Larotrectinib, a potent and selective inhibitor of tropomyosin receptor kinase (TRK) A, TRK-B, and TRK-C, is an antineoplastic agent.1, 2, 3, 4
Solid Tumors with Neurotrophic Receptor Tyrosine Kinase Gene Fusion
Larotrectinib sulfate is used for the treatment of adults 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.1, 2 The presence of NTRK gene fusion in tumor specimens should be confirmed prior to initiation of therapy; however, in patients with secretory breast cancer, mammary analogue secretory cancer, congenital mesoblastic nephroma, or infantile fibrosarcoma, consider treatment without confirmation of NTRK rearrangements in tumor specimens.1 In clinical studies, presence of NTRK fusion was determined by fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), or next-generation sequencing (NGS).1, 3, 4 Larotrectinib has been designated an orphan drug by FDA for the treatment of solid tumors with NTRK -fusion proteins.5
The current indication for larotrectinib in the treatment of solid tumors harboring NTRK fusion is based principally on data from 3 open-label noncomparative studies (LOXO-TRK-14001, SCOUT, and NAVIGATE) evaluating larotrectinib in patients with unresectable or metastatic solid tumors harboring NTRK fusion.1, 2, 3, 4 The primary efficacy population consisted of the initial 55 adult and pediatric patients enrolled in the LOXO-TRK-14001, SCOUT, and NAVIGATE studies with solid tumors harboring an NTRK fusion.1 Patients were eligible for these studies if they experienced disease progression following prior systemic therapy, if available, or if severe morbidity following surgical resection for locally advanced disease was expected.1 In these studies, adult patients received larotrectinib 100 mg orally twice daily and pediatric patients (18 years of age or younger) received larotrectinib 100 mg/m2 (maximum dose of 100 mg) orally twice daily.1, 2, 3, 4 Therapy was continued until the occurrence of unacceptable toxicity or disease progression.1, 2, 3, 4 The efficacy end points were overall response rate and duration of response (as evaluated by a blinded independent review committee) according to Response Evaluation Criteria in Solid Tumors (RECIST).1 In the primary efficacy population, the median age of patients was 38 years (range: 18 days to 90 years); 61% of patients were 18 years of age or older, 39% were younger than 18 years of age, 88% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 57% were white, 6% were Hispanic or Latino, 28% were Asian, and 2.4% were Black or African American.1 Most patients (63%) had metastatic disease (including brain metastases) and 22% had unresectable locally advanced disease.1 The majority (92%) of patients in the primary efficacy population had received prior surgery, radiation therapy, or systemic therapy for their disease.1 The most common cancers in the primary efficacy population were soft tissue sarcoma (21%), infantile fibrosarcoma (14%), and primary CNS tumor (14%).1
At the time of data analysis, the overall response rate in the primary efficacy population was 60%; complete response was achieved in 24% of patients.1 The estimated median duration of response was 43.3 months; 64 or 45% of patients had durable responses exceeding 12 or 24 months, respectively.1 The overall response rate in patients with soft tissue sarcoma, infantile fibrosarcoma, and primary CNS tumor was 70, 94, and 27%, respectively.1 Other solid tumor types with overall response rates >70% included lung, salivary gland, gastrointestinal stromal tumor, congenital mesoblastic nephroma, and external auditory canal.1 The overall response rate for patients with NTRK1 fusions was 59%, NTRK2 fusions 32%, and NTRK3 fusions 67%.1
The incidence of solid tumors harboring activating NTRK fusions is low (present in approximately 0.28% of cancers).145 Although a relatively small subset (less than 1%) of patients with common solid tumors (e.g., lung, colon, or prostate cancer) harbor NTRK fusions, such fusions have been frequently reported in certain rare cancers (i.e., 91-100% of mammary analogue secretory carcinomas, secretory breast carcinomas, or infantile fibrosarcomas; 61% of congenital mesoblastic nephromas; 12-15% of papillary thyroid cancers).3, 7, 12 Although NTRK fusions are rare in colorectal cancer, patients with RAS / BRAF wild-type colorectal cancer and high microsatellite instability and/or mismatch repair deficiency are more likely to exhibit NTRK fusions.145, 146
Testing for NTRK fusions is recommended in patients with metastatic or advanced solid tumors who may be candidates for tropomyosin receptor kinase (TRK) inhibitor therapy; American Society of Clinical Oncology (ASCO) states that clinicians should consider the prevalence of NTRK fusions in individual tumor types when deciding whether to perform NTRK fusion testing.145 International experts have published consensus statements on the treatment of TRK fusion cancers in adults and pediatric patients.146, 147
Treatment with a selective TRK inhibitor (e.g., entrectinib, larotrectinib) should be considered in adult patients with TRK fusion-positive cancers including radioactive iodine-refractory thyroid carcinoma, colorectal cancer (if alternative treatments are not suitable, but also may be considered in the first-line setting), non-small cell lung cancer, soft tissue sarcoma, salivary gland carcinoma, and other TRK fusion-positive cancers where no other effective or suitable treatment options are available.146
Because NTRK gene fusions are pathognomonic in infantile fibrosarcoma, international experts recommend considering a selective TRK inhibitor as first-line systemic therapy in patients with unresectable or metastatic infantile fibrosarcoma.147 TRK inhibitors have demonstrated high response rates in infantile fibrosarcoma with the potential to prevent disfiguring surgery, such as limb amputations, and to avoid cytotoxic chemotherapy in very young patients.147 Selective TRK inhibitors should also be considered in pediatric patients with other TRK fusion-positive cancers, including unresectable/metastatic non-rhabdomyosarcoma soft tissue sarcoma, differentiated thyroid carcinoma (if standard therapy is not effective or suitable), unresectable/metastatic glioma, and other TRK fusion-positive cancers without other effective or suitable treatment options.147
Larotrectinib is administered orally (as capsules or oral solution) twice daily without regard to meals; the capsule or oral solution may be used interchangeably.1 The capsules should be swallowed whole with water; they should not be chewed or crushed.1 The oral solution should be administered using an oral dosing syringe according to the manufacturer's directions.1
If a dose of larotrectinib is missed, the dose may be taken up to 6 hours prior to the next dose; do not take within 6 hours of the next scheduled dose.1 If vomiting occurs following administration of larotrectinib, a replacement dose should not be administered; take the next dose at the regularly scheduled time.1
Larotrectinib capsules should be stored at room temperature of 20-25°C (excursions permitted between 15-30°C).1
Larotrectinib 20 mg/mL oral solution (packaged in one bottle containing 100 mL) should be stored in a refrigerator at 2-8°C; the oral solution should not be frozen.1 Unused portions of this larotrectinib oral solution should be discarded after 90 days of opening the bottle.1
Larotrectinib 20 mg/mL oral solution (packaged in two bottles each containing 50 mL) should be stored in a refrigerator at 2-8°C; the oral solution should not be frozen.1 Unused portions of this larotrectinib oral solution should be discarded after 31 days of opening the bottles.1
Dosage of larotrectinib sulfate is expressed in terms of larotrectinib.1
Solid Tumors with Neurotrophic Receptor Tyrosine Kinase Gene Fusion
For the treatment of solid tumors harboring NTRK fusion (without a known acquired mutation for resistance) in patients who have metastatic disease or may experience severe morbidity following surgical resection and whose disease progressed following prior therapy or those who are not candidates for other treatment options, the recommended dosage of larotrectinib in adult and pediatric patients with a body surface area (BSA) of at least 1 m2 is 100 mg twice daily.1 In pediatric patients with a BSA less than 1 m2 , the recommended dosage of larotrectinib is 100 mg/m2 twice daily.1
Larotrectinib therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If a grade 2 or higher liver function test abnormalities occur, refer to Table 2.1 For all other grade 3 or 4 adverse reactions, larotrectinib therapy should be withheld.1 If the grade 3 or 4 adverse reaction resolves to grade 1 or baseline within 4 weeks of withholding larotrectinib, the drug should be resumed at a reduced dosage (or discontinued) as described in Table 1.1 If the grade 3 or 4 adverse reaction does not resolve within 4 weeks of withholding larotrectinib, the drug should be permanently discontinued.1
Dosage Modification | Dosage Modification after Recovery from Toxicity Adult and Pediatric Patients with BSA ≥1 m2 (Starting Dosage = 100 mg twice daily) | Dosage Modification after Recovery from Toxicity Pediatric Patients with BSA <1 m2 (Starting Dosage = 100 mg/m2 twice daily) |
|---|---|---|
First | Restart at 75 mg twice daily | Restart at 75 mg/m2 twice daily |
Second | Restart at 50 mg twice daily | Restart at 50 mg/m2 twice daily |
Third | Restart at 100 mg once daily | Restart at 25 mg/m2 twice dailya |
Fourth | Permanently discontinue larotrectinib | Permanently discontinue larotrectinib |
aIf BSA increases to >1 m2 in pediatric patients following dosage reduction to 25 mg/m2twice daily, do not increase dosage. Maximum dose should be 25 mg/m2twice daily at the third dosage modification1
Severity | Dosage Modification |
|---|---|
AST or ALT ≥5 times ULN with bilirubin ≤2 times ULN | Withhold until recovery to grade 1 or baseline then resume therapy at the next lower dose level Permanently discontinue if grade 4 AST and/or ALT elevation occurs after resuming therapy |
AST or ALT >3 times ULN with total bilirubin >2 times ULN in the absence of alternative etiologies | Permanently discontinue therapy |
Concomitant Use with CYP3A4 Inhibitors or Inducers
Concomitant use of larotrectinib with strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 should be avoided; however, if such concomitant use cannot be avoided, reduce dosage of larotrectinib by 50% (e.g., dosage of 100 mg twice daily reduced to 50 mg twice daily; dosage of 100 mg/m2 twice daily reduced to 50 mg/m2 twice daily).1 After the CYP3A4 inhibitor has been discontinued for 3-5 elimination half-lives, resume the larotrectinib dosage that was used prior to initiation of the strong CYP3A4 inhibitor.1
Concomitant use of larotrectinib with strong inducers of CYP3A4 should be avoided; however, if such concomitant use cannot be avoided, the dosage of larotrectinib should be doubled (e.g., dosage of 100 mg twice daily increased to 200 mg twice daily; dosage of 100 mg/m2 twice daily increased to 200 mg/m2 twice daily).1 In addition, for concurrent use with a moderate CYP3A4 inducer , the manufacturer recommends doubling the dosage of larotrectinib.1 After the strong or moderate CYP3A4 inducer has been discontinued for 3-5 elimination half-lives, resume the larotrectinib dosage that was used prior to initiating the CYP3A4 inducer.1
For patients with moderate or severe hepatic impairment (Child-Pugh class B or C), the manufacturer recommends reducing the initial dosage of larotrectinib by 50% (e.g., dosage of 100 mg twice daily reduced to 50 mg twice daily; dosage of 100 mg/m2 twice daily reduced to 50 mg/m2 twice daily).1 No initial dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A).1
The manufacturer states that no adjustment to the dosage of larotrectinib is necessary in patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Larotrectinib can cause a variety of adverse neurologic effects including dizziness, cognitive impairment, mood disorders, and sleep disturbances.1 In studies of larotrectinib, adverse CNS effects occurred in 40.3% of patients receiving the drug and were grade 3 or 4 in 3.8% of patients.1
Cognitive impairment occurred in 11% of patients receiving larotrectinib, with grade 3 cognitive adverse reactions occurring in 1.8% of patients and grade 4 cognitive adverse reactions occurring in 0.2% of patients.1 The most common types of cognitive impairment reported were memory impairment, disturbance in attention, confusional state, cognitive disorder, delirium, and hallucination; these occurred in 4.1, 3.6, 2.3, 1.6, 1.4, and 1.1% of patients, respectively.1 The median time to onset of cognitive impairment was 6 months (range: 2 days to 56 months).1 Temporary interruption or dosage modification of larotrectinib was necessary because of cognitive impairment in 18 or 6% of patients, respectively.1
Mood disorders occurred in 14% of patients receiving larotrectinib, with grade 3 mood disorders occurring in 0.9% of patients.1 The most common types of mood disorders reported were anxiety, agitation, depression, irritability, and restlessness; these occurred in 5, 3.2, 3.2, 2.3, and 1.1% of patients, respectively.1 The median time to onset of mood disorders was 3.3 months (range: 1 day to 65 months).1 Temporary interruption or dosage modification of larotrectinib was necessary because of mood disorders in 1.6% or 0% of patients, respectively.1
Dizziness was reported in 22% of patients and was grade 3 in 0.9% of patients; temporary interruption or dosage modification of larotrectinib was necessary because of dizziness in 5% or 6% of patients, respectively.1
Sleep disturbances were reported in 12% of patients and included insomnia, somnolence, or sleep disorder in 9, 3.4, or 0.5% of patients, respectively.1 Temporary interruption or dosage modification of larotrectinib because of sleep disturbances in 3.7% or 0% of patients, respectively.1
Temporary interruption of larotrectinib therapy followed by dosage reduction or permanent discontinuance of therapy may be necessary in patients experiencing neurologic events during therapy with the drug, and such patients should be advised not to drive or operate machinery.1
Skeletal fractures have been reported in patients receiving larotrectinib.1 Among 444 patients receiving larotrectinib in clinical trials, fractures were reported in 7% of patients; fractures were reported in 10% of 154 pediatric patients receiving the drug.1 The median time to onset of fracture was 13 months (range: 27 days-73 months).1 The most common fractures were of the rib (1.4%), fibula, foot, or wrist (0.7% each).1 Most fractures were associated with minimal or moderate trauma, and some fractures were associated with radiologic abnormalities suggestive of local tumor involvement.1 Interruption of larotrectinib therapy due to fracture occurred in 1.4% of patients.1
Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity).1 Data on the effects of larotrectinib on the healing of known fractures or risk of future fractures are not available.1
Hepatotoxicity, including drug-induced liver injury, has been reported in patients receiving larotrectinib.1 In studies of larotrectinib, elevations in serum concentrations of ALT or AST occurred in 61 or 62% of patients, respectively, receiving the drug and were grade 3-4 in 8 or 7%, respectively, of patients.1 The median time to occurrence of elevated ALT or AST concentration was 1.9 months (range: 1 day to 4.9 years).1 Dosage modification of larotrectinib was necessary because of elevated AST or ALT concentrations in 1.6 or 3.2%, respectively, of patients receiving the drug.1, 7 Therapy was permanently discontinued because of elevations in ALT or AST concentrations in 0.9% of patients receiving the drug.1
There have also been reports of grade ≥2 increases in ALT and/or AST with increases in bilirubin ≥2 times the upper limit of normal in adult patients.1
Obtain liver function tests (ALT, AST, alkaline phosphatase, bilirubin) before larotrectinib initiation.1 Monitor liver function tests every 2 weeks for the first 2 months of therapy and then monthly thereafter or more frequently following the occurrence of grade 2 or greater AST or ALT elevation.1 Temporary interruption of larotrectinib therapy followed by dosage reduction or permanent discontinuance of therapy may be necessary if hepatotoxicity occurs.1
Larotrectinib may cause fetal harm in humans based on its mechanism of action and animal findings; embryofetal toxicity and teratogenicity have been demonstrated in animals.1 There are no available data regarding use of larotrectinib in pregnant women.1 Larotrectinib has been shown to cross the placenta in animals.1 In animal reproduction studies, fetal anasarca and omphalocele were observed in rats and rabbits receiving larotrectinib at exposure levels approximately 11 and 0.7 times the human exposure, respectively, at the recommended dosage.1 Literature reports in individuals with congenital mutations in the tropomyosin receptor kinase (TRK) pathway suggest an association between decreased TRK-mediated signaling and obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.1
Pregnancy should be avoided during larotrectinib therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of larotrectinib in females of reproductive potential and states that such females should be advised to use effective contraceptive methods while receiving larotrectinib and for at least 1 week after discontinuance of the drug.1 In addition, males with such female partners should use effective methods of contraception while receiving larotrectinib and for at least 1 week after discontinuance of the drug.1 Patients should be apprised of the potential hazard to the fetus if larotrectinib is used during pregnancy.1
Larotrectinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
Possible association between decreased TRK-mediated signaling and obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis based on data from individuals with congenital mutations in the TRK pathway.1
It is not known whether larotrectinib or its metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to larotrectinib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 1 week after the last dose.1 The effects of the drug on breast-fed infants or on the production of milk are unknown.1
Females and Males of Reproductive Potential
The manufacturer recommends verifying pregnancy status prior to initiation of larotrectinib in females of reproductive potential and states that such patients should be advised to use effective contraceptive methods while receiving larotrectinib and for at least 1 week after discontinuance of the drug.1 In addition, males with such female partners should use effective methods of contraception while receiving larotrectinib and for at least 1 week after discontinuance of the drug.1
Based on animal studies, larotrectinib may impair female fertility; however, the effect of the drug on fertility in humans is not known.1 In a repeat-dose toxicity study, decreased uterine weight, uterine atrophy, decreased corpora lutea, and increased incidence of anestrus were observed in female rats receiving larotrectinib at exposure levels approximately 10-45 times the human exposure at the recommended dosage.1
Efficacy of larotrectinib in pediatric patients with solid tumors harboring a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion was established based upon data from three multicenter, open-label, single-arm clinical trials in adult or pediatric patients.1 Some adverse effects and laboratory abnormalities occurred more frequently in pediatric patients compared with adults; however, because the studies were uncontrolled, it is unclear whether this effect was related to larotrectinib or to other confounding factors (e.g., differences in susceptibility to infection).1
No differences in pharmacokinetics were observed between pediatric patients and adults.1
In clinical trials evaluating larotrectinib, 20% of patients receiving larotrectinib were 65 years of age or older, while 6% were 75 years of age or older.1 No overall differences in safety or efficacy of larotrectinib were seen between patients ≥65 years of age and younger adult patients.1
Following administration of a single 100-mg dose of larotrectinib, the area under the plasma concentration-time curve (AUC) in individuals with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) was increased by 1.3-, 2-, or 3.2-fold, respectively, compared with individuals with normal hepatic function; peak plasma concentrations were increased by 1.5-fold in individuals with severe hepatic impairment compared with individuals with normal hepatic function.1 Initial dosage adjustment is required in patients with moderate or severe hepatic impairment.1
Following administration of a single 100-mg dose of larotrectinib to individuals with end-stage renal disease requiring dialysis, AUC and peak plasma concentrations were increased by 1.5- and 1.3-fold, respectively, compared with individuals with normal renal function (creatinine clearance of 90 mL/minute or greater).1 Larotrectinib has not been studied in patients with moderate or severe renal impairment (creatinine clearance of 60 mL/minute or less).1
No dosage adjustment is necessary in patients with renal impairment of any severity.1
Adverse effects reported in >20% of patients receiving larotrectinib include increased AST concentrations, increased ALT concentrations, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase concentrations, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash.1
Larotrectinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1
In vitro studies indicate that larotrectinib is an inhibitor of CYP3A4.7 In vitro, larotrectinib does not inhibit or induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations.1
In vitro, larotrectinib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate for organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, or OATP1B3.1 In vitro studies indicate that larotrectinib does not inhibit P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, bile salt export pump (BSEP), multidrug and toxin extrusion (MATE) transporter 1, and MATE2K at clinically relevant concentrations.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of larotrectinib with strong or moderate inhibitors of CYP3A4 may increase systemic exposure to larotrectinib and possible toxicity.1 When the strong CYP3A inhibitor itraconazole (200 mg once daily for 7 days) was administered concomitantly with larotrectinib (single 100-mg dose), peak plasma concentration and area under the plasma concentration-time curve (AUC) of larotrectinib were increased by 2.8- and 4.3-fold, respectively.1, 7 The potential for weak CYP3A inhibitors to alter larotrectinib pharmacokinetics has not been established.1
Concomitant use of larotrectinib with strong inhibitors of CYP3A4 (e.g., itraconazole, grapefruit juice) should be avoided.1 If concomitant use of a strong CYP3A4 inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of larotrectinib by 50% (e.g., dosage of 100 mg twice daily reduced to 50 mg twice daily; dosage of 100 mg/m2 twice daily reduced to 50 mg/m2 twice daily).1 After the CYP3A4 inhibitor has been discontinued for 3-5 elimination half-lives, resume the larotrectinib dosage used prior to initiation of the strong CYP3A4 inhibitor.1
If concomitant use of a moderate CYP3A4 inhibitor with larotrectinib occurs, patients should be monitored more frequently for adverse reactions and the dosage of larotrectinib should be reduced based on the severity of the adverse reaction.1
Concomitant use of larotrectinib with strong or moderate inducers of CYP3A4 may decrease systemic exposure to larotrectinib and reduce larotrectinib efficacy.1 When the strong CYP3A inducer rifampin (600 mg once daily for 11 days) was administered concomitantly with larotrectinib (single 100-mg dose), peak plasma concentration and AUC of larotrectinib were decreased by 71 and 81%, respectively.1, 7 The potential for weak CYP3A inducers to alter larotrectinib pharmacokinetics has not been established.1
Concomitant use of larotrectinib with strong inducers of CYP3A4 (e.g., rifampin, St. John's wort [ Hypericum perforatum ]) should be avoided.1 If concomitant use of a strong CYP3A4 inducer cannot be avoided, the manufacturer recommends doubling the dosage of larotrectinib (e.g., dosage of 100 mg twice daily increased to 200 mg twice daily; dosage of 100 mg/m2 twice daily increased to 200 mg/m2 twice daily).1 In addition, for concurrent use with a moderate CYP3A4 inducer, the manufacturer recommends doubling the dosage of larotrectinib.1 After the strong or moderate CYP3A4 inducer has been discontinued for 3-5 elimination half-lives, resume the larotrectinib dosage used prior to initiation of the CYP3A4 inducer.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Larotrectinib may increase systemic exposure and risk of adverse effects of other drugs metabolized by CYP3A4.1, 7 When the sensitive CYP3A4 substrate midazolam (single 2-mg dose) was administered concomitantly with larotrectinib (100 mg twice daily for 10 days) in healthy individuals, peak plasma concentration and AUC of midazolam were both increased by 1.7-fold; peak plasma concentration and AUC of the major metabolite of midazolam (1-hydroxymidazolam) were both increased by 1.4-fold.1, 7 Concomitant use with sensitive substrates of CYP3A4 (e.g., midazolam) should be avoided.1 If concomitant use of a sensitive CYP3A4 substrate cannot be avoided, the patient should be monitored for CYP3A4 substrate-related toxicity.1
Drugs Affecting the P-glycoprotein Transport System
When the P-gp inhibitor rifampin (single 600-mg dose) was administered concomitantly with larotrectinib (single 100-mg dose) in healthy individuals, peak plasma concentration and AUC of larotrectinib were increased by 1.8- and 1.7-fold, respectively.1, 7
Larotrectinib, a potent and selective inhibitor of tropomyosin receptor kinase (TRK) A, TRK-B, and TRK-C, is an antineoplastic agent.1, 2, 3, 4 The TRK family of tyrosine kinases (encoded by the neurotrophic receptor tyrosine kinase genes NTRK1 , NTRK2 , and NTRK3 ) are involved in the initiation of various cascades of intracellular signaling events (i.e., Ras/MAPK/ERK, PI3K/Akt, and PLCγ1/Pkc signal transduction pathways), which leads to cell proliferation, differentiation, apoptosis, and regulation of processes critical to neuron survival in the central and peripheral nervous systems.1, 2, 4, 6, 9, 10, 11 Chromosomal rearrangements of the NTRK1 , NTRK2 , and NTRK3 genes result in fusions with an unrelated gene.1, 3, 4, 6, 9 These NTRK gene fusions encode a constitutively active chimeric TRK oncogenic fusion protein resulting in dysregulation of TRK signaling and subsequent tumorigenesis.1, 3, 4, 6, 9, 10 In vitro biochemical assays have shown that larotrectinib inhibits the activity of wild-type TRK-A, TRK-B, and TRK-C.1, 7 In vitro and in vivo, larotrectinib has demonstrated antitumor activity in cell lines with TRK expression from constitutive activation, deletion of a protein regulatory domain, or overexpression of wild-type TRK.1, 7 Larotrectinib also has demonstrated inhibition of tyrosine kinase nonreceptor 2 (TNK2).1
Clinical resistance to larotrectinib has been attributed to secondary point mutations of the NTRK kinase domain in 90% of cases.7 Larotrectinib has shown minimal activity in cell lines with point mutations in the TRK-A kinase domain, including the acquired resistance mutation G595R.1 Acquired resistance to larotrectinib also has been identified in cell lines with G623R, G696A, or F617L point mutations in the TRK-C kinase domain.1
Following oral administration of larotrectinib capsules, systemic exposure to larotrectinib increases in a dose-proportional manner over a dose range of 100-400 mg and increases in a slightly more than dose-proportional manner over a dose range of 600-900 mg.1 Following oral administration of larotrectinib capsules at a dosage of 100 mg twice daily, peak plasma concentrations of the drug were achieved in approximately 1 hour and steady-state concentrations were achieved within 3 days.1 The mean absolute oral bioavailability of larotrectinib capsules was 34%.1 The area under the plasma-concentration time curve (AUC) for larotrectinib oral solution was similar to the AUC for larotrectinib capsules; peak plasma concentrations were 36% higher for larotrectinib oral solution compared with larotrectinib capsules.1 Administration of larotrectinib capsules (single 100-mg dose) with a high-fat meal decreased peak plasma concentrations by 35% and delayed the time to peak plasma concentrations by 2 hours compared with administration in the fasted state, but did not substantially affect the extent of absorption.1, 7 Larotrectinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1 Larotrectinib is 70% bound to plasma proteins, and binding is independent of larotrectinib concentration.1 Following oral administration of a single 100-mg radiolabeled dose of larotrectinib, 58% of the dose was recovered in feces (5% as unchanged drug) and 39% was recovered in urine (20% as unchanged drug).1 The terminal half-life of larotrectinib is 2.9 hours.1
The pharmacokinetics of larotrectinib do not appear to be affected by age (range of 28 days to 82 years), sex, or body weight (range of 3.8-179 kg).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Larotrectinib sulfate can only be obtained through designated specialty pharmacies and distributors.8 Clinicians may contact the manufacturer (Bayer) at 844-634-8725 or consult the Vitrakvi® website ([Web]) for specific ordering and availability information.8
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 25 mg (of larotrectinib) | Vitrakvi® | Bayer |
100 mg (of larotrectinib) | Vitrakvi® | Bayer | ||
Solution | 20 mg (of larotrectinib) per mL | Vitrakvi® (available in a package containing one 100-mL bottle or a package of 2 bottles each containing 50 mL) | Bayer |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Bayer Healthcare Pharmaceuticals. Vitrakvi® (larotrectinib) capsules and oral solution prescribing information. Whippany, NJ: 2025 Apr.
2. Drilon A, Laetsch TW, Kummar S et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med . 2018; 378:731-9. [PubMed 29466156]
3. Hong DS, Bauer TM, Lee JJ et al. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol . 2019; 30:325-31. [PubMed 30624546]
4. Laetsch TW, DuBois SG, Mascarenhas L et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol . 2018; 19:705-14. [PubMed 29606586]
5. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and approvals. Rockville, MD. From FDA web site. [Web]
6. Lange AM, Lo H. Inhibiting TRK Proteins in Clinical Cancer Therapy. Cancers . 2018; 10:1-15.
7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210861Orig1s000 and 211710Orig1s000: Multi-discipline review. From FDA website. [Web]
8. Bayer. Patient support services. From Bayer for US Healthcare Professionals website. [Web]
9. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov . 2015; 5:25-34. [PubMed 25527197]
10. Ricciuti B, Genova C, Crinò L et al. Antitumor activity of larotrectinib in tumors harboring NTRK gene fusions: a short review on the current evidence. Onco Targets Ther . 2019; 12:3171-3179. [PubMed 31118670]
11. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open . 2016; 1:e000023. [PubMed 27843590]
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