Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Bayer AG, 51368 Leverkusen, Germany
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents, protein kinase inhibitors
ATC code: L01XE53
Larotrectinib is an adenosine triphosphate (ATP)-competitive and selective tropomyosin receptor kinase (TRK) inhibitor that was rationally designed to avoid activity with off-target kinases. The target for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC50 values between 5-11 nM. The only other kinase activity occurred at 100-fold higher concentrations. In in vitro and in vivo tumour models, larotrectinib demonstrated anti-tumour activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.
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-positive cancer.
Acquired resistance mutations after progression on TRK inhibitors have been observed. 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.
The molecular causes for primary resistance to larotrectinib are not known. It is therefore not known if the presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacy of TRK inhibition. The measured impact of any concomitant genomic alterations on larotrectinib efficacy is provided below (see clinical efficacy).
In 36 healthy adult subjects receiving single doses ranging from 100 mg to 900 mg, VITRAKVI did not prolong the QT interval to any clinically relevant extent. The 200 mg dose corresponds to a peak exposure (Cmax) similar to that observed with larotrectinib 100 mg BID at steady state. A shortening of QTcF was observed with VITRAKVI dosing, with a maximum mean effect observed between 3 and 24 hours after Cmax, with a geometric mean decrease in QTcF from baseline of -13.2 msec (range -10 to -15.6 msec). Clinical relevance of this finding has not been established.
The efficacy and safety of VITRAKVI were studied in three multicentre, open-label, single-arm clinical studies in adult and paediatric cancer patients (Table 4). The studies are still ongoing. Patients with and without documented NTRK gene fusion were allowed to participate in Study 1 and Study 3 (“SCOUT”). Patients enrolled to Study 2 (“NAVIGATE”) were required to have TRK fusion-positive cancer. The pooled primary analysis set of efficacy includes 164 patients with TRK fusion-positive cancer enrolled across the three studies that had measurable disease assessed by RECIST v1.1, a non-CNS primary tumour and received at least one dose of larotrectinib as of July 2019. These patients were required to have received prior standard therapy appropriate for their tumour type and stage of disease or who, in the opinion of the investigator, would have had to undergo radical surgery (such as limb amputation, facial resection, or paralysis causing procedure), or were unlikely to tolerate, or derive clinically meaningful benefit from available standard of care therapies in the advanced disease setting. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC). In addition, 24 patients with primary CNS tumours and measurable disease at baseline were treated in Study 2 (“NAVIGATE”) and in Study 3 (“SCOUT”). All primary CNS tumour patients had received prior cancer treatment (surgery, radiotherapy and/or previous systemic therapy). Tumour responses were assessed by the investigator using RANO or RECIST v1.1 criteria.
Identification of NTRK gene fusions relied upon the molecular test methods: next generation sequencing (NGS) used in 166 patients, reverse transcription-polymerase chain reaction (RT-PCR) used in 9 patients, fluorescence in situ hybridization (FISH) used in 12 patients, and Nanostring in 1 patient as routinely performed at certified laboratories.
Table 4. Clinical studies contributing to the efficacy analyses in solid and primary CNS tumours:
| Study name, design and patient population | Dose and formulation | Tumour types included in efficacy analysis | n |
|---|---|---|---|
| Study 1 NCT02122913 • Phase 1, open-label, dose escalation and expansion study; expansion phase required tumours with an NTRK gene fusion • Adult patients (≥18 years) with advanced solid tumours with an NTRK gene fusion | Doses up to 200 mg once or twice daily (25 mg, 100 mg capsules or 20 mg/mL oral solution) | Thyroid (n=4) Salivary gland (n=3) GIST (n=2)a Soft tissue sarcoma (n=2) NSCLC (n=1)b,c Unknown primary cancer (n=1) | 13 |
| Study 2 «NAVIGATE» NCT02576431 •Phase 2 multinational, open label, tumour “basket” study • Adult and paediatric patients ≥12 years with advanced solid tumours with an NTRK gene fusion | 100 mg twice daily (25 mg, 100 mg capsules or 20 mg/mL oral solution) | Thyroid (n=23)b Salivary gland (n=18) Soft tissue sarcoma (n=16) NSCLC (n=11)b,c Colorectal (n=8) Primary CNS (n=7) Melanoma (n=6) Breast, non-secretory (n=3) Breast, secretory (n=2) GIST (n=2)a Biliary (n=2) Pancreas (n=2) SCLC (n=1)b,d Appendix (n=1) Bone sarcoma (n=1) Hepatice (n=1) Prostate (n=1) | 105 |
| Study 3 “SCOUT” NCT02637687 • Phase ½ multinational, open-label, dose escalation and expansion study; Phase 2 expansion cohort required advanced solid tumours with an NTRK gene fusion, including locally advanced infantile fibrosarcoma • Paediatric patients ≥1 month to 21 years with advanced cancer or with primary CNS tumours | Doses up to 100 mg/m² twice daily (25 mg, 100 mg capsules or 20 mg/mL oral solution) | Infantile fibrosarcoma (n=32) Soft tissue sarcoma (n=18) Primary CNS (n=17) Bone sarcoma (n=1) Congenital mesoblastic nephroma (n=1) Melanoma (n=1) | 70 |
| Total number of patients (n)* | 188 | ||
* consist of 164 patients with IRC tumour response assessment and 24 patients with primary CNS tumours (including astrocytoma, glioblastoma, glioma, glioneuronal tumours, neuronal and mixed neuronal-glial tumours, and primitive neuro-ectodermal tumour) with investigator tumour response assessment
a GIST: gastrointestinal stromal tumour
b brain metastases observed in 6 NSCLC, 4 thyroid, 2 melanoma, 1 SCLC, and 1 breast (non-secretory) patient
c NSCLC: non-small cell lung cancer
d SCLC: small cell lung cancer
e hepatocellular carcinoma
Baseline characteristics for the pooled 164 patients with solid tumours with an NTRK gene fusion were as follows: median age 42 years (range 0.1-84 years); 34% <18 years of age, and 66% ≥18 years; 77% white and 49% male; and ECOG PS 0-1 (86%), 2 (12%), or 3 (2%). 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 systemic treatment regimen. Twenty-two percent of all patients had received no prior systemic therapy. Of those 164 patients the most common tumour types represented were soft tissue sarcoma (22%), infantile fibrosarcoma (20%), thyroid cancer (16%), salivary gland tumour (13%), and lung cancer (8%).
Baseline characteristics for the 24 patients with primary CNS tumours 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 patients had received prior treatment for their cancer, defined as surgery, radiotherapy, or systemic therapy. There was a median of 1 prior systemic treatment regimen received.
The pooled efficacy results for overall response rate, duration of response and time to first response, in the primary analysis population (n=164) and with post-hoc addition of primary CNS tumours (n=24) resulting in the pooled population (n=188), are presented in Table 5 and Table 6.
Table 5. Pooled efficacy results in solid tumours including and excluding primary CNS tumours:
| Efficacy parameter | Analysis in solid tumours excluding primary CNS tumours (n=164)a | Analysis in solid tumours including primary CNS tumours (n=188)a,b |
|---|---|---|
| Overall response rate (ORR) % (n) [95% CI] | 73% (119) [65, 79] | 66% (124) [59, 73] |
| Complete response (CR) | 19% (31) | 18% (33) |
| Pathological complete responsec | 5% (8) | 4% (8) |
| Partial response (PR) | 49% (80) | 44% (83)d |
| Time to first response (median, months) [range] | 1.84 [0.92, 14.55] | 1.84 [0.92, 14.55] |
| Duration of response (median, months) [range] % with duration ≥12 months % with duration ≥24 months | NR [0.0+, 50.6+] 76% 67% | NR [0.0+, 50.6+] 74% 65% |
NR: not reached
+ denotes ongoing
a Independent review committee analysis by RECIST v1.1 for solid tumours except primary CNS tumours (164 patients).
b Investigator assessment using either RANO or RECIST v1.1 criteria for primary CNS tumours (24 patients).
c A pathological CR was a CR achieved by patients who were treated with larotrectinib and subsequently underwent surgical resection with no viable tumour cells and negative margins on post-surgical pathology evaluation. The pre-surgical best response for these patients was reclassified pathological CR after surgery following RECIST v.1.1. d An additional 1% (2 patients with primary CNS tumours) had partial responses, pending confirmation.
Table 6. Overall response rate and duration of response by tumour type:
| Tumour type | Patients (n=188) | ORR | DOR | |||
|---|---|---|---|---|---|---|
| % | 95% CI | months | Range (months) | |||
| ≥12 | ≥24 | |||||
| Soft tissue sarcomaa | 36 | 81% | 64%, 92% | 69% | 69% | 0.0+, 50.6+ |
| Infantile fibrosarcomaa | 32 | 97% | 84%, 100% | 72% | 63% | 1.6+, 28.6+ |
| Thyroida | 27 | 56% | 35%, 75% | 93% | 58% | 3.7+, 32.9 |
| Primary CNSb | 24 | 21% | 7%, 42% | NR | NR | 1.7+, 10,1+ |
| Salivary glanda | 21 | 86% | 64%, 97% | 94% | 87% | 1,9+, 44,7+ |
| Lunga | 13 | 77% | 46%, 95% | 62% | 62% | 3,7, 36,8+ |
| Colona | 8 | 38% | 9%, 76% | 50% | NR | 5.4+, 20.7+ |
| Melanomaa | 7 | 43% | 10%, 82% | 50% | NR | 1.9+, 23.2+ |
| Breasta,c | 5 | 60% | 15%, 95% | NR | NR | 5.6+, 9.2+ |
| Gastrointestinal stromal tumoura | 4 | 100% | 40%, 100% | 75% | 38% | 9.5, 31.1+ |
| Bone sarcomaa | 2 | 50% | 1%, 99% | 0% | 0% | 9.5 |
| Cholangiocarcinomaa | 2 | SD, NE | NA | NA | NA | NA |
| Pancreasa | 2 | SD, SD | NA | NA | NA | NA |
| Congenital mesoblastic nephromaa | 1 | 100% | 3%, 100% | 100% | Δ/επετ. | 20.8+ |
| Unknown primary cancer | 1 | 100% | 3%, 100% | 0% | 0% | 7.4 |
| Appendixa | 1 | SD | NA | NA | NA | NA |
| Hepatic | 1 | NE | NA | NA | NA | NA |
| Prostate | 1 | PD | NA | NA | NA | NA |
DOR: duration of response
NA: not applicable due to small numbers or lack of response
NE: not evaluable
NR: not reached
PD: progressive disease
SD: stable disease
+ denotes ongoing response
a independent review committee analysis by RECIST v1.1
b patients with a primary CNS tumour were evaluated per investigator assessment using either RANO or RECIST v1.1 criteria
c with 3 patients having non-secretory (1 complete, 1 partial responder and 1 progressive disease) and 2 patients having secretory breast cancer (1 partial and 1 stable disease)
Due to the rarity of TRK fusion-positive cancer, patients were studied across multiple tumour types with a limited number of patients in some tumour types, causing uncertainty in the ORR estimate per tumour type. The ORR in the total population may not reflect the expected response in a specific tumour type.
In the adult sub-population (n=109), the ORR was 63%. In the paediatric sub-population (n=55), the ORR was 91%.
In 165 patients with wide molecular characterisation before larotrectinib treatment, the ORR in 79 patients who had other genomic alterations in addition to NTRK gene fusion was 58%, and in 86 patients without other genomic alterations ORR was 74%.
The pooled primary analysis set consisted of 164 patients and did not include primary CNS tumours. Median time on treatment before disease progression was 14.7 months (range: 0.10 to 51.6 months) based on July 2019 cut-off. Forty-four percent of patients had received VITRAKVI for 12 months or more and 21% had received VITRAKVI 24 months or more, with follow-up ongoing at the time of the analysis. At the time of analysis, the median duration of response had not been reached, an estimated 76% [95% CI: 67, 85] of responses lasted 12 months or longer, and 67% [95% CI: 55, 78] of responses lasted 24 months or longer. Ninety percent (90%) [95% CI: 85, 95] of patients treated were alive one year after the start of therapy and 82% [95% CI: 75, 90] after two years with the median for overall survival not yet being reached. Median progression free survival was 33.4 months at the time of the analysis, with a progression free survival rate of 66% [95% CI: 58, 74] after 1 year and 58% [95% CI: 48, 67] after 2 years. The median change in tumour size in the pooled primary analysis set was a decrease of 68%.
At the time of data cut-off, of the 24 patients with primary CNS tumours confirmed response was observed in 5 patients (21%) with 2 of the 24 patients (8%) being complete responders and 3 patients (12.5%) being partial responders. In 2 additional patients (8%) a not yet confirmed partial response was observed. Further 15 patients (63%) had stable disease. Two patients (8%) had progressive disease. At the time of data cut-off, time on treatment ranged from 1.2 to 21.4 months and was ongoing in 15 out of 24 patients, with one of these patients receiving post-progression treatment.
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
In cancer patients given VITRAKVI capsules, peak plasma levels (Cmax) of larotrectinib were achieved at approximately 1 hour after dosing. Half-life (t½) is approximately 3 hours and steady state is reached within 8 days with a systemic accumulation of 1.6 fold. At the recommended dose of 100 mg taken twice daily, steady-state arithmetic mean (± standard deviation) Cmax and daily AUC in adults were 914 ± 445 ng/mL and 5410 ± 3813 ng*h/mL, respectively. In vitro studies indicate that larotrectinib is not a substrate for either OATP1B1 or OATP1B3.
In vitro studies indicate that larotrectinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations and is unlikely to affect clearance of substrates of these CYPs.
In vitro studies indicate that larotrectinib does not inhibit the transporters BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations and is unlikely to affect clearance of substrates of these transporters.
VITRAKVI is available as a capsule and oral solution formulation. The mean absolute bioavailability of larotrectinib was 34% (range: 32% to 37%) following a single 100 mg oral dose. In healthy adult subjects, the AUC of larotrectinib in the oral solution formulation was similar to the capsule, with Cmax 36% higher with the oral solution formulation. Larotrectinib Cmax 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 Cmax and AUC after overnight fasting.
Larotrectinib has pH-dependent solubility. In vitro studies show that in liquid volumes relevant to the gastrointestinal (GI) tract larotrectinib is fully soluble over entire pH range of the GI tract. Therefore, larotrectinib is unlikely to be affected by pH-modifying agents.
The mean volume of distribution of larotrectinib in healthy adult subjects was 48 L following intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose. 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.
Larotrectinib was metabolised predominantly by CYP3A4/5 in vitro. Following oral administration of a single 100 mg dose of radiolabeled larotrectinib to healthy adult subjects, unchanged larotrectinib (19%) and an O-glucuronide that is formed following loss of the hydroxypyrrolidine-urea moiety (26%) were the major circulating radioactive drug components.
The half-life of larotrectinib in plasma of cancer patients given 100 mg twice daily of VITRAKVI was approximately 3 hours. Mean clearance (CL) of larotrectinib was approximately 34 L/h following intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose of VITRAKVI.
Following oral administration of 100 mg radiolabeled larotrectinib to healthy adult subjects, 58% of the administered radioactivity was recovered in faeces and 39% was recovered in urine and when an IV microtracer dose was given in conjunction with a 100 mg oral dose of larotrectinib, 35% of the administered radioactivity was recovered in faeces and 53% was recovered in urine. The fraction excreted as unchanged drug in urine was 29% following IV microtracer dose, indicating that direct renal excretion accounted for 29% of total clearance.
The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of larotrectinib after a single dose in healthy adult subjects were dose proportional up to 400 mg and slightly greater than proportional at doses of 600 to 900 mg.
Based on population pharmacokinetic analyses exposure (Cmax and AUC) in paediatric 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 Cmax in paediatric patients (≥3 months to <12 years of age) was higher than in adults, but the AUC was similar to that in adults. For paediatric patients older than 12 years of age, the recommended dose is likely to give similar Cmax and AUC as observed in adults. Data defining exposure in small children (1 month to <6 years of age) at the recommended dose is limited (n=33).
There are limited data in elderly. PK data is available only in 2 patients over 65 years.
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 AUC0-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. Cmax was observed to increase slightly by 1.1, 1.1 and 1.5-fold respectively.
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 Cmax and AUC0-inf, of 1.25 and 1.46-fold respectively was observed in renally impaired subjects versus those with normal renal function.
Gender did not appear to influence larotrectinib pharmacokinetics to a clinically significant extent. There was not enough data to investigate the potential influence of race on the systemic exposure of larotrectinib.
Systemic toxicity was assessed in studies with daily oral administration up to 3 months in rats and monkeys. Dose limiting skin lesions were only seen in rats and were primarily responsible for mortality and morbidity. Skin lesions were not seen in monkeys. Clinical signs of gastrointestinal toxicity were dose limiting in monkeys. In rats, severe toxicity (STD10) was observed at doses corresponding to 1- to 2-times the human AUC at the recommended clinical dose. No relevant systemic toxicity was observed in monkeys at doses which correspond to >10-times the human AUC at the recommended clinical dose.
Larotrectinib was not teratogenic and embryotoxic when dosed daily during the period of organogenesis to pregnant rats and rabbits at maternotoxic doses, i.e. corresponding to 32-times (rats) and 16-times (rabbits) the human AUC at the recommended clinical dose. Larotrectinib crosses the placenta in both species.
Fertility studies with larotrectinib have not been conducted. In 3-months toxicity studies, larotrectinib had no histological effect on the male reproductive organs in rats and monkeys at the highest tested doses corresponding to approximately 7-times (male rats) and 10-times (male monkeys) the human AUC at the recommended clinical dose. In addition, larotrectinib had no effect on spermatogenesis in rats.
In a 1-month repeat-dose study in rats, fewer corpora lutea, increased incidence of anestrus and decreased uterine weight with uterine atrophy were observed and these effects were reversible. No effects on female reproductive organs were seen in the 3-months toxicity studies in rats and monkeys at doses corresponding to approximately 3-times (female rats) and 17-times (female monkeys) the human AUC at the recommended clinical dose. Larotrectinib was administered to juvenile rats from postnatal day (PND) 7 to 70. Pre-weaning mortality (before PND 21) was observed at the high dose level corresponding to 2.5- to 4-times the AUC at the recommended dose. Growth and nervous system effects were seen at 0.5- to 4-times the AUC at the recommended dose. Body weight gain was decreased in pre-weaning male and female pups, with a post-weaning increase in females at the end of exposure whereas reduced body weight gain was seen in males also post-weaning without recovery. The male growth reduction was associated with delayed puberty. Nervous system effects (i.e. altered hindlimb functionality and, likely, increases in eyelid closure) demonstrated partial recovery. A decrease in pregnancy rate was also reported despite normal mating at the high-dose level.
Carcinogenicity studies have not been performed with larotrectinib. 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 at the maximum tolerated dose of 500 mg/kg.
The safety pharmacology of larotrectinib was evaluated in several in vitro and in vivo studies that assessed effects on the CV, CNS, respiratory, and GI systems in various species. Larotrectinib had no adverse effect on haemodynamic parameters and ECG intervals in telemetered monkeys at exposures (Cmax) which are approximately 6-fold the human therapeutic exposures. Larotrectinib had no neurobehavioural findings in adult animals (rats, mice, cynomolgus monkeys) at exposure (Cmax) at least 7-fold higher than the human exposure. Larotrectinib had no effect on respiratory function in rats; at exposures (Cmax) at least 8-times the human therapeutic exposure. In rats, larotrectinib accelerated intestinal transit and increased gastric secretion and acidity.
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