia can occur and was reported in 14% of patients, with 16% of these requiring urate-lowering medication without pre-existing gout or hyperuricemia. 0.3% of patients experienced Grade ≥3. Median time to first onset was 2.1 months (range: 7 days to 35.8 months). Dose interruption occurred in 0.3% of patients.
Monitor serum uric acid levels prior to initiating and periodically during treatment. Initiate urate-lowering medications as clinically indicated. Advise patients to report symptoms. Based upon severity and resolution, withhold, then resume at same or reduced dose, or permanently discontinue.
Myalgia with Creatine Phosphokinase (CPK) Elevation: Myalgia with or without CPK elevation can occur. Myalgia occurred in 10% of patients. Median time to first onset was 11 days (range: 2 days to 10 months).
Concurrent myalgia with increased CPK within a 7-day time period occurred in 0.9% of patients. Dose interruption occurred in 0.3% of patients with myalgia and concurrent CPK elevation.
Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during treatment every 2 weeks during the first month, and then as clinically indicated. Based on severity, withhold, then resume at 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. 3.4% of patients experienced fractures, including 1.4% Grade 3. Some fractures occurred in the setting of a fall or other predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions. 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.
Advise patients to immediately report symptoms. 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, animal studies, and its mechanism of action, IBTROZI can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating IBTROZI. Advise females to inform their healthcare provider of a known or suspected pregnancy.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential and male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks following the last dose.
ADVERSE REACTIONS
Among patients who received IBTROZI, the most frequently reported adverse reactions (≥20%) were diarrhea (64%), nausea (47%), vomiting (43%), dizziness (22%), rash (22%), constipation (21%), and fatigue (20%).
The most frequently reported Grade 3/4 laboratory abnormalities (≥5%) were increased ALT (13%), increased AST (10%), decreased neutrophils (5%), and increased creatine phosphokinase (5%).
DRUG INTERACTIONS
- Strong and Moderate CYP3A Inhibitors: Avoid concomitant use.
- Strong and Moderate CYP3A Inducers: Avoid concomitant use.
- Gastric Acid Reducing Agents: Avoid concomitant use with PPIs and H2 receptor antagonists. If an acid-reducing agent cannot be avoided, administer locally acting antacids at least 2 hours before or 2 hours after taking IBTROZI.
- Drugs that Prolong the QTc Interval: Avoid concomitant use. 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.
OTHER CONSIDERATIONS
- Pregnancy: Please see important information in Warnings and Precautions under Embryo-Fetal Toxicity.
- Lactation: Advise women not to breastfeed during treatment and for 3 weeks after the last dose.
- Effect on Fertility: Based on findings in animals, IBTROZI may impair fertility in males and females. The effects on animal fertility were reversible.
- Pediatric Use: The safety and effectiveness of IBTROZI in pediatric patients has not been established.
- Photosensitivity: IBTROZI can cause photosensitivity. Advise patients to minimize sun exposure and to use sun protection, including broad-spectrum sunscreen, during treatment and for at least 5 days after discontinuation.