Vitrakvi

Dosage Forms, Strengths, Composition and Packaging: See Table 1.

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VITRAKVI (larotrectinib) is supplied as white opaque hard gelatin capsules containing 25 mg and 100 mg of larotrectinib and as oral solution containing 20 mg/mL of larotrectinib.
Capsules: The 25 mg capsules are white opaque hard gelatin capsules (size 2) with blue printing of "BAYER" cross and "25 mg" on the body of capsule. They are supplied in 75 mL bottles of 56 capsules.
The 100 mg capsules are white opaque hard gelatin capsules (size 0) with blue printing of "BAYER" cross and "100 mg" on the body of capsule. They are supplied in 120 mL bottles of 56 capsules.
Oral Solution: The 20 mg/mL oral solution is a colourless to yellow or orange or red or brownish liquid solution of strawberry flavour supplied in brown glass bottles of 50 mLs. Each carton contains two bottles.
Pharmaceutical Information: Common name: larotrectinib sulfate.
Chemical name: (3S)-N-{5-[(2R)-2-(2,5-Difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate.
Molecular formula: C₂₁H₂₄F₂N₆O₆S.
Molecular mass: 526.51 g/mol.
Physicochemical properties: Larotrectinib is a crystalline sulfate salt, appearing as an off-white to yellow to pinkish yellow solid. The solubility of larotrectinib sulfate is pH dependent, having > 10 mg/mL solubility below pH 1.5, ~ 2-3 mg/mL solubility at pH 2.5, and dropping to ~ 1 mg/mL above pH 3.5. Larotrectinib sulfate has only been observed as a single polymorph.

Pharmacology: Mechanism of Action: Larotrectinib is an orally-bioavailable, adenosine triphosphate (ATP)-competitive, potent and highly selective Tropomyosin Receptor Kinase (TRK) kinase inhibitor. Larotrectinib targets the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by NTRK1, NTRK2, and NTRK3 genes, respectively. Larotrectinib has minimal activity with off-target kinases tested.
In-frame gene fusion events resulting from chromosomal rearrangements of the human genes NTRK1, NTRK2, and NTRK3 lead to the formation of oncogenic TRK fusion proteins. These resultant novel chimeric oncogenic proteins are aberrantly expressed driving constitutive kinase activity subsequently activating downstream cell signalling pathways involved in cell proliferation and survival leading to TRK fusion cancer.
Larotrectinib demonstrated potent inhibition of TRK proteins and inhibition of proliferation of cell lines containing NTRK gene fusions in a concentration-dependent manner. In TRK fusion-driven mouse xenograft models larotrectinib treatment induced significant tumour growth inhibition.
Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.
Pharmacodynamics: Cardiac Electrophysiology: Potential effects of larotrectinib on the QT interval were examined with the use of concentration-response modeling of the QTc data. The model was built on a single data set containing 36 healthy adult subjects receiving single doses ranging from 100 mg to 900 mg (n=6 per treatment arm receiving larotrectinib). Based on the model, larotrectinib at C_max did not prolong the QT interval to any clinically relevant extent.
Clinical Trials: Trial Design and Study Demographics: Three ongoing multicenter, open-label, single-arm clinical studies in patients with advanced cancer contributed patients to a pooled efficacy analysis evaluating VITRAKVI for the treatment of adult and pediatric patients with unresectable or metastatic solid tumours with a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion, as follows (see Table 2): 1) Phase 1 adult dose-finding study (Study 1 [LOXO-TRK-14001] [n=13]); 2) Phase 2 adult and pediatric "basket" study (Study 2 [NAVIGATE] [n=98]); and 3) Phase 1/2 pediatric dose-finding/efficacy and safety study (Study 3 [SCOUT] [n=53]).
Enrollment to Study 1 and the Phase 1 portion of Study 3 was not restricted to patients with a documented NTRK gene fusion but patients with prospectively identified NTRK gene fusions were included in the pooled efficacy analysis. Patients enrolled to Study 2 were required to have tropomyosin receptor kinase (TRK) fusion cancer. All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity. Protocol amendments excluded patients with prior progression on approved or investigational kinase inhibitors with anti-TRK activity from Studies 2 and 3.
The assessment of efficacy is based on an analysis of 164 patients comprising an extended primary analysis set (ePAS). The ePAS includes the first 55 patients with solid tumours with an NTRK gene fusion who were enrolled across the three clinical studies (the primary analysis set [PAS]) plus additional patients who subsequently started treatment and with ≥ 6 months follow up at the July 15, 2019 cutoff date. Patients in the ePAS were required to have a documented NTRK gene fusion as determined by local testing; a non-Central Nervous System (non-CNS) primary tumour with ≥ 1 measurable lesion at baseline, per investigator assessment based on Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1 (v1.1); and to have received ≥ 1 dose of VITRAKVI.
Identification of NTRK gene fusions was prospectively determined in local certified laboratories primarily using next generation sequencing (NGS), in some cases, by fluorescence in situ hybridization (FISH) and by reverse transcription-polymerase chain reaction (RT-PCR) in one case.
The majority of adult patients received a starting dose of VITRAKVI of 100 mg orally twice daily and the majority of pediatric patients received VITRAKVI 100 mg/m² up to a maximum dose of 100 mg orally twice daily until unacceptable toxicity or disease progression. (See Table 2.)

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For the pooled efficacy analysis, the primary endpoint was overall response rate (ORR), while the duration of response (DOR) was a secondary endpoint, both determined by a blinded Independent Review Committee (IRC) according to RECIST, v1.1. Additional secondary efficacy outcomes assessed included time to first response. A lower boundary of 30% for ORR, considered to be clinically meaningful, was predefined as statistically significant for response. The ORR was defined as the proportion of patients with the best overall response of confirmed complete response (CR) or confirmed partial response (PR).
Baseline characteristics for the pooled 164 patients with solid tumours harbouring an NTRK gene fusion were as follows: median age 42 years (range 0.1-84 years); 34% < 18 years of age, 66% ≥ 18 years, and 21% > 65 years; 77% white and 49% male; and Eastern Cooperative Oncology Group (ECOG) Performance Status (ECOG PS) 0-1 (86%), 2 (12%), or 3 (2%). Seventy-four percent of patients had metastatic disease and 26% of patients had locally advanced, unresectable disease. Median time from diagnosis was 1.7 years (range: 0.02-31.5 years). Ninety-four percent of patients had received prior treatment for their cancer, defined as surgery, radiotherapy, or systemic therapy. Of these, 77% had received prior systemic therapy with a median of 1 prior regimen received (range: 0-10). Twenty-seven percent of all patients had received 3 or more prior systemic therapies and 51% of all patients had received 1-2 prior systemic therapies. Twenty-two percent of all patients had received no prior systemic therapy.
The most common tumour types represented were soft tissue sarcoma (22%), infantile fibrosarcoma (20%), thyroid cancer (16%), salivary gland tumour (13%) and lung (8%). NTRK gene fusions were identified by NGS, FISH, and RT-PCR in 92.3%, 6.4%, and 1.3% of patients, respectively. The TRK fusions involved NTRK1 (in 41% of patients), NTRK2 (in 2%), or NTRK3 (in 56%) and 31 unique upstream fusion partners. In nine patients (5%) with infantile fibrosarcoma who had a documented ETV6 translocation identified by FISH, NTRK3 gene fusions were inferred.
Study Results: In the ePAS (n=164), with a median duration of follow-up of 15.7 months, the overall response rate (ORR) was 73% (95% confidence interval [CI]: 65, 79). The ORR included a CR in 31 patients (19%), a surgical CR (sCR) in 8 (5%), and a PR in 80 (49%). Seventy-six percent of responders (90 of 164 patients) were still in response, and the duration of response exceeded 6 months in 89%; the median duration of response (DOR) was not yet estimable. The pooled efficacy results for overall response rate and best overall response are presented in Table 3. (See Table 3.)

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The median time to first response was 1.8 months (range: 0.9 to 14.6 months) and 81% of responses occurred within the first 2 months of treatment which coincides with the timing of the first assessment protocol. ORR in the adult sub-population (n=109) was 63% and 91% in the pediatric sub-population (n=55).
In an updated analysis, with a median duration of follow-up of 23.3 months, the median DOR for the ePAS (n=164) was 34.5 months (95% CI: 27.6, 54.7).
Changes in target lesion size for individual patients are illustrated in the Waterfall plot in the figure. (See figure.)

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Additional efficacy results by tumour type and by NTRK gene fusion partner are presented in Table 4 and Table 5, respectively. (See Tables 4 and 5.)

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Patients with CNS Tumors: Twenty-four patients with primary CNS tumors and measurable disease at baseline were enrolled in study 2 ("NAVIGATE") and in study 3 ("SCOUT"). Baseline characteristics for the 24 patients with primary CNS tumors with an NTRK gene fusion assessed by investigator were as follows: median age 8 years (range 1.3-79 years); 20 patients < 18 years of age and 4 patients ≥ 18 years, and 19 patients white and 11 patients male; and ECOG PS 0-1 (22 patients), or 2 (1 patient). All CNS tumor patients had received prior cancer treatment (surgery, radiotherapy and/or previous systemic therapy). There was a median of 1 prior systemic treatment regimen received. Tumor responses for primary CNS tumors were assessed by the investigator using Response Assessment in Neuro Oncology (RANO) Criteria or Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
Of the 24 patients with primary CNS tumors, confirmed response was observed in 5 patients (21%) with 2 of the 24 patients (8%) being complete responders and 3 (12.5%) being partial responders. At a median follow-up time of 10.1 months, the median duration of response was 4.9 months (1.7+ months, 10.1+ months). Further, 17 patients (71%) had stable disease. Two patients (8%) had a progressive disease.
Pharmacokinetics: See Table 6.

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Absorption: VITRAKVI is available as a capsule and oral solution formulation. In healthy adult subjects, the AUC of larotrectinib in the oral solution formulation was similar to the capsule; C_max was 36% higher with the oral solution formulation.
The mean absolute bioavailability of larotrectinib was 34% (range: 32% to 37%) following a single 100 mg oral dose.
C_max and AUC in the capsule formulation were dose proportional in healthy adult subjects up to 400 mg and slightly greater than proportional at doses of 600 to 900 mg. Systemic accumulation is 1.6 fold at steady state.
Effect of Food: Larotrectinib C_max was reduced by approximately 35% and there was no effect on AUC in healthy subjects administered VITRAKVI after a high-fat and high-calorie meal compared to the C_max and AUC after overnight fasting.
Distribution: Binding of larotrectinib to human plasma proteins in vitro was approximately 70% and was independent of drug concentration. The blood-to-plasma concentration ratio was approximately 0.9.
Metabolism: Larotrectinib is metabolized predominantly by CYP3A4/5 (see Interactions). Following oral administration of a single 100 mg dose of radiolabeled larotrectinib to healthy adult subjects, unchanged larotrectinib (19%) and O-glucuronide larotrectinib that is formed following loss of the hydroxypyrrolidine-urea moiety (26%) were the major circulating radioactive drug components in plasma.
Elimination: Following oral administration of 100 mg radiolabeled larotrectinib as an oral solution to healthy adult subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine.
Special Populations and Conditions: Pediatrics: Based on population pharmacokinetic analyses exposure (C_max and AUC) in pediatric patients (1 month to < 3 months of age) at the recommended dose of 100 mg/m² with a maximum of 100 mg BID was 3-fold higher than in adults (≥ 18 years of age) given the dose of 100 mg BID. At the recommended dose, the C_max in pediatric patients (≥ 3 months to < 12 years of age) was higher than in adults, but the AUC was similar to that in adults. For pediatric patients older than 12 years of age, the recommended dose is likely to give similar C_max and AUC as observed in adults.
Geriatrics: Based on population pharmacokinetic analyses, C_max and AUC in patients > 65 years were similar to those in younger patients (< 65 years).
Sex: Gender had no significant effect on the systemic exposure of larotrectinib based on population pharmacokinetic analyses.
Ethnic Origin: Race had no significant effect on the systemic exposure of larotrectinib based on population pharmacokinetic analyses. Caucasians accounted for 72% of the analysis population.
Hepatic Insufficiency: A pharmacokinetic study was conducted in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, and in healthy adult control subjects with normal hepatic function matched for age, body mass index and sex. All subjects received a single 100 mg dose of larotrectinib. An increase in larotrectinib AUC_0-inf was observed in subjects with mild, moderate and severe hepatic impairment of 1.3, 2 and 3.2-fold respectively versus those with normal hepatic function. C_max was observed to increase slightly by 1.1, 1.1 and 1.5-fold respectively. Reduce the starting dose of VITRAKVI by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with mild (Child-Pugh A) hepatic impairment.
Renal Insufficiency: A pharmacokinetic study was conducted in subjects with end stage renal disease requiring dialysis, and in healthy adult control subjects with normal renal function matched for age, body mass index and sex. All subjects received a single 100 mg dose of larotrectinib. An increase in larotrectinib C_max and AUC_0-inf, of 1.25 and 1.46-fold respectively was observed in renally impaired subjects versus those with normal renal function. No dose adjustment is recommended for patients with renal impairment of any severity.
Body Weight: Body weight from 5.0 kg to 179.4 kg had no significant effect on the AUC of larotrectinib based on population pharmacokinetic analyses. The mean AUC of larotrectinib may be increased in children weighing < 5.0 kg (see Pediatrics as previously mentioned).
Toxicology: Non-Clinical Toxicology: General Toxicity: Repeated-dose toxicity was assessed in studies with daily oral administration up to 13-weeks in rats and monkey. Dose limiting skin lesions were only seen in rats and were primarily responsible for mortality and morbidity. In rats, severe toxicity was observed at doses corresponding to human AUC at the recommended clinical dose. Clinical signs of gastrointestinal toxicity including emesis, were dose limiting in monkeys. No relevant systemic toxicity were observed in monkeys at exposures which correspond to > 10-times the human AUC at the recommended clinical dose.
Increased body weight, increased food consumption, and elevated serum liver enzymes (ALT and/or AST) are additional relevant findings that were observed in both species.
Genotoxicity and Carcinogenicity: Larotrectinib was not mutagenic in bacterial reverse mutation (Ames) assays and in in vitro mammalian mutagenesis assays. Larotrectinib was negative in the in vivo mouse micronucleus test.
Carcinogenicity studies have not been performed with larotrectinib.
Reproductive and Developmental Toxicology: Reproduction Toxicity: Fertility studies with larotrectinib have not been conducted. In 13-week repeated-dose studies, larotrectinib had no effects on spermatogenesis in rats and on the histopathology of male reproductive organs in rats and monkeys at doses corresponding to approximately 7-times (rats) and 10-times (monkeys) the human AUC at the recommended clinical dose.
In a 1-month study in female rats, fewer corpora lutea, increased incidence of anestrus and decreased uterine weight with uterine atrophy were observed at doses corresponding to approximately 8-times the human AUC at the recommended clinical dose; these effects were reversible. No effects on reproductive organs were seen in the 13-week study in rats and monkeys at doses corresponding to approximately 3 times (rats) and approximately 17-times (monkeys) the human AUC at the recommended clinical dose.
Development: In embryo-fetal development studies where pregnant rats and rabbits were dosed with larotrectinib during the period of organogenesis, malformations were observed at maternal exposures that were approximately 9- and 0.6-times, respectively, those observed at the clinical dose of 100 mg twice daily. Larotrectinib was not embryotoxic up to maternally toxic doses. Larotrectinib crosses the placenta in both species and can be detected in blood samples obtained from fetuses at termination.
Juvenile Toxicity: Larotrectinib was administered in a juvenile toxicity study in rats at twice daily doses of 0.2, 2 and 7.5 mg/kg from postnatal day (PND) 7 to 27 and at twice daily doses of 0.6, 6 and 22.5 mg/kg between PND 28 and 70. The dosing period was equivalent to human pediatric populations from newborn to adulthood. The lowest dose (0.2/0.6 mg/kg BID), equivalent to 0.02-fold the recommended clinical exposure, was considered the NOAEL. At doses ≥ 2/6 mg/kg BID (0.5-fold the recommended clinical exposure), increased mortality, neuronal effects (increased incidence of partially closed eyelids, lower hindlimb grip strength and foot splay), decreased growth (shorter tibial length and lower body weight gain with lower food intake) and delay in sexual development were noted. At doses 7.5/22.5 mg/kg BID (3-fold the recommended clinical exposure), central nervous system-related signs including head flick and circling, increased escape time and number of errors in a maze swim test when the original path is reversed, skin lesions, and swollen abdomen (females) were noted. Lower fertility was noted in animals at 3-times the recommended clinical exposure.
Microbiology: No microbiological information is required for this drug product.

VITRAKVI (larotrectinib) is indicated for the treatment of adult and pediatric patients with solid tumours that: have a Neurotrophic Tyrosine Receptor 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 treatment options.
This indication is approved based on overall response rate (ORR) and duration of response (DOR) in a pooled patient population in which most patients had rare tumours (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
Treatment with VITRAKVI should be initiated following confirmation of an NTRK gene fusion in a tumour specimen using a validated test (see Pharmacology: Mechanism of Action under Actions).
VITRAKVI should only be administered under the supervision of a health professional experienced in the use of antineoplastic agents.
Pediatrics: Pediatrics (< 18 years of age): The safety and efficacy of VITRAKVI in pediatric patients 28 days and older were established based upon data from three multicenter, open-label, single-arm clinical studies. There are no data in pediatric patients less than one month of age (see Use in Children under Precautions).
Geriatrics: Geriatrics (≥ 65 years of age): The safety and efficacy of VITRAKVI in geriatric patients were established based upon data from three multicenter, open-label, single-arm clinical studies. Insufficient numbers of patients aged 65 and over were included to determine whether they respond differently from younger subjects (see Use in the Elderly under Precautions).

Dosing Considerations: Confirm the presence of an NTRK gene fusion in a tumour specimen using a validated test prior to initiation of treatment with VITRAKVI (see Pharmacology: Mechanism of Action under Actions).
Recommended Dose and Dosage Adjustment: Adults: The recommended dose of VITRAKVI in adults is 100 mg taken orally, twice daily (total dose of 200 mg) until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.
Pediatrics: Dosing in pediatric patients is based on body surface area (BSA). The recommended dose of VITRAKVI in pediatric patients (1 month to 18 years) is 100 mg/m² taken orally, twice daily with a maximum of 100 mg per dose (maximum total dose of 200 mg) until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. For those subjects following the BSA-based dosing algorithm (mg/m²), oral solution dose volumes under 1.0 mL can be rounded to the nearest 0.1 mL. Oral solution dose volumes above 1.0 mL can be rounded to the nearest 0.5 mL.
Geriatrics: Clinical data indicate that age has no effect on the systemic exposure of larotrectinib (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Geriatrics under Actions). No dose adjustment is necessary in elderly patients.
Patients with Hepatic Impairment: Clinical data from a pharmacokinetic study indicate that larotrectinib exposure was increased in patients with hepatic impairment up to 3.2-fold (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Hepatic Insufficiency under Actions). Reduce the starting dose of VITRAKVI by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with mild (Child-Pugh A) hepatic impairment.
Patients with Renal Impairment: Clinical data from a pharmacokinetic study indicate that larotrectinib exposure was increased 1.46-fold in patients with end-stage renal disease (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Renal Insufficiency under Actions). No dose adjustment is required for patients with renal impairment.
Dose Modifications: For an adverse reaction ≥ Grade 3, consider interrupting dosing of VITRAKVI and reevaluating regularly at least weekly. VITRAKVI can be withheld for up to 4 weeks to allow recovery to Grade 1 or back to baseline and resumed at the next dosage modification. Permanently discontinue VITRAKVI if an adverse reaction does not resolve within 4 weeks of the start of withholding the dose.
Recommended dose modifications for VITRAKVI for adverse reactions are provided in Table 7. (See Table 7.)

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Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications.
For all Grade 2 adverse reactions, continued dosing may be appropriate, though close monitoring to ensure no worsening of the toxicity is advised.
Administration: VITRAKVI is for oral use and may be administered with or without food. VITRAKVI is available as a capsule or oral solution formulation with equivalent oral bioavailability, and may be used interchangeably.
Capsule: The patient should be advised to swallow the capsule whole with water. The capsule should not be opened, chewed, or crushed.
Oral solution: Administer the oral solution by mouth or enterally by naso- or gastric-feeding tube with a dosing syringe.
Missed Dose: If a dose is missed, the patient should not take two doses at the same time to make up for a missed dose. Patients should take the next dose at the next scheduled time.
If the patient vomits after taking a dose, the patient should not take an additional dose to make up for vomiting.

There is no known antidote for VITRAKVI. The treatment of overdose with VITRAKVI should consist of general supportive measures.
In clinical trials, the highest single dose of VITRAKVI was 900 mg, which is equivalent to 9-times a single recommended dose when taken twice daily. Among 12 healthy adult subjects who received a single dose of either 700 or 900 mg VITRAKVI, adverse events reported in ≥ 2 subjects consisted of nausea, vomiting, dizziness, and headache.

VITRAKVI is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Description.

Hepatic/Biliary/Pancreatic: Among the 279 patients who received VITRAKVI, treatment-emergent adverse events (TEAEs) of alanine transaminase (ALT) increased and aspartate transaminase (AST) increased of any grade were reported in 28% and 25% of patients, respectively. The maximum grades elevations were Grade 4 ALT increased in 2 patients (1%), Grade 4 AST increased in 1 patient (< 1%), Grade 3 ALT increased in 7 patients (3%) and Grade 3 AST increased in 6 patients (2%) (see Clinical Trial Adverse Reactions: Additional Information in Selected Adverse Reactions: Transaminase Elevations under Adverse Reactions). The median time to onset of ALT increased was 1.8 months (range: 0 days to 21.3 months). The median time to onset of AST increased was 1.5 months (range: 0 days to 21.3 months). Transaminase elevations led to dose modification and permanent discontinuation of VITRAKVI in 3% and 2% of patients, respectively.
Monitor for liver function including ALT and AST assessments. VITRAKVI can cause transaminase elevations. Consider baseline assessment of liver function, including transaminase levels, before the first dose and monthly for the first 3 months of treatment, then periodically during treatment, with more frequent testing in patients who develop transaminase elevations. Withhold or permanently discontinue VITRAKVI based on the severity and persistence of the transaminase elevation. If withheld, modify the VITRAKVI dosage when resumed (see Recommended Dose and Dosage Adjustment: Dose Modifications under Dosage & Administration). Patients with Grade 2 transaminase elevations should be followed with serial laboratory evaluations every one to two weeks after the observation of Grade 2 toxicity to establish whether a dose interruption or reduction is required. In patients with ≥ Grade 3 events in whom VITRAKVI has been withheld, regular reevaluation at least weekly is recommended.
Neurologic/Psychiatric: Among the 279 patients who received VITRAKVI, neurologic/psychiatric TEAEs of any grade occurred in 63% of patients, including Grade 3 and Grade 4 adverse events in 11% and < 2% of patients, respectively. Grade 4 encephalopathy, brain edema, seizure and cerebrovascular accident were reported in one patient each. Grade 3 events included delirium (1%), dizziness (1%), mental status change (1%), gait disturbance (1%), paresthesia (1%), and syncope (1%). The majority (80%) of neurologic adverse events occurred within the first three months of treatment (range: 0 days to 35.5 months). Dose modification (interruption, increase or reduction) based on neurologic toxicity of all grades occurred in 11% of patients, most commonly for dizziness (2%) (see Clinical Trial Adverse Reactions: Additional Information in Selected Adverse Reactions: Neurologic/Psychiatric events under Adverse Reactions).
Withholding, reducing, or permanently discontinuing VITRAKVI dosing should be considered, depending on the severity and persistence of these symptoms.
Sexual Health: Reproduction: Based on the mechanism of action and non-clinical data, there may be a risk of fetal harm when administering larotrectinib to a pregnant woman. Females of childbearing potential should have a pregnancy test prior to starting treatment with VITRAKVI.
Advise female patients of reproductive potential to use highly effective contraception during treatment with VITRAKVI and for at least one month after the final dose.
For males of reproductive potential with a non-pregnant female partner of child-bearing potential, advise use of highly effective contraception during treatment with VITRAKVI and for at least one month after the final dose.
Fertility: There are no clinical data on the effect of VITRAKVI on fertility. Non-clinical fertility studies with larotrectinib have not been conducted; however, changes to the female reproductive organs in rats were observed in a repeated-dose toxicity study. Lower fertility was noted in juvenile rats at high dose (see Pharmacology: Toxicology: Non-Clinical Toxicology under Actions).
Excipients with known effects (oral solution only): Each ml of VITRAKVI oral solution contains 2 mg of sodium benzoate. Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).
Driving and Operating Machinery: Neurologic adverse events and fatigue have very commonly been reported in patients receiving VITRAKVI and may influence the patient's ability to drive and use machines. Caution patients and caretakers about driving and operating potentially hazardous machinery, until they are reasonably certain VITRAKVI therapy does not affect them adversely (see Neurologic/Psychiatric as previously mentioned).
Use in Pregnancy: See Pregnant Women under Use in Pregnancy & Lactation.
Use in Lactation: See Breast-feeding under Use in Pregnancy & Lactation.
Use in Children: Among the 279 patients who received VITRAKVI, 92 (33%) were pediatric. Of these 92 patients, 36% were < 2 years (n=33), 41% were 2 years to < 12 years (n=38), and 23% were 12 years to < 18 years (n=21). The median duration of exposure was 7.4 months (range: 0.36 to 38.6 months). Treatment-emergent adverse events of Grade 3 or 4 severity occurring more frequently in pediatric patients compared to adult patients included increased weight (2% versus 0%) and neutropenia (9% versus 0%). Two pediatric patients discontinued VITRAKVI due to an adverse reaction Grade 3 ALT increased and neutrophil count decreased (see Clinical Trial Adverse Reactions: Clinical Trial Adverse Reactions (Pediatrics) under Adverse Reactions).
Based on a population pharmacokinetic analysis, in pediatric patients from 1 to 3 months of age, the drug exposure was 3-fold higher than in adults when using recommended doses. The clinical relevance is unknown (see Pharmacology: Pharmacokinetics under Actions).
Use in the Elderly: Among the 279 patients who received VITRAKVI, 54 (19%) patients were ≥ 65 years of age and 13 (5%) patients were ≥ 75 years of age. Clinical studies of VITRAKVI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects (see Clinical Trial Adverse Reactions: Clinical Trial Adverse Reactions (Geriatrics) under Adverse Reactions).

Pregnant Women: There are no clinical data on the use of VITRAKVI in pregnant women. In embryo-fetal development studies where pregnant rats and rabbits were dosed with larotrectinib during the period of organogenesis, malformations were observed at maternal exposures that were approximately 9- and 0.6-times, respectively, those observed at the clinical dose of 100 mg twice daily (see Pharmacology: Toxicology: Non-Clinical Toxicology under Actions). Larotrectinib crosses the placenta in animals.
Based on its mechanism of action and non-clinical data, there may be risk of fetal harm when larotrectinib is administered to a pregnant woman (see Pharmacology: Mechanism of Action under Actions). Advise pregnant women of the potential risk to a fetus.
Breast-feeding: There are no data on the presence of larotrectinib in human milk, the effects of larotrectinib on the breastfed child, or the effects of larotrectinib on milk production. Because of the unknown risk of larotrectinib in nursing infants, advise a nursing woman to discontinue breastfeeding during treatment with VITRAKVI and for 1 week following the final dose.

Adverse Reaction Overview: The safety of VITRAKVI was evaluated in 279 patients. Overall, 99% of patients experienced at least one TEAE. The most commonly reported TEAEs (≥ 20%), in order of decreasing frequency, were fatigue, cough, ALT increased, constipation, diarrhea, dizziness, anemia, AST increased, vomiting, nausea, and pyrexia.
The most common serious adverse events (≥ 2%) regardless of attribution included pneumonia, pyrexia, abdominal pain, diarrhea, and dyspnea.
Grade 3 or 4 TEAEs occurred in 53% of patients. Grade 4 events included sepsis, neutrophil count decreased, lymphocyte count decreased, ALT increased, hyponatremia, and hypoglycemia (1% for each). Grade 3 events included anemia (9%), weight increased (4%), hypophosphatemia (3%), fatigue (3%), ALT increased (3%), neutrophil count decreased (6%), dyspnea (3%), lymphocyte count decreased (4%), pneumonia (3%) and hypokalemia (3%).
Dose modification (interruption or reduction) of VITRAKVI dosage due to a TEAE occurred in 41% of patients. The most common TEAEs (≥ 3%) leading to dose modification were ALT increased (5%), AST increased (5%), and neutrophil count decreased (4%). The majority of adverse events leading to dose modification occurred in the first three months of treatment.
Permanent discontinuation of VITRAKVI for treatment emergent adverse events occurred in 9% of patients. The TEAEs that led to discontinuation of VITRAKVI and occurred in more than one patient were dehydration, malignant neoplasm progression, increased ALT, and increased AST.
Clinical Trial Adverse Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The safety of VITRAKVI was evaluated in 279 patients (overall safety population) who received at least one dose of VITRAKVI in one adult dose-finding trial [Study 1 (LOXO-TRK-14001) (n=75)], one single arm trial [Study 2 (NAVIGATE) (n=116)], and one pediatric trial [Study 3 (SCOUT) (n=88)]. The median time on treatment was 6.8 months (range: 0.03 month to 51.6 months). One hundred fifty (54%) patients were exposed to VITRAKVI for ≥ 6 months and 83 (30%) patients were exposed for ≥ 1 year. The majority of patients had an unresectable or metastatic solid tumour, including metastatic (72%) and locally advanced (18%) disease extent at enrollment.
Overall, patients had a median age of 46 years (range: 0.1 year to 84 years) with 33% of patients being pediatric patients. Forty-eight percent of patients were males and 74% were white.
The majority (86%) of adult patients (18 years and older) received 100 mg VITRAKVI taken twice daily as their starting dose. Three pediatric dose levels were evaluated with 85% of pediatric patients having received a starting dose of 100 mg/m² (with a maximum of 100 mg) taken twice daily. The dose ranged from 50 mg daily to 200 mg twice daily in adults and 9.6 mg/m² twice daily to 120 mg/m² twice daily in pediatric patients. (See Table 8.)

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Additional Information in Selected Adverse Reactions: Neurologic/Psychiatric events: In the overall safety database (n=279), neurologic/psychiatric TEAEs of any grade were reported in 63% of patients. Neurologic/psychiatric adverse events occurring in > 5% of patients included dizziness (26%), headache (15%), mood disorders (14%), cognitive impairment (11%), sleep disorders (10%), gait disturbance (6%), paresthesia (6%), dysgeusia (6%), and peripheral sensory neuropathy (5%). Mood disorders is collectively made up of the adverse events anxiety (5%), depression (4%), agitation (3%), irritability (3%), depressed mood (< 1%), and euphoric mood (< 1%). Cognitive impairment is collectively made up of the adverse events memory impairment (4%), confusional state (3%), disturbance in attention (3%), delirium (2%), cognitive disorder (1%), aphasia (1%), hallucination (2%), mental status change (1%), amnesia (< 1%), and mental impairment (< 1%). Sleep disorders is collectively made up of the adverse events insomnia (7%), somnolence (3%), and sleep disorder (< 1%). Grade 3 and Grade 4 neurologic/psychiatric events were reported in 11% and < 2% of patients, respectively. Events led to dose modification (interruption or reduction) in 30 (11%) patients.
Transaminase Elevations: In the overall safety database (n=279), TEAEs of ALT increased occurred in 28% of patients, and AST increased occurred in 25% of patients. The maximum grade transaminase elevations observed were Grade 4 ALT increased in 2 patients (1%), Grade 4 AST increased in 1 patient (< 1%), Grade 3 ALT increased in 7 (3%) patients and Grade 3 AST increased in 6 (2%) patients. The incidence of transaminase elevations was higher in pediatric compared with adult patients (see Clinical Trial Adverse Reactions (Pediatrics) as follows).
ALT and AST increases leading to study drug interruption or dose modifications occurred in 14 (5%) patients and 13 (5%) patients, respectively. Increased transaminases led to permanent discontinuation of VITRAKVI in 2% of patients.
Clinical Trial Adverse Reactions (Geriatrics): Of 279 patients in the overall safety population who received VITRAKVI, 54 (19%) patients were ≥ 65 years of age and 13 (5%) patients were ≥ 75 years of age. The safety profile in elderly patients (≥ 65 years) was generally consistent with that seen in adult patients < 65 years of age. The TEAEs that were more frequent in patients ≥ 65 years of age included fatigue, anemia, dizziness, fall, gait disturbance, and hyponatremia.
Clinical Trial Adverse Reactions (Pediatrics): Of 279 patients treated with VITRAKVI, 92 (33%) patients were pediatrics, including 33 infants and toddlers aged up to 23 months, 38 children aged 2 to 11 years, and 21 adolescents aged 12 to < 18 years. The safety profile in the pediatric population was generally consistent in the types of reported adverse events to those observed in the adult population. A majority of adverse events were Grade 1 or 2 in severity and were resolved without VITRAKVI dose modification or discontinuation. The TEAEs that were more frequent in pediatric patients compared with adult patients regardless of attribution (≥ 10% difference) included vomiting (42% versus 17% in adults); transaminase elevations (ALT 37% versus 24% and AST 32% versus 22%); neutrophil count decreased (29% versus 5%); diarrhea (34% versus 22%); pyrexia (43% versus 13%); platelet count decreased (13% versus 3%); upper respiratory tract infection (23% versus 8%); leukocyte count decreased (20% versus 7%); nasopharyngitis (16% versus 6%); otitis media (13% versus 1%) and rhinitis (14% versus 1%). Treatment-emergent adverse events reported in the infant and toddler subgroup (n=33) at a higher incidence than in the other pediatric subgroups included vomiting (n=19); cough (n=15); diarrhea (n=19); pyrexia (n=26); ALT increased (n=15); neutrophil count decreased (n=15); and anemia (n=10).
Abnormal Laboratory Findings (Hematologic, Clinical Chemistry and other Quantitative Data): Clinically relevant laboratory abnormalities are shown in Table 9. (See Table 9.)

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Drug Interactions Overview: Larotrectinib is a substrate of cytochrome P450 (CYP) 3A, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Coadministration of VITRAKVI with strong CYP3A inhibitors, P-gp and BCRP inhibitors may increase larotrectinib plasma concentrations.
Coadministration of VITRAKVI with strong CYP3A and P-gp inducers may decrease larotrectinib plasma concentrations.
In vitro, larotrectinib is not a substrate for the transporters OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3.
In vitro studies indicate that larotrectinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. In vitro, larotrectinib is a metabolism-dependent irreversible inhibitor of CYP3A4/5 (contributing to weak inhibition clinically) (see Drug-Drug Interactions as follows).
In vitro studies indicate that larotrectinib induces CYP2B6, but does not induce CYP1A2.
In vitro studies indicate that larotrectinib does not inhibit the transporters BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations.
Drug-Drug Interactions: See Table 10.

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Effects of Other Agents on Larotrectinib: P-gp and BCRP Inhibitors: Clinical data in healthy adult subjects indicate that coadministration of a single 100 mg VITRAKVI dose with a single dose of rifampin (a P-gp and BCRP inhibitor) increased larotrectinib C_max and AUC by 1.8-fold and 1.7-fold, respectively.
Gastric pH-elevating Agents: Larotrectinib has pH-dependent solubility. In vitro studies show that in liquid volumes relevant to the gastrointestinal tract (GI) larotrectinib at the recommended dose is fully soluble over entire pH range of the GI tract. Therefore, larotrectinib is unlikely to be affected by pH-modifying agents.
Drug-Food Interactions: Larotrectinib may be administered with or without food (see Pharmacology: Pharmacokinetics: Absorption under Actions). Avoid grapefruit or grapefruit juice as these may also increase plasma concentrations of larotrectinib.
Drug-Herb Interactions: Avoid Hypericum perforatum (a CYP3A4 inducer), also known as St. John's wort, as it may decrease plasma concentrations of larotrectinib.

Oral solution: Discard 30 days after first opening.

Targeted Cancer Therapy

L01EX12 - larotrectinib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.

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