Frequency of NTRK* gene fusions
across various tumor types
Estimated NTRK gene fusion frequencies in various cancers are based on reports from isolated studies that used variable testing methodologies. Not all of these tumor types were treated in the clinical trial with VITRAKVI®.
Frequency in selected common cancers
- Lung1,2a 0.2%-3.3%
- Thyroid1,3 2.4%-12%b
- Glioblastoma4 1.2%
- Sarcoma1 1%
- GI* Cancer1,5-7c 0.7%-3.6%
Frequency in Other Cancers
|80% to 100%||
|5% to 20%||
|1% to 5%||
TEST EARLY FOR ACTIONABLE ALTERATIONS SUCH AS
NTRK GENE FUSIONS
Select patients for treatment with VITRAKVI based on the presence of an NTRK gene fusion in tumor specimens. An FDA*-approved test for the detection of NTRK gene fusion is not currently available.17
NTRK gene fusions can be identified by sensitive and specific molecular testing18-20
NGS* testing allows for efficient multiplex testing, with the ability to find NTRK gene fusions, as well as other genomic targets, such as ROS1,* BRAF,* EGFR,* HER2,* and KRAS18,21-24*
- RNA testing is preferred over DNA testing because it offers more wide-ranging fusion identification25
- NTRK1, NTRK2, and NTRK3 should be included in the NGS panel
IHC* may be used as a screening diagnostic18
Following a positive TRK* IHC test, confirmation of NTRK gene fusions is needed prior to initiation of VITRAKVI treatment26
- There are currently research-use-only antibodies commercially available. Pan-TRK antibodies detect TRK proteins A,B,C, which are known to be conserved across wild-type and chimeric fusion proteins. Therefore, protein expression may not be related to a gene fusion
DNA FISH* can be used to detect NTRK gene fusions; however, in order to detect fusions at multiple locations, such as the 3 NTRK genes, multiple FISH tests would need to be run22
- There is utility in using FISH in diseases such as IFS,* where the predominant driver for IFS is ETV6-NTRK10,27
RT-PCR* is designed to identify only known translocation partners and breakpoints and cannot identify novel breakpoints or novel fusion partners28
- Turnaround time is rapid with RT-PCR testing29
*BRAF, B-Raf proto-oncogene; EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IFS, infantile fibrosarcoma; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma; NGS, next-generation sequencing; ROS1, c-ros oncogene 1; RT-PCR, reverse transcription polymerase chain reaction; TRK, tropomyosin receptor kinase.
VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that:
- have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation,
- are metastatic or where surgical resection is likely to result in severe morbidity, and
- have no satisfactory alternative treatments or that have progressed following treatment.
This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Important Safety Information
Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurological adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).
Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed.
Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.
Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.
Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily.
Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.
Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).
Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.
Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.
For important risk and use information about VITRAKVI, please see the full Prescribing Information.
You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.
For Bayer products you can report these directly to Bayer by clicking here.
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