Summary of Product Characteristics (SmPC) - Vitrakvi 25 mg hard capsules

1 NAME OF THE MEDICINAL PRODUCT

VITRAKVI 25 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains larotrectinib sulfate equivalent to 25 mg of larotrectinib.
For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Hard capsule (capsule).
White opaque hard gelatine capsule, size 2 (18 mm long x 6 mm wide), with blue
printing of BAYER-cross and “25 mg” on body of capsule.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

VITRAKVI as monotherapy is indicated for the treatment of adult and paediatric patients with solid tumours that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion,

who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and
who have no satisfactory treatment options (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Treatment with VITRAKVI should be initiated by physicians experienced in the

administration of anticancer therapies.

The presence of an NTRK gene fusion in a tumour specimen should be confirmed by

a validated test prior to initiation of treatment with VITRAKVI.

Posology

Adults

The recommended dose in adults is 100 mg larotrectinib twice daily, until diseas

progression or until unacceptable toxicity occurs.

Paediatric population

Dosing in paediatric patients is based on body surface area (BSA). The recommended

dose in paediatric patients is 100 mg/m²larotrectinib twice daily with a maximum of

100 mg per dose until disease progression or until unacceptable toxicity occurs.

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 t

make up for vomiting.

Dose modification

For all Grade 2 adverse reactions, continued dosing may be appropriate,

though close monitoring to ensure no worsening of the toxicity is advised.

Patients with Grade 2 ALT and/or AST increases, should be followed with

serial laboratory evaluations every one to two weeks after the observation of

Grade 2 toxicity until resolved to establish whether a dose interruption or reduction is required.

For Grade 3 or 4 adverse reactions:

VITRAKVI should be withheld until the adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dose modification if resolution occurs within 4 weeks.
VITRAKVI should be permanently discontinued if an adverse reaction does not resolve within 4 weeks.

The recommended dose modifications for VITRAKVI for adverse reactions are provided in Table 1.

Table 1: Recommended dose modifications for VITRAKVI for adverse reactions

Dose modification	Adult and paediatric patients with body surface area of at least 1.0 m²	Paediatric patients with body surface area less than 1.0 m²
First	75 mg twice daily	75 mg/m²twice daily
Second	50 mg twice daily	50 mg/m²twice daily
Third	100 mg once daily	25 mg/m²twice daily^a

^aPaediatric patients on 25 mg/m²twice daily should remain on this dose even if body surface area becomes greater 1.0 m²during the treatment. Maximum dose should be 25 mg twice daily at the third dose modification.

VITRAKVI should be permanently discontinued in patients who are unable to tolerate VITRAKVI after three dose modifications.

Special populations

Elderly

No dose adjustment is recommended in elderly patients (see section 5.2).

Hepatic impairment

The starting dose of VITRAKVI should be reduced 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 hepatic impairment (Child-Pugh A) (see

section 5.2).

Renal impairment

No dose adjustment is required for patients with renal impairment (see section 5.2).

Co-administration with strong CYP3A4 inhibitors

If co-administration with a strong CYP3A4 inhibitor is necessary, the VITRAKVI dose

should be reduced by 50%. After the inhibitor has been discontinued for 3 to 5

elimination half-lives, VITRAKVI should be resumed at the dose taken prior to

initiating the CYP3A4 inhibitor (see section 4.5).

Method of administration

VITRAKVI is for oral use.

VITRAKVI is available as a capsule or oral solution with equivalent oral

bioavailability and may be used interchangeably.

The patient should be advised to swallow the capsule whole with a glass of water.

Due to the bitter taste, the capsule should not be opened, chewed or crushed.

The capsules can be taken with or without food but should not be taken with

grapefruit or grapefruit juice.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1.

4.4 Special warnings and precautions for use

Efficacy across tumour types

The benefit of VITRAKVI has been established in single arm trials encompassing a

relatively small sample of patients whose tumours exhibit NTRK gene fusions.

Favourable effects of VITRAKVI have been shown on the basis of overall response

rate and response duration in a limited number of tumour types. The effect may b

quantitatively different depending on tumour type, as well as on concomitant geneti

alterations (see section 5.1). For these reasons, VITRAKVI should only be used i

there are no treatment options for which clinical benefit has been established, or

where such treatment options have been exhausted (i.e., no satisfactory treatment

options).

Neurologic reactions

Neurologic reactions including dizziness, gait disturbance and paraesthesia were

reported in patients receiving larotrectinib (see section 4.8). For the majority o

neurologic reactions, onset occurred within the first three months of treatment.

Withholding, reducing, or discontinuing VITRAKVI dosing should be considered

depending on the severity and persistence of these symptoms (see section 4.2).

Transaminase elevations

ALT and AST increase were reported in patients receiving larotrectinib (see

section 4.8). The majority of ALT and AST increases occurred in the first 3 months

of treatment.

Liver function including ALT and AST assessments should be monitored before the

first dose and monthly for the first 3 months of treatment, then periodically durin

treatment, with more frequent testing in patients who develop transaminase

elevations. Withhold or permanently discontinue VITRAKVI based on the severity. If

withheld, the VITRAKVI dose should be modified when resumed (see section 4.2).

Co-administration with CYP3A4/P-gp inducers

Avoid co-administration of strong or moderate CYP3A4/P-gp inducers with

VITRAKVI due to a risk of decreased exposure (see section 4.5).

Contraception in female and male

Women of childbearing potential must use highly effective contraception while taking

VITRAKVI and for at least one month after stopping treatment (see sections 4.5 and

4.6).

Males of reproductive potential with a non-pregnant woman partner of child bearing

potential should be advised to use highly effective contraception during treatment

with VITRAKVI and for at least one month after the final dose (see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other agents on larotrectinib

Effect of CYP3A, P-gp and BCRP inhibitors on larotrectinib

Larotrectinib is a substrate of cytochrome P450 (CYP) 3A, P-glycoprotein (P-gp) and breast

cancer resistance protein (BCRP). Co-administration of VITRAKVI with strong CYP3A

inhibitors, P-gp and BCRP inhibitors (e.g. atazanavir, clarithromycin, indinavir, itraconazole,

ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin,

voriconazole or grapefruit) may increase larotrectinib plasma concentrations (see section 4.2).

Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg

VITRAKVI dose with itraconazole (a strong CYP3A inhibitor and P-gp and BCRP inhibitor)

200 mg once daily for 7 days increased larotrectinib C_maxand AUC by 2.8-fold and 4.3-fold,

respectively.

Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg

VITRAKVI dose with a single dose of 600 mg rifampin (a P-gp and BCRP inhibitor)

increased larotrectinib C_maxand AUC by 1.8-fold and 1.7-fold, respectively.

Effect of CYP3A and P-gp inducers on larotrectinib

Co-administration of VITRAKVI with strong or moderate CYP3A and P-gp inducers (e.g.

carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, or St. John’s Wort) may

decrease larotrectinib plasma concentrations and should be avoided (see section 4.4).

Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg

VITRAKVI dose with rifampin (a strong CYP3A and P-gp inducer) 600 mg once daily for

11 days decreased larotrectinib C_maxand AUC by 71% and 81%, respectively. No clinical data

is available on the effect of a moderate inducer, but a decrease in larotrectinib exposure is

expected.

Effects of larotrectinib on other agents

Effect of larotrectinib on CYP3A substrates

Clinical data in healthy adult subjects indicate that co-administration of VITRAKVI (100 mg

twice daily for 10 days) increased the C_maxand AUC of oral midazolam 1.7-fold compared to

midazolam alone, suggesting that larotrectinib is a weak inhibitor of CYP3A.

Exercise caution with concomitant use of CYP3A substrates with narrow therapeutic range

(e.g. alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine,

sirolimus, or tacrolimus) in patients taking VITRAKVI. If concomitant use of these CYP3A

substrates with narrow therapeutic range is required in patients taking VITRAKVI, dose

reductions of the CYP3A substrates may be required due to adverse reactions.

Effect of larotrectinib on CYP2B6 substrates

In vitro studies indicate that larotrectinib induces CYP2B6. Co-administration of larotrectinib

with CYP2B6 substrates (e.g. bupropion, efavirenz) may decrease their exposure.

Effect of larotrectinib on other transporter substrates

In vitro studies indicate that larotrectinib is an inhibitor of OATP1B1.

No clinical studies

have been performed to investigate interactions with OATP1B1 substrates. Therefore, it

cannot be excluded whether co-administration of larotrectinib with OATP1B1 substrates (e.g.

valsartan, statins) may increase their exposure.

Effect of larotrectinib on substrates of PXR regulated enzymes
In vitro studies indicate that larotrectinib is a weak inducer of PXR regulated enzymes (e.g.
CYP2C family and UGT). Co-administration of larotrectinib with CYP2C8, CYP2C9 or
CYP2C19 substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease
their exposure.
Hormonal contraceptives
It is currently unknown whether larotrectinib may reduce the effectiveness of systemically
acting hormonal contraceptives. Therefore, women using systemically acting hormonal
contraceptives should be advised to add a barrier method.

4.6 Fertility, Pregnancy and lactation

Women of childbearing potential / Contraception in males and females

Based on the mechanism of action, foetal harm cannot be excluded when administering larotrectinib to a pregnant woman. Women of childbearing potential should have a pregnancy test prior to starting treatment with VITRAKVI.

Women of reproductive potential should be advised to use highly effective contraception during treatment with VITRAKVI and for at least one month after the final dose. As it is currently unknown whether larotrectinib may reduce the effectiveness of systemically acting hormonal contraceptives, women using systemically acting hormonal contraceptives should be advised to add a barrier method.

Males of reproductive potential with a non-pregnant woman partner of child-bearing potential should be advised to use highly effective contraception during treatment with VITRAKVI and for at least one month after the final dose.

Pregnancy

There are no data from the use of larotrectinib in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of VITRAKVI during pregnancy.

Breast-feeding

It is unknown whether larotrectinib/metabolites are excreted in human milk.

A risk to the newborns/infants cannot be excluded.

Breast-feeding should be discontinued during treatment with VITRAKVI and for 3 days following the final dose.

Fertility

There are no clinical data on the effect of larotrectinib on fertility. No relevant effects on fertility were observed in repeat-dose toxicity studies (see section 5.3).

4.7 Effects on ability to drive and use machines

VITRAKVI has a moderate influence on the ability to drive and use machines.
Dizziness and fatigue have been reported in patients receiving larotrectinib, mostly
Grade 1 and 2 during the first 3 months of treatment. This may influence the ability to
drive and use machines during this time period. Patients should be advised not to
drive and use machines, until they are reasonably certain VITRAKVI therapy does
not affect them adversely (see section 4.4).

4.8 Undesirable effects

Summary of the safety profile
The most common adverse drug reactions (≥ 20%) of VITRAKVI in order of decreasing
frequency were increased ALT (31%), increased AST (29%), vomiting (29%), constipation
(28%), fatigue (26%), nausea (25%), anaemia (24%), dizziness (23%), and myalgia (20%).
The majority of adverse reactions were Grade 1 or 2. Grade 4 was the highest reported grade
for adverse reactions neutrophil count decreased (2%), ALT increased (1%), AST increased,
leucocyte count decreased and blood alkaline phosphatase increased (each in < 1%). The
highest reported grade was Grade 3 for adverse reactions anaemia, weight increased, fatigue,
dizziness, paraesthesia, muscular weakness, nausea, myalgia, gait disturbance, and vomiting.
All the reported Grade 3 adverse reactions occurred in less than 5% of patients, with the
exception of anaemia (7%).
Permanent discontinuation of VITRAKVI for treatment emergent adverse reactions occurred
in 2% of patients (one case each of ALT increased, AST increased, gait disturbance,
neutrophil count decreased). The majority of adverse reactions leading to dose reduction
occurred in the first three months of treatment.

Tabulated list of adverse reactions
The safety of VITRAKVI was evaluated in 248 patients with TRK fusion-positive cancer in
one of three on-going clinical trials, Studies 1, 2 (“NAVIGATE”), and 3 (“SCOUT”). The
safety population characteristics were comprised of patients with a median age of 32.5 years
(range: 0.1, 84) with 39% of patients being paediatric patients. Median time on treatment for
the overall safety population (n=248) was 12.5 months (range: 0.03, 57.5).
The adverse drug reactions reported in patients (n=248) treated with VITRAKVI are shown in
Table 2 and Table 3.
The adverse drug reactions are classified according to the System Organ Class.
Frequency groups are defined by the following convention: very common (≥ 1/10); common
(≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very
rare (< 1/10,000), and not known (cannot be estimated from available data).
Within each frequency group, undesirable effects are presented in order of decreasing
seriousness.
Table 2: Adverse drug reactions reported in TRK fusion-positive cancer patients treated
with VITRAKVI at recommended dose (overall safety population, n=248)

System organ class

Frequency

All grades

Grades 3 and 4

Blood and lymphatic

Very common

Anaemia

system disorders

Neutrophil count decreased

(Neutropenia)

Leukocyte count decreased

(Leukopenia)

Common

Anaemia

Neutrophil coun

decreased (Neutropenia)^a

Uncommon

Leukocyte count

decreased (Leukopenia)

Nervous system

Very common

Dizzines

disorders

Common

Gait disturbance Paraesthesia

Dizziness

Paraesthesia Gait disturbance

Gastrointestinal

Very common

Nausea

disorders

Constipation

Vomiting

Common

Dysgeusia^b

Vomiting

Uncommon

Nausea

Musculoskeletal and

Very common

Myalgia

connective tissue

Common

Muscular weakness

Myalgia

disorders

Muscular weakness

General disorders and

Very common

Fatigue

administration site

Common

Fatigue

conditions

Very common

Alanine aminotransferase

(ALT) increased

Aspartate aminotransferase

(AST) increased

Weight increased

(Abnormal weight gain)

Common

Blood alkaline phosphatase

Alanine aminotransferase

increased

(ALT) increased^a

Aspartate

aminotransferase (AST)

increased^a

Weight increased

(Abnormal weight gain)

Investigations

Uncommon

Blood alkaline

phosphatase increased

^aGrade 4 reactions were reported

^bADR dysgeusia includes the preferred terms “dysgeusia” and “taste disorder”

Table 3: Adverse drug reactions reported in TRK fusion-positive paediatric cancer

patients treated with VITRAKVI at recommended dose (n=98); all Grades

System organ class

Frequency

Infants and

Children

Adolescents

Paediat

ric

toddlers

patients

(n=35)

(n=45)^b

(n=18)

(n=98)

Blood and

Very

Anaemia

Neutrophil count

Anaemia

lymphatic

common

Neutrophil count

decreased

Neutrophil count

system

decreased

(Neutropenia)

decrease

disorders

(Neutropenia)

Leukocyte count

(Neutropenia

)

Leukocyte count

decreased

Leukocyte count

decreased

(Leukopenia)

decreased

(Leukopenia)

Common

Anaemia

Very

Dizziness

common

Nervous system
disorders

Common

Dizziness

Paraesthesia

Dizzines

Paraesthesia

Gait disturbance

Very

Nausea

common

Constipation

Vomiting

Constipation

Vomiting

Vomitin

Gastrointestinal
disorders

Common

Dysgeusia

Constipation

Dysgeus

Musculoskeletal

Common

Myalgia

and connectiv

Muscular

tissue disorders

weakness

General

Very

Fatigue

disorders and

common

administration

site conditions

Investigations

Very

Alanine

common

aminotransferase

(ALT) increased

Aspartate

aminotransferase

(AST) increased

Weight increased

Blood alkaline

Weight increased

(Abnormal

phosphatase

(Abnormal

weight gain)

increased

weight gain)

Blood alkaline

Weight increased

Blood alkaline

phosphatase

(Abnormal

phosphatase

increased

weight gain)

increased

Common

Blood alkaline

phosphatase

increased

^aInfant/toddlers (28 days to 23 months): four Grade 4 Neutrophil count decreased (Neutropenia) reactions and one
Blood alkaline phosphatase increased reported. Grade 3 reactions included ten cases of Neutrophil count
decreased (Neutropenia), three cases of Anaemia, three cases of Weight increased (Abnormal weight gain), and
one case each of ALT increased and Vomiting.
^bChildren (2 to 11 years): One Grade 4 Leucocytes count decreased reported. Six reported Grade 3 cases of
Neutrophil count decreased (Neutropenia), two cases of Anaemia, and one case each of ALT increased, AST
increased, Gait disturbance, Vomiting, Paraesthesia and Myalgia.
^cAdolescents (12 to <18 years): no Grades 3 and 4 reactions were reported.
Description of selected adverse reactions
Neurologic reactions
In the overall safety database (n=248), the maximum grade neurologic adverse reactio	n
observed was Grade 3 which was observed in five (3%) patients and included dizziness (tw		o
patients, 1%), paraesthesia (three patients, 1%), and gait disturbance (one patient, <1%). Th		e
overall incidence was 23% for dizziness, 7% for paraesthesia and 4% for gait disturbance.
Neurologic reactions leading to dose modification included dizziness (1%) and paraesthesia
(1%). One patient permanently discontinued the treatment due to Grade 3 gait disturbance.		In
all cases except of one, patients with evidence of anti-tumour activity who required a dose
reduction were able to continue dosing at a reduced dose and/or schedule (see section 4.4).
Transaminase elevations
In the overall safety database (n=248), the maximum grade transaminase elevation observe		d
was Grade 4 ALT increase in 3 patients (1%) and AST increase in 2 patients (1%). Grade 3
ALT and AST increases in 11 (4%) and 10 (4%) of patients, respectively. Majority of Grade 3
elevations were transient appearing in the first three months of treatment and resolving to
Grade 1 by months 3-4. Grade 2 ALT and AST increases were observed in 18 (7%) and 20
(8%) of patients, respectively, and Grade 1 ALT and AST increases were observed in 122
(49%) and 115 (46%) of patients, respectively.
ALT and AST increases leading to dose modifications occurred in 13 (5%) patients and 12
(5%) patients, respectively (see section 4.4). No patient permanently discontinued the
treatment due to Grade 3-4 ALT and AST increases.

Additional information on special populations
Paediatric patients
Of the 248 patients treated with VITRAKVI, 98 (40%) patients were from 28 days to 18 years
of age. Of these 98 patients, 36% were 28 days to < 2 years (n=35), 46% were 2 years to
< 12 years (n=45), and 18% were 12 years to < 18 years (n=18). The safety profile in the
paediatric population (< 18 years) was consistent in types of reported adverse reactions to
those observed in the adult population. The majority of adverse reactions were Grade 1 or 2 in
severity (see Table 3) and were resolved without VITRAKVI dose modification or
discontinuation. The adverse reactions of vomiting (48% versus 16% in adults), leucocyte
count decrease (17% versus 9% in adults), neutrophil count decrease (31% versus 6% in
adults), and blood alkaline phosphatase increased (13% versus 5% in adults) were more
frequent in paediatric patients compared to adults.
Elderly
Of the 248 patients in the overall safety population who received VITRAKVI, 40 (16%)
patients were 65 years or older and 11 (4%) patients were 75 years or older. The safety profile
in elderly patients (≥ 65 years) is consistent with that seen in younger patients. The adverse
reaction dizziness (48% versus 35% in all adults), anaemia (38% versus 24% in all adults),
muscular weakness (23% versus 12% in all adults), and gait disturbance (10% versus 5% in
all adults) were more frequent in patients of 65 years or older.
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is limited experience of overdose with VITRAKVI. Symptoms of overdose are
not established. In the event of overdose, physicians should follow general supportive
measures and treat symptomatically.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic
agents, protein kinase inhibitors, ATC code:	L01EX12	.

Mechanism of action

Larotrectinib is an adenosine triphosphate (ATP)-competitive and selective tropomyosin

receptor kinase (TRK) inhibitor that was rationally designed to avoid activity with off-targ

kinases. The target for larotrectinib is the TRK family of proteins inclusive of TRKA, TRK

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 IC

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-tumo

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 gen

NTRK1, NTRK2, and NTRK3 lead to the formation of oncogenic TRK fusion proteins. The

resultant novel chimeric oncogenic proteins are aberrantly expressed, driving constitutive

kinase activity subsequently activating downstream cell signalling pathways involved in ce

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 n

known if the presence of a concomitant oncogenic driver in addition to an NTRK gene fusi

affects the efficacy of TRK inhibition. The measured impact of any concomitant genomic

alterations on larotrectinib efficacy is provided below (see clinical efficacy).

Pharmacodynamic effect

Cardiac electrophysiology

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 (C_max) similar to that observed wit

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

C_max, 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.

Clinical efficacy

Overview of studies

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 requir

to have TRK fusion-positive cancer. The pooled primary analysis set of efficacy includes

192 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 2020. These patients were required to have receive

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, o

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, 33 patients with primary CNS tumours and measurable disease at baseline were
treated in Study 2 (“NAVIGATE”) and in Study 3 (“SCOUT”). Thirty-two of the 33 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 196 patients, polymerase chain reaction (PCR) used in 12 patients,
fluorescence in situ hybridization (FISH) used in 14 patients, and Nanostring, Sanger
sequencing, and Chromosome Microarray in 1 patient each.

Table 4: Clinical studies contributing to the efficacy analyses in solid and primary CNS

tumours

Study name, design and patient

Dose and

Tumour types included in

population

formulation

efficacy analysi

Study 1

Doses up to 200 mg

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)

NCT02122913

once or twice daily

(25 mg, 100 mg

•

Phase 1, open-label, dose escalation

capsules or 20 mg/mL

and expansion study; expansion

oral solution)

phase required tumours with an

NTRK gene fusion

•

Adult patients (≥ 18 years) with

advanced solid tumours with an

NTRK gene fusion

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

Thyroid (n=24)^b

118

(25 mg, 100 mg

Soft tissue sarcoma (n=20)

capsules or 20 mg/mL

Salivary gland (n=19)

oral solution)

NSCLC (n=13)^b,

Primary CNS (n=9)

Colorectal (n=8)

Melanoma (n=6)

Breast, secretory (n=4)

Breast, non-secretory (n=3)

GIST (n=2)^a

Biliary (n=2)

Pancreas (n=2

)

SCLC (n=1)^{b, d}

Appendix (n=1)

Bone sarcoma (n=1)

Hepatic^e(n=1)

Prostate (n=1)

Cervix (n=1)

Study 3 “SCOUT”

Doses up to

Infantile fibrosarcoma (n=40)

Soft tissue sarcoma (n=26) Primary CNS (n=24) Congenital mesoblastic nephroma (n=2)

Bone sarcoma (n=1) Melanoma (n=1)

NCT02637687

100 mg/m²twice daily

(25 mg, 100 mg

•

Phase 1/2 multinational, open-label,

capsules or 20 mg/mL

dose escalation and expansion study

;

oral solution)

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

Total number of patients (n)^*

225

* consist of 192 patients with IRC tumour response assessment and 33 patients with primary CNS tumours (including astrocytoma, glioblastoma, glioma, glioneuron

tumours, neuronal and mixed neuronal-glial tumours, and primitive neuro-ectodermal tumour, not specified) with investigator tumour response assessment

^aGIST: gastrointestinal stromal tumour

^bbrain metastases observed in 7 NSCLC, 4 thyroid, 2 melanoma, 1 SCLC, and 1 breast (non-secretory) patient

^cNSCLC: non-small cell lung cance

^dSCLC: small cell lung cancer

^ehepatocellular carcinoma

Baseline characteristics for the pooled 192 patients with solid tumours with an NTRK gene

fusion were as follows: median age 38 years (range 0.1-84 years); 37% < 18 years of age, and

64% ≥ 18 years; 72% white and 51% male; and ECOG PS 0-1 (87%), 2 (11%), or 3 (2%

Ninety-two percent of patients had received prior treatment for their cancer, defined as

surgery, radiotherapy, or systemic therapy. Of these, 73% had received prior systemic therapy

with a median of 1 prior systemic treatment regimen. Twenty-seven percent of all patients had

received no prior systemic therapy. Of those 192 patients the most common tumour typ

represented were soft tissue sarcoma (25%), infantile fibrosarcoma (21%), thyroid canc

(15%), salivary gland tumour (11%), and lung cancer (8%).

Baseline characteristics for the 33 patients with primary CNS tumours with an NTRK ge

fusion assessed by investigator were as follows: median age 9 years (range 1.3-79 years

);

26 patients < 18 years of age, and 7 patients ≥ 18 years, and 24 patients white and 17 patients

male; and ECOG PS 0-1 (28 patients), or 2 (4 patients). Thirty-two (97%) 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.

Efficacy results

The pooled efficacy results for overall response rate, duration of response and time to fi

rst

response, in the primary analysis population (n=192) and with post-hoc addition of primary

CNS tumours (n=33) resulting in the pooled population (n=225), 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

tumours including

primary CNS tumours

(n=192)^a

(n=225)^{a, b}

Overall response rate (ORR) ^{% (n)}

72% (139)

65% (147)

[95% CI]

[65, 79]

[59, 72]

Complete response (CR)

23% (44)

21% (47)

Pathological complete response^c

7% (13)

6% (13)

Partial response (PR)

43% (82)

39% (87)^d

Time to first response (median, months)

1.84

[range]

[0.89, 16.20]

Duration of response (median, months)

34.5

[range]

[1.6+, 58.5+]

% with duration ≥ 12 months

79%

% with duration ≥ 24 months

66%

+ denotes ongoing

^aIndependent review committee analysis by RECIST v1.1 for solid tumours except primary CNS tumours

(192 patients).

^bInvestigator assessment using either RANO or RECIST v1.1 criteria for primary CNS tumours (33 patien

ts).

^cA 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 patholog

evaluation. The pre-surgical best response for these patients was reclassified pathological CR after surger

following RECIST v.1.1.

^dAn 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			Patient s (n=225 )	ORR^a		DOR
				%	95% CI	months		Range (months)
				%	95% CI	≥ 12	≥ 24	Range (months)
Soft tissue sarcoma			48	69%	54%, 81%	78%	63%	1.9+, 54.7
Infantile fibrosarcoma			40	93%	80%, 98%	80%	62%	1.6+, 38.5+
Primary CNS			33	24%	11%, 42%	75%	NR	3.8, 22.0+
Thyroid			28	64%	44%, 81%	94%	76%	2.8+, 39.2+
Salivary gland			22	86%	65%, 97%	89%	84%	7.4, 58.5+
Lung			15	87%	60%, 98%	64%	64%	1.9+, 45.1+
Colon			8	38%	9%, 76%	67%	67%	5.6, 27.3
Melanoma			7	43%	10%, 82%	50%	NR	1.9+, 23.2+
Breast			7
Secretory^b			4	75%	19%, 99%	0%	0%	9.4+, 11.1
Non-secretory^c			3	67%	9%, 99%	100%	NR	15.2, 23.0+
Gastrointestinal stromal tumour			4	100%	40%, 100%	75%	38%	9.5, 31.1+
Bone sarcoma			2	50%	1%, 99%	0%	0%	9.5
Cholangiocarcinom a^d			2	0%	NA	NA	NA	NA
Pancreas			2	0%	NA	NA	NA	NA
Congenital mesoblastic nephroma			2	100%	16%, 100%	100%	100%	6.4+, 24.2+
	Unknown primary	1	100%	3%, 100%	0%	0%	7.4
	cancer	1	100%	3%, 100%	0%	0%	7.4
Appendix			1	0%	NA	NA	NA	NA
Hepatic^d			1	0%	NA	NA	NA	NA
Prostate			1	0%	NA	NA	NA	NA
Cervix			1	0%	NA	NA	NA	NA

DOR: duration of response

NA: not applicable due to small numbers or lack of response NR: not reached

+ denotes ongoing response

^{a evaluated}per independent review committee analysis by RECIST v1.1 for all tumour types except ^{patients with a primary}
	^{CNS tumour who were evaluated per}investigator assessment using either RANO or RECIST v1.1 criteria
^bwith 2 complete, 1 partial response
^cwith 1 complete, 1 partial response

^done patient who is not evaluable

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=122), the ORR was 64%. In the paediatric sub-population
(n=70), the ORR was 87%.

In 198 patients with wide molecular characterisation before larotrectinib treatment, the ORR
in 95 patients who had other genomic alterations in addition to NTRK gene fusion was 55%,
and in 103 patients without other genomic alterations ORR was 70%.
Pooled primary analysis set
The pooled primary analysis set consisted of 192 patients and did not include primary CNS
tumours. Median time on treatment before disease progression was 34.5 months (range: 1.6 t				o
58.5 months) based on July 2020 cut-off. Seventy-nine percent of patients had received
VITRAKVI for 12 months or more and 66% 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 is 34.5 months (range: 1.6+ to
58.5+), an estimated 79% [95% CI: 72, 86] of responses lasted 12 months or longer, and 66%
[95% CI: 57, 73] of responses lasted 24 months or longer. Eighty-nine percent (89%) [95%
CI: 85, 94] of patients treated were alive one year after the start of therapy and 82% [95% CI				:
76, 88] 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 67% [95% CI: 60, 74] after 1 year and 57% [95% CI: 49, 65] after 2 years.
The median change in tumour size in the pooled primary analysis set was a decrease of 70%.
Patients with primary CNS tumours
At the time of data cut-off, of the 33 patients with primary CNS tumours confirmed response
was observed in 8 patients (24%) with 3 of the 33 patients (9%) being complete responders
and 5 patients (15%) being partial responders. In 2 additional patients (6%) a not yet
confirmed partial response was observed. Further 20 patients (61%) had stable disease. Three
patients (9%) had progressive disease.		At the time of data cut-off, time on treatment	ranged
from 1.2 to 31.3 months	and was ongoing in 18 out of 33 patients, with one of these patients
receiving post-progression treatment.
Conditional approval
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 Medicines and Healthcare products Regulatory Agency (MHRA) will review new
information on this medicinal product at least every year and this SmPC will be updated as
necessary.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic
agents, protein kinase inhibitors, ATC code:	L01EX12	.