AYVAKYT 200mg tablets medication leaflet

AYVAKYT 25 mg film-coated tablets

AYVAKYT 50 mg film-coated tablets

AYVAKYT 100 mg film-coated tablets

AYVAKYT 200 mg film-coated tablets

AYVAKYT 300 mg film-coated tablets

AYVAKYT 25 mg film-coated tablets

Each film-coated tablet contains 25 mg of avapritinib.

AYVAKYT 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of avapritinib.

AYVAKYT 100 mg film-coated tablets

Each film-coated tablet contains 100 mg of avapritinib.

AYVAKYT 200 mg film-coated tablets

Each film-coated tablet contains 200 mg of avapritinib.

AYVAKYT 300 mg film-coated tablets

Each film-coated tablet contains 300 mg of avapritinib.

For the full list of excipients, see section 6.1.

Film-coated tablet.

AYVAKYT 25 mg film-coated tablets

Round, white film-coated tablet of 5 mm diameter with debossed text. One side reads “BLU” and theother side reads “25”.

AYVAKYT 50 mg film-coated tablets

Round, white film-coated tablet of 6 mm diameter with debossed text. One side reads “BLU” and theother side reads “50”.

AYVAKYT 100 mg film-coated tablets

Round, white film-coated tablet of 9 mm diameter, printed with blue ink “BLU” on one side and“100” on the other.

AYVAKYT 200 mg film-coated tablets

Oval, white film-coated tablet of 16 mm in length and 8 mm in width, printed with blue ink “BLU” onone side and “200” on the other.

AYVAKYT 300 mg film-coated tablets

Oval, white film-coated tablet of 18 mm in length and 9 mm in width, printed with blue ink “BLU” onone side and “300” on the other.

Unresectable or metastatic gastrointestinal stromal tumour (GIST)

AYVAKYT is indicated as monotherapy for the treatment of adult patients with unresectable ormetastatic gastrointestinal stromal tumours (GIST) harbouring the platelet-derived growth factorreceptor alpha (PDGFRA) D842V mutation.

Advanced systemic mastocytosis (AdvSM)

AYVAKYT is indicated as monotherapy for the treatment of adult patients with aggressive systemicmastocytosis (ASM), systemic mastocytosis with an associated haematological neoplasm (SM-AHN)or mast cell leukaemia (MCL), after at least one systemic therapy.

Indolent systemic mastocytosis (ISM)

AYVAKYT is indicated for the treatment of adult patients with indolent systemic mastocytosis (ISM)with moderate to severe symptoms inadequately controlled on symptomatic treatment (seesection 5.1).

Therapy should be initiated by a healthcare professional experienced in the diagnosis and treatment ofconditions for which avapritinib is indicated (see section 4.1).

Unresectable or metastatic GIST

For GIST, the recommended starting dose of avapritinib is 300 mg orally once daily, on an emptystomach (see Method of administration). Treatment should be continued until disease progression orunacceptable toxicity occurs.

Patient selection for treatment of unresectable or metastatic GIST harbouring the PDGFRA D842Vmutation should be based on a validated test method.

Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided. Ifconcomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinibmust be reduced from 300 mg to 100 mg orally once daily (see section 4.5).

Advanced systemic mastocytosis

For AdvSM, the recommended starting dose of avapritinib is 200 mg orally once daily, on an emptystomach (see Method of administration). This once daily 200 mg dose is also the maximumrecommended dose that must not be exceeded by patients with AdvSM. Treatment should becontinued until disease progression or unacceptable toxicity occurs.

Treatment with avapritinib is not recommended in patients with platelet count < 50 x 109/L (see

Table 2 and section 4.4).

Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided. Ifconcomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinibmust be reduced from 200 mg to 50 mg orally once daily (see section 4.5).

Indolent systemic mastocytosis

For ISM, the recommended dose of avapritinib is 25 mg orally once daily, on an empty stomach (see

Method of administration). This once daily 25 mg dose is also the maximum recommended dose thatmust not be exceeded in patients with ISM. Treatment of ISM should be continued until diseaseprogression or unacceptable toxicity occurs.

Concomitant use of avapritinib with strong or moderate CYP3A inhibitors must be avoided (seesection 4.5).

Dose modifications for adverse reactions

Irrespective of indication, interruption of treatment with or without dose reduction may be consideredto manage adverse reactions based on severity and clinical presentation.

The dose should be adjusted as recommended, based on safety and tolerability.

Dose reductions and modifications for adverse reactions are recommended in patients with GIST,

AdvSM or ISM and are provided in Tables 1 and 2.

Table 1. Recommended dose reductions for AYVAKYT for adverse reactions

Dose GIST (starting dose AdvSM (starting dose ISM (starting dosereduction 300 mg) 200 mg) 25 mg)*

First 200 mg once daily 100 mg once daily 25 mg once every other day

Second 100 mg once daily 50 mg once daily -

Third - 25 mg once daily -

* ISM patients requiring dose reduction below 25 mg once every other day must discontinue treatment.

Table 2. Recommended dose modifications for AYVAKYT for adverse reactions

Adverse reaction Severity* Dose modification

Patients with GIST, AdvSM or ISM

Intracranial haemorrhage All Grades Permanently discontinue(see section 4.4) AYVAKYT.

Cognitive effects** Grade 1 Continue at the same dose,(see section 4.4) reduce dose or interrupt untilimprovement to baseline orresolution. Resume at the samedose or at a reduced dose.

Grade 2 or Grade 3 Interrupt therapy untilimproved to baseline, Grade 1,or resolution. Resume at thesame dose or at a reduced dose.

Grade 4 Permanently discontinue

AYVAKYT.

Other adverse reactions Grade 3 or Grade 4 Interrupt therapy until less than(also see section 4.4 and or equal to Grade 2. Resume atsection 4.8) the same dose or at a reduceddose, if warranted.

Patients with AdvSM

Thrombocytopenia Less than 50 x 109/L Interrupt dosing until platelet(see section 4.4) count is ≥ 50 x 109/L, thenresume at reduced dose (see

Table 1). If platelet count doesnot recover above 50 x 109/L,consider platelet support.

* The severity of adverse reactions graded by the National Cancer Institute (NCI) Common

Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0

** Adverse reactions with impact on Activities of Daily Living (ADLs) for Grade 2 or higher adversereactions

If a dose of avapritinib is missed, the patient should make up for the missed dose unless the nextscheduled dose is within 8 hours (see Method of administration). If the dose has not been taken at least8 hours prior to the next dose, then that dose must be omitted and the patient should resume treatmentwith the next scheduled dose.

If vomiting occurs after taking a dose of avapritinib, the patient must not take an additional dose butcontinue with the next scheduled dose.

No dose adjustment is recommended for patients aged 65 years and above (see section 5.2). Clinicaldata in ISM patients aged 75 years and above is limited (see section 5.1).

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin withinupper limit of normal [ULN] and aspartate aminotransferase (AST) > ULN or total bilirubin greaterthan 1 to 1.5 times ULN and any AST) and moderate hepatic impairment (total bilirubin >1.5 to3.0 times ULN and any AST). A modified starting dose of avapritinib is recommended for patientswith severe hepatic impairment (Child-Pugh Class C). The starting dose of avapritinib should bereduced from 300 mg to 200 mg orally once daily for patients with GIST, from 200 mg to 100 mgorally once daily for patients with AdvSM, and from 25 mg orally once daily to 25 mg orally everyother day for patients with ISM (see section 5.2).

No dose adjustment is recommended for patients with mild and moderate renal impairment (creatinineclearance [CLcr] 30-89 mL/min estimated by Cockcroft-Gault). Avapritinib has not been studied inpatients with severe renal impairment (CLcr 15-29 mL/min) or end-stage renal disease (CLcr<15 mL/min), therefore its use in patients with severe renal impairment or end-stage renal diseasecannot be recommended (see section 5.2).

The safety and efficacy of AYVAKYT in children aged 0 to 18 years have not yet been established.

No data are available.

AYVAKYT is for oral use.

The tablets must be taken on an empty stomach at least 1 hour before or at least 2 hours after a meal(see section 5.2).

Patients must swallow the tablets whole with a glass of water.

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

Haemorrhages

Avapritinib has been associated with an increased incidence of haemorrhagic adverse reactions,including serious and severe adverse reactions, like gastrointestinal haemorrhage and intracranialhaemorrhage, in patients with unresectable or metastatic GIST and AdvSM. Gastrointestinalhaemorrhagic adverse reactions were the most commonly reported haemorrhagic adverse reactionsduring avapritinib treatment of unresectable or metastatic GIST patients, while hepatic and tumourhaemorrhage also occurred in GIST patients (see section 4.8).

Routine surveillance of haemorrhagic adverse reactions in patients with GIST or AdvSM must includephysical examination. Complete blood counts, including platelets, and coagulation parameters must bemonitored in patients with GIST or AdvSM, particularly in patients with conditions predisposing tobleeding, and in those treated with anticoagulants (e.g. warfarin and phenprocoumon) or otherconcomitant medicinal products that increase the risk of bleeding.

Intracranial haemorrhages

Adverse reactions of intracranial haemorrhage occurred in GIST and AdvSM patients who receivedavapritinib.

Before initiating avapritinib at any dose the risk for intracranial haemorrhage should be carefullyconsidered in patients with potential increased risk including those with a history of vascularaneurysm, intracranial haemorrhage, cerebrovascular accident within the prior year, concomitant useof anticoagulants or thrombocytopenia.

Patients who experience clinically relevant neurological signs and symptoms (e.g. severe headache,vision problems, somnolence, and/or focal weakness) during treatment with avapritinib must interruptdosing of avapritinib and inform their healthcare professional immediately. Brain imaging bymagnetic resonance imaging (MRI) or computed tomography (CT) may be performed at the discretionof the physician based on severity and the clinical presentation.

For patients with observed intracranial haemorrhage during treatment with avapritinib in anyindication, regardless of severity grade, avapritinib must be permanently discontinued (seesection 4.2).

Unresectable or metastatic GIST

Serious adverse reactions of intracranial haemorrhage were reported in patients with unresectable ormetastatic GIST receiving avapritinib (see section 4.8). The exact mechanism is unknown.

There is no clinical study experience using avapritinib in patients with brain metastases.

Advanced systemic mastocytosis

Serious adverse reactions of intracranial haemorrhage were reported in patients with AdvSM receivingavapritinib (see section 4.8). The exact mechanism is unknown. The incidence of intracranialhaemorrhage was higher in patients with platelet counts <50 x 109/L and in patients with a startingdose of ≥300 mg.

Considering the above, a platelet count must be performed prior to initiating therapy. Avapritinib isnot recommended in patients with platelet counts <50 x 109/L. Following treatment initiation, plateletcounts must be performed every 2 weeks for the first 8 weeks regardless of baseline platelet count.

After 8 weeks of treatment, monitor platelet counts every 2 weeks (or more frequently as clinicallyindicated) if values are less than 75 x 109/L, every 4 weeks if values are between 75 and 100 x 109/L,and as clinically indicated if values are greater than 100 x 109/L.

Manage platelet counts of <50 x 109/L by temporarily interrupting avapritinib. Platelet support may benecessary, and the recommended dose modification in Table 2 must be followed (see section 4.2).

Thrombocytopenia was generally reversible by reducing or interrupting avapritinib in clinical studies.

The maximum dose for patients with AdvSM must not exceed 200 mg once daily.

Cognitive effects

Cognitive effects, such as memory impairment, cognitive disorder, confusional state, andencephalopathy, can occur in patients receiving avapritinib (see section 4.8). The mechanism of thecognitive effects is not known.

It is recommended that patients with GIST or AdvSM are clinically monitored for signs and symptomsof cognitive events such as new or increased forgetfulness, confusion, and/or difficulty with cognitivefunctioning. Patients with GIST or AdvSM must notify their healthcare professional immediately ifthey experience new or worsening cognitive symptoms.

For GIST or AdvSM patients with observed cognitive effects related to treatment with avapritinib, therecommended dose modification in Table 2 must be followed (see section 4.2). In clinical studiesconducted in patients with GIST and AdvSM, dose reductions or interruptions improved Grade ≥2cognitive effects compared to no action.

In patients with ISM, cognitive effects can be one of the disease symptoms. Patients with ISM mustnotify their healthcare professional if they experience new or worsening cognitive symptoms.

Fluid retention

Occurrences of fluid retention, including severe cases of localised oedema (facial, periorbital,peripheral oedema and/or pleural effusion) or generalised oedemas, have been reported with afrequency category of at least common in patients with unresectable or metastatic GIST takingavapritinib. Other localised oedemas (laryngeal oedema and/or pericardial effusion) have beenreported uncommonly (see section 4.8).

In patients with AdvSM, localised (facial, periorbital, peripheral, pulmonary oedema, pericardialand/or pleural effusion) or generalised oedema, and ascites have been observed with a frequencycategory of at least common (see section 4.8). Other localised oedemas (laryngeal oedema) have beenreported uncommonly.

Therefore, it is recommended that patients with GIST or AdvSM be evaluated for these adversereactions including regular assessment of weight and respiratory symptoms. An unexpected rapidweight gain or respiratory symptoms indicating fluid retention must be carefully investigated andappropriate supportive care and therapeutic measures, such as diuretics, should be undertaken. For

GIST or AdvSM patients presenting with ascites, it is recommended to evaluate the aetiology ofascites.

In patients with ISM, localised (peripheral, facial) oedemas have been reported with a frequencycategory of at least common (see section 4.8).

QT interval prolongation

Prolongation of QT interval has been observed in patients with unresectable or metastatic GIST and

AdvSM treated with avapritinib in clinical studies (see section 4.8 and 5.1). QT interval prolongationmay induce an increased risk of ventricular arrhythmias, including Torsade de pointes.

Avapritinib should be used with caution in GIST or AdvSM patients with known QT intervalprolongation or at risk of QT interval prolongation (e.g. due to concomitant medicinal products, pre-existing cardiac disease and/or electrolyte disturbances). Concomitant administration with strong ormoderate CYP3A4 inhibitors should be avoided due to the increased risk of adverse reactions,including QT prolongation and related arrhythmias (see section 4.5). If concomitant use of moderate

CYP3A4 inhibitors cannot be avoided, see section 4.2 for dose modification instructions.

In patients with GIST or AdvSM, interval assessments of QT by electrocardiogram (ECG) should beconsidered if avapritinib is taken concurrently with medicinal products that can prolong QT interval.

In patients with ISM, QT interval assessments by ECG should be considered, in particular in patientswith concurrent factors that could prolong QT (e.g. age, pre-existing heart rhythm disorders, etc.).

Diarrhoea, nausea and vomiting were the most commonly reported gastrointestinal adverse reactionsin patients with unresectable or metastatic GIST and AdvSM (see section 4.8). GIST or AdvSMpatients who present with diarrhoea, nausea and vomiting should be evaluated to exclude disease-related aetiologies. Supportive care for gastrointestinal adverse reactions requiring treatment mayinclude medicinal products with antiemetic, antidiarrheal, or antacid properties.

The hydration status of GIST or AdvSM patients experiencing gastrointestinal adverse reactions mustbe closely monitored and treated as per standard clinical practice.

Treatment with avapritinib in patients with unresectable or metastatic GIST and AdvSM is associatedwith anaemia, neutropenia and/or thrombocytopenia. Complete blood counts must be performed on aregular basis during the treatment with avapritinib in patients with GIST or AdvSM. See alsointracranial haemorrhages above in this section and in section 4.8.

Treatment with avapritinib is associated in patients with unresectable or metastatic GIST and AdvSMwith elevations in bilirubin and liver transaminases (see section 4.8). Liver function (transaminasesand bilirubin) should be monitored regularly in patients with GIST or AdvSM receiving avapritinib.

CYP3A4 inhibitors and inducers

Co-administration with strong or moderate CYP3A inhibitors should be avoided because it mayincrease the plasma concentration of avapritinib (see sections 4.2 and 4.5).

Co-administration with strong or moderate CYP3A inducers should be avoided because it maydecrease the plasma concentrations of avapritinib (see section 4.5).

Photosensitivity reaction

Exposure to direct sunlight must be avoided or minimised due to the risk of phototoxicity associatedwith avapritinib. Patients must be instructed to use measures such as protective clothing and sunscreenwith high sun protection factor (SPF).

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.

Active substances that may have an effect on avapritinib

Strong and moderate CYP3A inhibitors

Co-administration of avapritinib with a strong CYP3A inhibitor increased avapritinib plasmaconcentrations and may result in increased adverse reactions. Co-administration of itraconazole(200 mg twice daily on Day 1 followed by 200 mg once daily for 13 days) with a single 200 mg doseof avapritinib on Day 4 in healthy subjects increased avapritinib Cmax by 1.4-fold and AUC0-inf by4.2-fold, relative to a 200 mg dose of avapritinib administered alone.

Concomitant use of avapritinib with strong or moderate CYP3A inhibitors (such as antifungalsincluding ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such aserythromycin, clarithromycin and telithromycin; active substances to treat human immunodeficiencyvirus infections/acquired immunodeficiency syndrome (HIV/AIDS) such as cobicistat, indinavir,lopinavir, nelfinavir, ritonavir and saquinavir; as well as conivaptan for hyponatremia and boceprevirto treat hepatitis) including grapefruit or grapefruit juice should be avoided. If concomitant use with amoderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinib should be reduced from300 mg to 100 mg orally once daily for patients with GIST, and from 200 mg to 50 mg orally oncedaily for patients with AdvSM. For patients with ISM, concomitant use of avapritinib with strong ormoderate CYP3A inhibitors must be avoided (see sections 4.2 and 4.4).

Strong and moderate CYP3A inducers

Co-administration of avapritinib with a strong CYP3A inducer decreased avapritinib plasmaconcentrations and may result in decreased efficacy of avapritinib. Co-administration of rifampicin(600 mg once daily for 18 days) with a single 400 mg dose of avapritinib on Day 9 in healthy subjectsdecreased avapritinib Cmax by 74% and AUC0-inf by 92%, relative to a 400 mg dose of avapritinibadministered alone.

Co-administration of avapritinib with strong and moderate CYP3A inducers (e.g. dexamethasone,phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone, bosentan, efavirenz,etravirine, modafinil, dabrafenib, nafcillin or Hypericum perforatum, also known as St. John’s wort)should be avoided.

Effect of avapritinib on other active substances

In vitro studies demonstrated that avapritinib is a direct inhibitor of CYP3A and a time-dependentinhibitor of CYP3A. Therefore, avapritinib may have the potential to increase plasma concentrationsof co-administered medicinal products that are substrates of CYP3A.

In vitro studies indicated that avapritinib is an inducer of CYP3A. Therefore, avapritinib may have thepotential to decrease plasma concentrations of co-administered medicinal products that are substratesof CYP3A.

Caution must be exercised with co-administration of avapritinib with narrow therapeutic index

CYP3A substrates as their plasma concentrations may be altered.

Avapritinib is an inhibitor of P-gp, BCRP, MATE1, MATE2-K, and BSEP in vitro. Therefore,avapritinib has the potential to alter concentrations of co-administered substrates of these transporters.

Women of childbearing potential must be informed that avapritinib may cause foetal harm (seesection 5.3).

The pregnancy status of women of reproductive potential must be verified prior to initiating

AYVAKYT treatment.

Women of childbearing potential must use effective contraception during treatment and for 6 weeksafter the last dose of AYVAKYT. Males with female partners of childbearing potential must useeffective contraception during treatment and for 2 weeks after the last dose of AYVAKYT.

Patients must be advised to contact their healthcare professional immediately if they become pregnant,or if pregnancy is suspected, while taking AYVAKYT.

There are no data from the use of avapritinib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

AYVAKYT is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

If AYVAKYT is used during pregnancy or if the patient becomes pregnant while taking AYVAKYT,the patient must be advised of the potential risk to the foetus.

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

A risk to the newborns/infants cannot be excluded.

Breast-feeding must be discontinued during treatment with AYVAKYT and for 2 weeks following thefinal dose.

There are no data on the effect of AYVAKYT on human fertility. However, based on nonclinicalfindings in animals, male and female fertility may be compromised by treatment with avapritinib (seesection 5.3).

AYVAKYT may cause adverse reactions such as cognitive effects that may influence the ability todrive and use machines.

Patients should be made aware of the potential for adverse reactions that affect their ability toconcentrate and react. Patients who experience these adverse effects must take special care whendriving a car or operating machinery.

The safety database includes a total of 585 patients with GIST (all doses), of which 550 patientsreceived avapritinib at a starting dose of 300 mg or 400 mg; 193 patients enrolled in studies for

AdvSM (all doses), of which 126 patients received avapritinib at a starting dose of 200 mg, and246 patients with ISM (doses 25 mg - 100 mg), of which 141 patients received avapritinib at therecommended dose of 25 mg in Part 2, pivotal part of the PIONEER study (see section 5.1).

Unresectable or metastatic GIST

The most common adverse reactions of any grade during treatment with avapritinib at a starting doseof 300 mg or 400 mg were nausea (45%), fatigue (40%), anaemia (39%), periorbital oedema (33%),face oedema (27%), hyperbilirubinaemia (28%), diarrhoea (26%), vomiting (24%), oedema peripheral(23%), lacrimation increased (22%), decreased appetite (21%) and memory impairment (20%).

Serious adverse reactions occurred in 23% of patients receiving avapritinib. The most common seriousadverse reactions during treatment with avapritinib were anaemia (6%), and pleural effusion (1%).

The most common adverse reactions leading to permanent treatment discontinuation were fatigue,encephalopathy and intracranial haemorrhage (< 1% each). Adverse reactions leading to a dosereduction included anaemia, fatigue, neutrophil count decreased, blood bilirubin increased, memoryimpairment, cognitive disorder, periorbital oedema, nausea and face oedema.

Advanced systemic mastocytosis

The most common adverse reactions of any grade during treatment with avapritinib at a starting doseof 200 mg were periorbital oedema (38%), thrombocytopenia (37%), oedema peripheral (33%), andanaemia (22%).

Serious adverse reactions occurred in 12% of patients receiving avapritinib. The most common seriousadverse reactions during treatment with avapritinib were subdural haematoma (2%), anaemia (2%),and haemorrhage (2%).

In AdvSM patients treated at 200 mg, 7.1% had adverse reactions leading to permanent treatmentdiscontinuation. In two patients (1.6%), subdural haematoma occurred. Cognitive disorder, depressedmood, diarrhoea, disturbance in attention, haemoglobin decreased, hair colour changes, libidodecreased, nausea, neutropenia, premature menopause and thrombocytopenia occurred in one patient(0.8% each). Adverse reactions leading to a dose reduction included thrombocytopenia, neutropenia,periorbital oedema, cognitive disorder, oedema peripheral, platelet count decreased, neutrophil countdecreased, anaemia, asthenia, fatigue, arthralgia, blood alkaline phosphatase increased, blood bilirubinincreased, and white blood cell count decreased.

Indolent systemic mastocytosis

In Part 2 of PIONEER, the most common adverse reaction during treatment with avapritinib at therecommended dose of 25 mg was peripheral oedema (12%). Overall, the majority of oedema adversereactions reported were Grade 1 (94% for peripheral oedema, 90% for face oedema); none were

Grade ≥3 or led to treatment discontinuation.

No serious adverse reactions or fatal adverse reactions occurred in 141 patients receiving avapritinib atthe recommended dose of 25 mg in Part 2 of PIONEER. Treatment discontinuation due to adversereactions occurred in <1% of patients receiving avapritinib.

Adverse reactions that were reported in clinical studies in ≥1% of patients with GIST are listed below(Table 3) except for adverse reactions mentioned in the section 4.4 which are included regardless offrequency, according to the MedDRA System Organ Class and frequency. For patients with AdvSM,adverse reactions that were reported in clinical studies in ≥3% of patients are listed below (Table 4).

For patients with ISM, adverse reactions reported in Part 2 of the PIONEER study in ≥5% of patientsare listed in Table 5.

Frequencies are defined using 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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Unresectable or metastatic GIST

Table 3. Adverse reactions reported in clinical studies in patients with unresectable ormetastatic GIST treated with avapritinib

System Organ

Class /frequency Adverse reactions All grades Grades ≥3% %category

Common Conjunctivitis 2.0 -

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon Tumour haemorrhage 0.2 0.2

Anaemia 39.6 20.4

Very common White blood cell count decreased 14.0 3.1

Neutrophil count decreased 15.8 8.9

Common Thrombocytopenia 8.4 0.9

Lymphocyte count decreased 4.7 2.2

Very common Decreased appetite 21.1 0.5

Hypophosphataemia 8.9 2.5

Hypokalaemia 6.0 0.9

Hypomagnesaemia 3.8 0.4

Common Hyponatraemia 1.3 0.7

Dehydration 1.8 0.5

Hypoalbuminaemia 2.4 -

Hypocalcaemia 2.2 0.4

Confusional state 4.7 0.5

Common Depression 4.2 0.4

Anxiety 1.8 -

Insomnia 3.8 -

Memory impairment 22.7 0.9

Very common Cognitive disorder 11.8 0.9

Dizziness 10.5 0.2

Taste effect 12.7 -

Intracranial haemorrhage1 1.6 1.1

Mental impairment2 5.6 0.7

Neuropathy peripheral 8.5 0.4

Somnolence 1.8 -

Common Aphasia 1.8 -

Hypokinesia 1.3 0.2

Headache 8.0 0.2

Balance disorder 1.6 -

Speech disorder 4.5 -

Tremor 2.2 0.2

Uncommon Encephalopathy 0.9 0.5

Very common Lacrimation increased 22.2 -

Ocular haemorrhage3 1.1 -

Common Vision blurred 2.9 -

Conjunctival haemorrhage 2.4 -

Photophobia 1.6 -

Ear and labyrinth disorders

Common Vertigo 2.4 -

System Organ

Class/Adverse reactions All grades Grades ≥3frequency % %category

Uncommon Pericardial effusion 0.9 0.2

Common Hypertension 3.3 1.1

Pleural effusion 6.0 0.9

Common Dyspnoea 6.0 0.7

Nasal congestion 1.5 -

Cough 2.2 -

Abdominal pain 10.9 1.1

Vomiting 24.2 0.7

Very common Diarrhoea 26.4 2.7

Nausea 45.1 1.5

Dryness 10.9 0.2

Gastroesophageal reflux disease 12.9 0.5

Gastrointestinal haemorrhage4 2.2 1.6

Ascites 7.5 1.3

Constipation 5.8 -

Common Dysphagia 2.4 0.4

Stomatitis 2.4 -

Flatulence 1.6 -

Salivary hypersecretion 1.5 -

Very common Hyperbilirubinaemia 27.5 5.8

Uncommon Hepatic haemorrhage 0.2 0.2

Very common Hair colour changes 15.3 0.2

Rash 12.7 1.6

Palmar-plantar erythrodysaesthesia syndrome 1.3 -

Photosensitivity reaction 1.1 -

Common Skin hypopigmentation 1.1 -

Pruritus 2.9 -

Alopecia 9.6 -

Myalgia 2.0 -

Common Arthralgia 1.8 -

Back pain 1.1 -

Muscle spasms 1.6 -

Acute kidney injury 2.0 0.9

Common Blood creatinine increased 4.4 -

Haematuria 1.1 -

Very common Oedema 70.2 4.7

Fatigue 39.6 5.3

Asthenia 7.8 1.6

Common Pyrexia 1.8 0.2

Malaise 2.5 0.2

Feeling cold 2.9 -

Very common Transaminases increased 12.4 0.9

System Organ

Class/Adverse reactions All grades Grades ≥3frequency % %category

Electrocardiogram QT prolonged 2.0 0.2

Blood creatine phosphokinase increased 3.3 0.4

Common Weight decreased 7.5 0.2

Weight increased 4.7 -

Blood lactate dehydrogenase increased 1.3 -1Intracranial haemorrhage (including Cerebral haemorrhage, Haemorrhage intracranial, Subduralhaematoma, Cerebral haematoma)2Mental impairment (including Disturbance in attention, Mental impairment, Mental status changes,

Dementia)3Ocular haemorrhage (including Eye haemorrhage, Retinal haemorrhage, Vitreous haemorrhage)4Gastrointestinal haemorrhage (including Gastric haemorrhage, Gastrointestinal haemorrhage, Uppergastrointestinal haemorrhage, Rectal haemorrhage, Melaena)5Oedema (including Periorbital oedema, Oedema peripheral, Face oedema, Eyelid oedema, Fluidretention, Generalised oedema, Orbital oedema, Eye oedema, Oedema, Peripheral swelling, Swellingface, Eye swelling, Conjunctival oedema, Laryngeal oedema, Localised oedema, Lip swelling)

- : no adverse reactions reported with Grades ≥3

Advanced systemic mastocytosis

Table 4. Adverse reactions reported in clinical studies in patients with advanced systemicmastocytosis treated with avapritinib starting at 200 mg

System

Organ

Class/Adverse reactions All grades Grades ≥3frequency % %category

Very Thrombocytopenia* 46.8 23.0common Anaemia* 23.0 11.9

Neutropenia* 21.4 19.0

Common Leukopenia* 8.7 2.4

Common Confusional state 1.6 -

Very Taste effect* 15.9 0.8common Cognitive disorder 11.9 1.6

Headache 7.9 -

Memory impairment* 5.6 -

Common Dizziness 5.6 -

Neuropathy peripheral1 4.8 -

Intracranial haemorrhage2 2.4 0.8

Common Lacrimation increased 6.3 -

Uncommon Pericardial effusion 0.8 -

Common Epistaxis 5.6 -

Pleural effusion 2.4 -

Very Diarrhoea 14.3 1.6common Nausea 12.7 -

Common Vomiting* 8.7 0.8

System

Organ

Class/Adverse reactions All grades Grades ≥3frequency % %category

Gastroesophageal reflux disease* 4.8 -

Ascites* 4.0 0.8

Dryness* 4.0 -

Constipation 3.2 -

Abdominal pain* 3.2 -

Gastrointestinal haemorrhage3 2.4 1.6

Common Hyperbilirubinaemia* 7.9 0.8

Very Hair colour changes 15.1 -common

Common Rash* 7.9 0.8

Alopecia 7.1 -

Uncommon Photosensitivity reaction 0.8 -

Uncommon Acute kidney injury* 0.8 -

Common Arthralgia 4.8 0.8

Very Oedema4 69.8 4.8common Fatigue* 18.3 2.4

Common Pain 3.2 -

Weight increased 6.3 -

Common Blood alkaline phosphatase increased 4.8 1.6

Transaminases increased* 4.8 -

Electrocardiogram QT prolonged 1.6 0.8

Common Contusion 3.2 -1Neuropathy peripheral (including Paraesthesia, Neuropathy peripheral, Hypoaesthesia)2Intracranial haemorrhage (including Haemorrhage intracranial, Subdural haematoma)3Gastrointestinal haemorrhage (including Gastric haemorrhage, Gastrointestinal haemorrhage,

Melaena)4Oedema (including Periorbital oedema, Oedema peripheral, Face oedema, Eyelid oedema, Fluidretention, Generalised oedema, Oedema, Peripheral swelling, Swelling face, Eye swelling,

Conjunctival oedema, Laryngeal oedema, Localised oedema)

*Comprises pooled terms representing similar medical concepts.

- : no adverse reactions reported

Indolent systemic mastocytosis

Table 5. Adverse reactions reported in clinical studies in patients with indolent systemicmastocytosis

System Organ Avapritinib (25 mg

Class/Adverse reactions once daily) + Best Grades ≥3frequency Supportive Care %category All grades%

Common Insomnia 5.7 -

Common Flushing 9.2 1.4

System Organ Avapritinib (25 mg

Class/Adverse reactions once daily) + Best Grades ≥3frequency Supportive Care %category All grades%

Common Photosensitivity reaction 2.8 -

Very common Peripheral oedema1 12.1 -

Common Face oedema 7.1 -

Common Blood alkaline phosphatase increased 6.4 0.71Peripheral oedema (including oedema peripheral and peripheral swelling)

- : no adverse reactions reported

Intracranial haemorrhage

Unresectable or metastatic GIST

Intracranial haemorrhage occurred in 10 (1.7%) of the 585 patients with GIST (all doses) and in9 (1.6%) of the 550 patients with GIST who received avapritinib at a starting dose of 300 mg or400 mg once daily (see section 4.4).

Events of intracranial haemorrhage (all grades) occurred in a range from 8 weeks to 84 weeks afterinitiating avapritinib, with a median time to onset of 22 weeks. The median time to improvement andresolution was 25 weeks for intracranial haemorrhage of Grade ≥2.

Advanced systemic mastocytosis

Intracranial haemorrhage occurred in a total (regardless of causality) of 4 (3.2%) of the 126 patientswith AdvSM who received avapritinib at a starting dose of 200 mg once daily regardless of plateletcount prior to initiation of therapy. In 3 of these 4 patients, the event was assessed as related toavapritinib (2.4%). The risk of intracranial haemorrhagic events is higher in patients with plateletcounts <50 x 109/L. Intracranial haemorrhage occurred in a total (regardless of causality) of 3 (2.5%)of the 121 patients with AdvSM who received a starting dose of 200 mg once daily and had a plateletcount ≥50 x 109/L prior to initiation of therapy (see section 4.4). In 2 of the 3 patients, the event wasassessed as related to avapritinib (1.7 %). Of 126 patients treated with the recommended starting doseof 200 mg once daily, 5 had platelet counts <50 x 109/L prior to initiation of therapy, of which onepatient experienced an intracranial haemorrhage.

Events of intracranial haemorrhage (all grades) occurred in a range from 12.0 weeks to 15.0 weeksafter initiating avapritinib, with a median time to onset of 12.1 weeks.

In clinical studies with avapritinib, the incidence of intracranial haemorrhage was higher in patientswho received a starting dose of ≥300 mg once daily, as compared to patients who received therecommended starting dose of 200 mg once daily. Of the 50 patients who received a starting dose of≥300 mg once daily, 8 (16.0%) experienced an event (regardless of causality) of intracranial bleedingregardless of platelet count prior to initiation of therapy. In 6 of the 8 patients, the event was assessedas related to avapritinib (12.0 %). Of these 50 patients, 7 had platelet counts <50 x 109/L prior toinitiation of therapy, of which 4 patients experienced an intracranial haemorrhage, that were assessedas related to avapritinib in 3 of 4 cases. Four of 43 patients with platelet counts ≥50 x 109/L prior toinitiation of therapy experienced an intracranial haemorrhage, which were assessed as related toavapritinib in 3 of 4 cases.

Fatal events of intracranial haemorrhage have occurred in less than 1% of patients with AdvSM (alldoses).

The maximum dose for patients with AdvSM must not exceed 200 mg once daily.

Indolent systemic mastocytosis

No intracranial haemorrhages were reported in 141 patients with ISM receiving 25 mg of avapritinibduring the 24-week duration of Part 2 of the PIONEER study.

Cognitive effects

A broad spectrum of cognitive effects that are generally reversible (with intervention) can occur inpatients receiving avapritinib. Cognitive effects were managed with dose interruption and/or reduction,and 2.7% led to permanent discontinuation of avapritinib treatment in patients with GIST and AdvSM.

Unresectable or metastatic GIST

Cognitive effects occurred in 194 (33%) of the 585 patients with GIST (all doses) and in 182 (33%) ofthe 550 patients with GIST who received avapritinib at starting doses of either 300 or 400 mg oncedaily (see section 4.4). In the patients who had an event (any grade), the median time to onset was8 weeks.

Most cognitive effects were Grade 1, with Grade ≥2 occurring in 11% of 550 patients. Among patientswho experienced a cognitive effect of Grade ≥2 (impacting activities of daily living) the median timeto improvement was 15 weeks.

Memory impairment occurred in 20% of patients, <1% of these events were Grade 3. Cognitivedisorder occurred in 12% of patients; <1% of these events were Grade 3. Confusional state occurred in5% of patients; <1% of these events were Grade 3. Encephalopathy occurred in <1% of patients; <1%of these events were Grade 3. Serious adverse reactions of cognitive effects were reported for 9 of 585(1.5%) of the GIST patients (all doses), of which 7 of the 550 (1.3%) patients were observed in the

GIST group receiving a starting dose of either 300 or 400 mg once daily.

Overall, 1.3% of patients required permanent discontinuation of avapritinib for a cognitive effect.

Cognitive effects occurred in 37% of the patients aged ≥65 years receiving a starting dose of either300 or 400 mg once daily.

Advanced systemic mastocytosis

Cognitive effects occurred in 51 (26%) of the 193 patients with AdvSM (all doses) and in 23 (18%) ofthe 126 patients with AdvSM who received avapritinib at a starting dose of 200 mg (see section 4.4).

In the patients with AdvSM treated at a starting dose of 200 mg who had an event (any grade), themedian time to onset was 12 weeks (range: 0.1 weeks to 108.1 weeks).

Most cognitive effects were Grade 1, with Grade ≥2 occurring in 7% of 126 patients treated at astarting dose of 200 mg. Among patients who experienced a cognitive effect of Grade ≥2 (impactingactivities of daily living) the median time to improvement was 6 weeks.

For patients with AdvSM treated at a starting dose of 200 mg, cognitive disorder occurred in 12% ofpatients, memory impairment occurred in 6% of patients and confusional state occurred in 2% ofpatients. None of these events were Grade 4.

Serious adverse reactions of cognitive effects were reported for 1 of 193 (<1%) AdvSM patients (alldoses), none were observed in the AdvSM group receiving a starting dose of 200 mg once daily.

Overall, 1.6% of AdvSM patients (all doses) required permanent discontinuation of avapritinib for acognitive adverse reaction, 8% required a dose interruption, and 9% required dose reduction.

Cognitive effects occurred in 20% of the patients aged ≥65 years receiving a starting dose of 200 mgonce daily.

Indolent systemic mastocytosis

In Part 2 of the PIONEER study, cognitive effects occurred in 2.8% of patients with ISM whoreceived 25 mg of avapritinib (see section 4.4); all cognitive effects were Grade 1 or 2. Overall, noneof the patients who received avapritinib in Part 2 of PIONEER required permanent treatmentdiscontinuation for cognitive effects.

Anaphylactic adverse reactions

Indolent systemic mastocytosis

Anaphylaxis is a common clinical manifestation of ISM. In Part 2 of the PIONEER study, patientswho received 25 mg of avapritinib had fewer episodes of anaphylaxis over time (5% during the ~8-week screening period versus 1% during Part 2).

Unresectable or metastatic GIST

In NAVIGATOR and VOYAGER (N=550) (see section 5.1), 39% of patients were 65 years of ageand older, and 9% were 75 years of age and older. Compared with younger patients (<65), morepatients ≥65 years old had reported adverse reactions that led to dose reductions (55% versus 45%)and dose discontinuation (18% versus 4%). The types of adverse reactions reported were similarregardless of age. Older patients reported more Grade 3 or higher adverse reactions compared toyounger patients (63% versus 50%).

Advanced systemic mastocytosis

In patients treated at 200 mg in EXPLORER and PATHFINDER (N=126) (see section 5.1), 63% ofpatients were 65 years of age or older, and 21% were 75 years of age and older. Compared withyounger patients (<65), more patients ≥65 years old reported adverse reactions that led to dosereductions (62% versus 73%). A similar fraction of patients reported adverse reactions that led to dosediscontinuation (9% versus 6%). The types of adverse reactions reported were similar regardless ofage. Older patients reported more Grade 3 or higher adverse reactions (63.3%) compared to youngerpatients (53.2%).

Indolent systemic mastocytosis

In Part 2 of PIONEER (N=141) (see section 5.1), 9 (6%) patients were 65 years of age or older, and 1(<1%) patient was 75 years of age or older. No patients over the age of 84 were included. Overall, nomeaningful differences in safety were observed between patients ≥65 years and those <65 years.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited experience with cases of overdose reported in clinical studies with avapritinib. Themaximum dose of avapritinib studied clinically is 600 mg orally once daily. Adverse reactionsobserved at this dose were consistent with the safety profile at 300 mg or 400 mg once daily (seesection 4.8).

There is no known antidote for avapritinib overdose. In the event of suspected overdose, avapritinibshould be interrupted and supportive care instituted. Based on the large volume of distribution ofavapritinib and extensive protein binding, dialysis is unlikely to result in significant removal ofavapritinib.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitor, ATC code: L01EX18.

Avapritinib is a Type 1 kinase inhibitor that has demonstrated biochemical in vitro activity on the

PDGFRA D842V and KIT D816V mutants associated with resistance to imatinib, sunitinib andregorafenib with half maximal inhibitory concentrations (IC50) of 0.24 nM and 0.27 nM, respectively,and greater potency against clinically relevant KIT exon 11, KIT exon 11/17 and KIT exon 17 mutantsthan against the KIT wild-type enzyme.

In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842Vwith IC50 of 4 nM and 30 nM, respectively. In cellular assays, avapritinib inhibited the proliferation in

KIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukaemia cellline. Avapritinib also showed growth inhibitory activity in a xenograft model of murine mastocytomawith KIT exon 17 mutation.

Potential to prolong the QT interval

The ability of avapritinib to prolong the QT interval was assessed in 27 patients administeredavapritinib at doses of 300/400 mg (1.33 times the 300 mg dose recommended for GIST patients, 12 to16 times the 25 mg dose recommended for ISM patients) once daily in an open-label, single-arm studyin patients with GIST. The estimated mean change from baseline in QTcF was 6.55 ms (90%confidence interval [CI]: 1.80 to 11.29) at the observed steady state geometric mean Cmax of899 ng/mL (12.8-fold higher than the steady state geometric mean Cmax of avapritinib at 25 mg doseonce daily in patients with ISM). No effect on heart rate or cardiac conduction (PR, QRS, and RRintervals) was observed.

Clinical studies in unresectable or metastatic GIST

The efficacy and safety of avapritinib was assessed in a multi-centre, single-arm, open-label clinicalstudy (BLU-285-1101; NAVIGATOR). Patients with a confirmed diagnosis of GIST and an Eastern

Clinical Oncology Group (ECOG) performance status (PS) of 0 to 2 (58% and 3% of patients had

ECOG status 1 and 2, respectively) were included in the study. A total of 217 patients received astarting dose of either 300 mg or 400 mg once daily.

Efficacy was assessed on the basis of overall response rate (ORR) according to Response Evaluation

Criteria In Solid Tumours (RECIST) v1.1 modified for patients with unresectable or metastatic GIST(mRECIST v1.1) and duration of response (DOR), as evaluated by a Blinded Independent Central

Review (BICR).

In addition, a total of 239 patients have received treatment with avapritinib at the relevant starting dosein an ongoing open-label, randomised phase 3 study (BLU-285-1303; VOYAGER) in which PFS isthe primary endpoint. Ninety six additional patients received avapritinib in this study after diseaseprogression on the regorafenib control treatment (crossover). As of the last data cut-off date, 9th

March 2020, the median treatment duration was 8.9 months in patients with GIST harbouring the

PDGFRA D842V mutation included in this study, which provides some preliminary comparativesafety data.

PDGFRA D842V mutation

A total of 38 patients with unresectable or metastatic GIST harbouring the PDGFRA D842V mutationwere enrolled and treated with avapritinib at a starting dose of either 300 mg or 400 mg once daily. Inthe NAVIGATOR study 71% of patients with unresectable or metastatic GIST harbouring the

PDGFRA D842V mutation had dose reductions to 200 mg or 100 mg once daily during the course oftherapy. Median time to dose reduction was 12 weeks. The GIST patients were required to haveunresectable or metastatic disease and have a documented PDGFRA D842V mutation determined by alocally available diagnostic test. At 12 months, 27 patients were still on avapritinib with 22%receiving 300 mg once daily, 37% receiving 200 mg once daily and 41% receiving 100 mg once daily.

Baseline demographics and disease characteristics were median age of 64 years (range: 29 to90 years), 66% male, 66% white, ECOG PS of 0-2 (61% and 5% of patients had ECOG status 1 and 2,respectively), 97% had metastatic disease, largest target lesion was >5 cm for 58%, 90% had priorsurgical resection, and median number of prior lines of tyrosine kinase inhibitors of 1 (range: 0 to 5).

Efficacy results from study BLU-285-1101 (NAVIGATOR) for GIST patients harbouring the

PDGFRA D842V mutation are summarised in Table 6. The data represent a median duration offollow-up of 26 months across all patients with PDGFRA D842V mutations who were alive, themedian OS had not been reached with 74% of patients alive. The median progression free survival was24 months. Radiographic tumour reductions were observed in 98% of patients.

Table 6. Efficacy results for PDGFRA D842V-Mutation in GIST patients (NAVIGATORstudy)

Efficacy Parameter N = 38mRECIST 1.1 ORR1, (%) (95% CI) 95 (82.3, 99.4)

CR 13

PR 82

DOR (months), median (CI) 22.1 (14.1, NE)

Abbreviations: CI=confidence interval; CR=complete response; DOR=duration of response;mRECIST 1.1=Response Evaluation Criteria In Solid Tumours v1.1 modified for patients withunresectable or metastatic GIST; N=number of patients; NE=not estimable; ORR=overall responserate; PR=partial response1 ORR is defined as patients who achieved a CR or PR (CR + PR)

In patients with PDGFRA D842V-mutant GIST treated at starting doses of 300 or 400 mg once dailythe ORR based on central radiology review by mRECIST v1.1 criteria was 95%.

Based on preliminary results from the ongoing phase 3 study BLU-285-1303 (VOYAGER) in a subsetof 13 patients with PDGFRA D842V mutations, partial response was reported in 3 out of 7 patients inthe avapritinib group (43% ORR) and none of the 6 patients in the regorafenib group (0% ORR). Themedian PFS there was not estimable in patients with PDGFRA D842V mutations randomized toavapritinib (95% CI: 9.7, NE) compared to 4.5 months in patients receiving regorafenib (95% CI: 1.7,

NE).

Clinical studies in advanced systemic mastocytosis

The efficacy and safety of avapritinib was assessed in a multi-center, single-arm, open-label Phase 2study BLU-285-2202 (PATHFINDER). Eligible patients were required to have an ECOG PS of 0 to 3.

Patients with high and very high risk AHNs such as AML or high risk MDS, and Philadelphiachromosome-positive malignancies were excluded. Palliative and supportive care medications wereallowed. The response-evaluable population according to modified IWG-MRT-ECNM criteria asadjudicated by a central committee includes patients with a diagnosis of AdvSM, who had received atleast 1 dose of avapritinib, had at least 2 post-baseline bone marrow assessments and had been onstudy for at least 24 weeks, or had an end of study visit. The primary efficacy outcome measure was

ORR per modified IWG-MRT-ECNM criteria as adjudicated by the central committee.

Of 107 patients enrolled in the study, 67 patients had at least one prior systemic therapy and weretreated at a starting dose of 200 mg orally once daily.

The assessment of the primary efficacy endpoint was based on a total of 47 AdvSM patients, evaluableaccording to the modified IWG-MRT-ECNM response criteria, enrolled in the study, who received atleast one prior systemic therapy and a starting dose of 200 mg avapritinib once daily with 78.7% ofpatients having received prior midostaurin, 17.0% prior cladribine, 14.9 % prior interferon alpha,10.6% prior hydroxycarbamide and 6.4% prior azacytidine. Thirty seven (79%) out of the 47 patientswith AdvSM who received at least one prior systemic therapy and a starting dose of 200 mgavapritinib had one or more dose reductions during the course of therapy with a median time to dosereduction of 6 weeks. The study population characteristics were: median age of 69 years (range: 31 to86 years), 70% male, 92% white, ECOG PS of 0-3 (66% and 34% of patients had an ECOG PS of 0-1and 2-3, respectively), and 89% had a detectable KIT D816V mutation. Before initiation of avapritinibtreatment, the median bone marrow mast cell infiltrate was 70%, the median serum tryptase level was325 ng/mL, and the median KIT D816V mutant allele fraction (MAF) was 26.2%.

Efficacy results in patients with AdvSM enrolled in the study, who received at least one prior systemictherapy and a starting dose of 200 mg avapritinib once daily, with a median duration of follow-up of12 months are summarized in Table 7.

Table 7. Efficacy results for patients with advanced systemic mastocytosis who received atleast one prior systemic therapy in PATHFINDER

Efficacy parameter Overall ASM SM-AHN MCL

ORR1 per modified IWG- N = 47 N = 8 N = 29 N = 10

MRT-ECNM, n (%) (95%confidence interval) 28 (60) 5 (63) 19 (66) 4 (40)

Response per modified IWG- (44.3, 73.6) (24.5, 91.5) (45.7, 82.1) (12.2, 73.8)

MRT-ECNM category, n (%)

CR 1 (2) 0 1 (3) 0

CRh 4 (9) 2 (25) 2 (7) 0

PR 19 (40) 3 (38) 13 (45) 3 (30)

CI 4 (9) 0 3 (10) 1 (10)

DOR2 (months), median (95% N = 28 N = 5 N = 19 N = 4confidence interval)

NR NR NR NR(NE, NE) (NE, NE) (NE, NE) (NE, NE)

DOR rate at 12 months, % 100.0 100.0 100.0 100.0

DOR rate at 24 months, % 85.6 NE 83.3 NE

Time to response (months), N = 28 N = 5 N = 19 N = 4median (min, max) 1.9 2.3 1.9 3.6(0.5, 12.2) (1.8, 5.5) (0.5, 5.5) (1.7, 12.2)

Time to CR/CRh (months), N = 5 N = 2 N = 3 N = 0median (min, max) 3.7 2.8 5.6 NE(1.8, 14.8) (1.8, 3.7) (1.8, 14.8)

Abbreviations: CI=clinical improvement; CR=complete remission; CRh=complete remission withpartial recovery of peripheral blood counts; DOR=duration of response; NE=not estimable; NR=notreached; ORR=overall response rate; PR=partial remission1 ORR per modified IWG-MRT-ECNM is defined as patients who achieved a CR, CRh, PR or CI (CR+ CRh + PR+CI)2 Estimated from Kaplan-Meier analysis

Among patients treated with avapritinib at a starting dose of 200 mg once daily following at least oneprior systemic therapy, 83.1% of patients had ≥50% decrease of bone marrow mast cells with 58.5%patients having complete elimination of bone marrow mast cell aggregates; 88.1% of patients had≥50% reduction in serum tryptase with 49.3% reducing serum tryptase <20 ng/mL; 68.7% of patientshad a ≥50% decrease in KIT D816V MAF in blood and 60.0% of patients had ≥35% spleen volumereduction from baseline.

In a supportive multi-center, single-arm, open-label Phase 1 study BLU-285-2101 (EXPLORER), the

ORR according to the mIWG-MRT-ECNM criteria was 73% (95% confidence interval: 39.0, 94.0) for11 AdvSM patients who received at least one prior systemic therapy and a starting dose of 200 mgavapritinib once daily.

Clinical studies in indolent systemic mastocytosis

The efficacy and safety of avapritinib was assessed in study BLU-285-2203 (PIONEER), arandomised, double-blind, placebo-controlled, 3-part study conducted in adult patients with ISM withmoderate-to-severe symptoms not adequately controlled by best supportive care. In Part 2 (pivotalpart), patients were randomised to receive avapritinib at the recommended dose of 25 mg orally oncedaily with best supportive care (141 patients) versus placebo with best supportive care (71 patients).

The randomized portion of the study consisted of a 24-week period. Part 3 of study BLU-285-2203 isongoing.

The primary endpoint in Part 2 was mean change from baseline to Week 24 in total symptom score(TSS) as measured by the ISM Symptom Assessment Form (ISM-SAF). The ISM-SAF is a patient-reported outcome tool made up of a 12-item questionnaire developed specifically to assess symptomsin patients with ISM. Patient-reported severity scores for 11 ISM symptoms (bone pain, abdominalpain, nausea, spots, itching, flushing, fatigue, dizziness, brain fog, headache, diarrhoea; 0=none;10=worst imaginable) are summed to calculate the TSS (range 0-110), with higher scores representinggreater symptom burden. The 12th item of the questionnaire assesses the number of diarrhoea episodes.

For the purpose of the study, enrolled patients needed a total symptom score (TSS) of 28 or greater atscreening. Patients were required to have failed to achieve adequate symptom control for 1 or morebaseline symptoms with at least 2 symptomatic therapies, including but not limited to: H1antihistamines, H2 antihistamines, proton pump inhibitors, leukotriene inhibitors, cromolyn sodium,corticosteroids, or omalizumab.

Additional patient-reported key secondary efficacy endpoints were the proportion of avapritinib-treated patients achieving ≥50% and ≥30% reduction from baseline through Week 24 in TSScompared to placebo. Objective measures of mast cell burden were also reported as key secondaryefficacy endpoints and included the proportion of patients with a ≥50% reduction from baselinethrough Week 24 in serum tryptase, peripheral blood KIT D816V allele fraction and in bone marrowmast cells.

The study population characteristics were: median age of 51 years (range: 18 to 79 years), 73% werefemale, 80% were white, and 94% had a KIT D816V mutation. At baseline, the mean TSS was 50.93(range: 12.1 to 104.4), the median serum tryptase level was 39.20 ng/mL (range: 3.6 to 501.6 ng/mL),the median KIT D816V mutant allele fraction was 0.32% by digital-droplet polymerase chain reaction(ddPCR) and the median bone marrow mast cell infiltrate was 7%.

The majority of patients (99.5%) received concomitant best supportive care at baseline (median of 3therapies). The most common therapies were H1 antihistamines (98.1%), H2 antihistamines (66%),leukotriene inhibitors (34.9%) and cromolyn sodium (32.1%).

Avapritinib treatment demonstrated statistically significant improvements for all primary and keysecondary efficacy endpoints compared to placebo, as summarized in Table 8.

Table 8. Reduction in ISM-SAF TSS and measures of mast cell burden in patients withindolent systemic mastocytosis in PIONEER at Week 24

AYVAKYT (25 mg Placebo + BSC

Efficacy Parameter once daily) + BSC One-sided p-value

N = 141 N = 71

ISM-SAF TSS

Mean change in TSS

Change from baseline -15.58 -9.15(95% CI) (-18.61, -12.55) (-13.12, -5.18)0.003

Difference from -6.43*placebo (95% CI) (-10.90, -1.96)% of patients achieving 25 10≥50% reduction in TSS 0.005(95% CI) (17.9, 32.8) (4.1, 19.3)% of patients achieving 45 30≥30% reduction in TSS 0.009(95% CI) (37.0, 54.0) (19.3, 41.6)

Measures of mast cell burden% of patients with a N = 141 N = 71≥50% reduction in serumtryptase (95% CI) 54 0 <0.0001(45.3, 62.3) (0.0, 5.1)% of patients with a N = 118 N = 63≥50% reduction inperipheral blood KIT 68 6 <0.0001

D816V allele fraction or (58.6, 76.1) (1.8, 15.5)undetectable (95% CI)% of patients with a N = 106 N = 57≥50% reduction in bonemarrow mast cells or no 53 23 <0.0001aggregates (95% CI) (42.9, 62.6) (12.7, 35.8)

Abbreviations: BSC=best supportive care, CI=confidence interval, ISM-SAF=indolent systemicmastocytosis symptom assessment form, TSS=total symptom score

* Reduction in TSS is a result of a mean decrease in all individual symptoms that make up the ISM-

SAF.

The long-term efficacy of avapritinib is assessed in an open-label extension of PIONEER in patientsreceiving 25 mg of avapritinib (Part 3). Overall, 201 patients rolled over from Part 2 into Part 3 of

PIONEER. Avapritinib-treated patients from Part 2 continued to report improvements in TSS overtime out to approximately 48 weeks (Part 3 C7D1) of treatment with a mean change from baseline in

TSS of -18.05 points (95% CI -21.55, -14.56). Placebo-treated patients from Part 2 who receivedavapritinib in Part 3 reported substantial additional reductions in their TSS scores within the first24 weeks of treatment (Part 3 C7D1) with a total mean change from baseline in TSS of -19.71 points(95% CI -24.32, -15.11), which included a further 10.78 point reduction from Part 3 baseline just priorto rolling over to avapritinib.

Unresectable or metastatic GIST

Forty-two percent of the patients who received AYVAKYT at a starting dose of 300 mg and 400 mgonce daily in NAVIGATOR were 65 years or older. No overall differences in efficacy were observedin comparison with younger patients. Only limited data are available from the use of avapritinib inpatients aged 75 years or older (8% (3 out of 38)).

Advanced systemic mastocytosis

Of the 47 patients who received AYVAKYT at a starting dose of 200 mg and who received at leastone prior systemic therapy in PATHFINDER, 64% were 65 years or older, while 21% were 75 yearsand older. No overall differences in efficacy were observed between patients ≥65 years and those<65 years.

Indolent systemic mastocytosis

Of the 141 patients with ISM who received AYVAKYT in Part 2 (pivotal part) of PIONEER, 9 (6%)patients were 65 years or older, while 1 (<1%) patient was 75 years and older. No patients over the ageof 84 were included. Overall, no meaningful differences in efficacy were observed between patients≥65 years and those <65 years.

The European Medicines Agency has deferred the obligation to submit the results of studies with

AYVAKYT in one or more subsets of the paediatric population with a relapsed/refractory solidtumour harbouring mutations in either KIT or PDGFRA (see section 4.2 for information on paediatricuse).

The European Medicines Agency has waived the obligation to submit the results of studies with

AYVAKYT in all subsets of the paediatric population with mastocytosis (see section 4.2 forinformation on paediatric use).

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 everyyear and this SmPC will be updated as necessary.

Following administration of avapritinib once daily, steady state was reached by 15 days.

Unresectable or metastatic GIST (300 mg once daily dose)

After a single dose and repeat dosing of avapritinib, systemic exposure of avapritinib was dose-proportional over the dose range of 30 to 400 mg once daily in patients with unresectable or metastatic

GIST. The steady state geometric mean (CV%) maximum concentration (Cmax) and area under theconcentration-time curve (AUC0-tau) of avapritinib at 300 mg once daily was 813 ng/mL (52%) and15400 h*ng/mL (48%), respectively. The geometric mean accumulation ratio after repeat dosing was3.1 to 4.6.

Advanced systemic mastocytosis (200 mg once daily dose)

Steady-state Cmax and AUC of avapritinib increased proportionally over the dose range of 30 mg to400 mg once daily in patients with AdvSM. The steady state geometric mean (CV%) Cmax and AUC0-24of avapritinib at 200 mg once daily was 377 ng/mL (62%) and 6600 h*ng/mL (54%), respectively. Thegeometric mean accumulation ratio after repeat dosing (30-400 mg) was 2.6 to 5.8.

Indolent systemic mastocytosis (25 mg once daily dose)

The Cmax and AUC of avapritinib increased proportionally over the dose range of 25 mg to 100 mgonce daily in patients with ISM. The steady state geometric mean (CV%) Cmax and AUC0-24 ofavapritinib at 25 mg once daily was 70.2 ng/mL (47.8%) and 1330 h*ng/mL (49.5%), respectively.

The geometric mean accumulation ratio after repeat dosing was 3.59.

Following administration of single oral doses of avapritinib of 25 to 400 mg, the median time to peakconcentration (Tmax) ranged from 2 to 4 hours postdose. The absolute bioavailability has not beendetermined. The population estimated mean oral bioavailability of avapritinib in patients with GISTand AdvSM is 16% and 47% lower, respectively, compared to that in patients with ISM.

Avapritinib Cmax and AUCinf were increased by 59% and 29%, respectively, in healthy subjectsadministered avapritinib after a high fat meal (approximately 909 calories, 58 grams carbohydrate,56 grams fat and 43 grams protein) compared to the Cmax and AUCinf after overnight fasting.

Avapritinib is 98.8% bound to human plasma proteins in vitro and the binding is not concentration-dependent. The blood-to-plasma ratio is 0.95. Population estimated apparent central volume ofdistribution of avapritinib (Vc/F) is 971 L at median lean body weight of 54 kg. The inter-individualvariability of Vc/F is 50.1%.

In vitro studies demonstrated that oxidative metabolism of avapritinib is predominantly mediated by

CYP3A4, CYP3A5 and to a minor extent by CYP2C9. The relative contributions of CYP2C9 and

CYP3A to the in vitro metabolism of avapritinib were 15.1% and 84.9%, respectively. The formationof the glucuronide M690 is catalysed mainly by UGT1A3.

Following a single dose of approximately 310 mg (~100 µCi) [14C]avapritinib to healthy subjects,oxidation, glucuronidation, oxidative deamination and N-dealkylation were the primary metabolicpathways. Unchanged avapritinib (49%) and metabolites, M690 (hydroxy glucuronide; 35%) and

M499 (oxidative deamination; 14%) were the major circulating radioactive components. Followingoral administration of avapritinib 300 mg once daily in patients, the steady state AUC of theconstitutive enantiomers of M499, BLU111207 and BLU111208 are approximately 35% and 42% ofthe AUC of avapritinib. At a dose of 25 mg once daily, the metabolite to parent ratio for BLU111207and BLU111208 was 10.3% and 17.5 % respectively. Compared to avapritinib (IC50 = 4 nM), theenantiomers BLU111207 (IC50 = 41.8 nM) and BLU111208 (IC50 = 12.4 nM) are 10.5- and 3.1-foldless potent, respectively, against KIT D816V in vitro.

In vitro studies demonstrated that avapritinib is a direct inhibitor of CYP3A4 and a time-dependentinhibitor of CYP3A4, at clinically relevant concentrations (see section 4.5). In vitro, avapritinib didnot inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevantconcentrations.

In vitro, at clinically relevant concentrations, avapritinib induced CYP3A (see section 4.5). In vitro,avapritinib did not induce CYP1A2 or CYP2B6 at clinically relevant concentrations.

Following single doses of AYVAKYT in patients with GIST, AdvSM and ISM, the mean plasmaelimination half-life of avapritinib was 32 to 57 hours, 20 to 39 hours and 38 to 45 hours, respectively.

Population estimated mean apparent clearance (CL/F) of avapritinib is 16.9 L/h. In AdvSM patients,time-dependent CL/F on Day 9 was reduced to 39.4% compared to GIST and ISM patients. The inter-individual variability in CL/F is 44.4%.

Following a single oral dose of approximately 310 mg (~100 µCi) [14C]avapritinib to healthy subjects,70% of the radioactive dose was recovered in faeces and 18% excreted in urine. Unchangedavapritinib accounted for 11% and 0.23% of the administered radioactive dose excreted in faeces andurine, respectively.

Effects of avapritinib on transport proteins

In vitro, avapritinib is not a substrate of P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1,

OATP1B3, MATE1, MATE2-K and BSEP at clinically relevant concentrations.

Avapritinib is an inhibitor of P-gp, BCRP, MATE1, MATE2-K, and BSEP in vitro (see section 4.5).

In vitro, avapritinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2 at clinicallyrelevant concentrations.

Gastric acid reducing active substances

No clinical drug-drug interaction studies have been conducted. Based on both population andnoncompartmental pharmacokinetic analyses, the effect of gastric acid reducing agents on thebioavailability of avapritinib is not clinically relevant.

Population pharmacokinetic analyses indicate that age (18-90 years), body weight (40-156 kg), sexand albumin concentration have no effect on the exposure of avapritinib. Concomitant use of protonpump inhibitors (PPI) on bioavailability (F) and lean body weight on the apparent central volume ofdistribution (Vc/F) were identified as statistically significant covariates with impact on avapritinibexposure. Lean body weight (30 kg to 80 kg) showed modest impact on Cmax at steady state (+/- 5%),while concomitant use of PPIs led to ~19% reduction in AUC and Cmax. These minor effects onexposure are not clinically significant given the PK variability (>40% CV) and are not expected toimpact efficacy or safety. No significant effect of race on the pharmacokinetics of avapritinib wasfound, although the low number of Black (N=27) and Asian (N=26) subjects limits the conclusionsthat can be derived based on race.

As hepatic elimination is a major route of excretion for avapritinib, hepatic impairment may result inincreased plasma avapritinib concentrations. Based on a population pharmacokinetic analysis,avapritinib exposures were similar between 72 subjects with mild hepatic impairment (total bilirubinwithin upper limit of normal [ULN] and AST > ULN or total bilirubin >1 to 1.5 times ULN and any

AST), 13 subjects with moderate hepatic impairment (total bilirubin >1.5 to 3.0 times ULN and any

AST), and 402 subjects with normal hepatic function (total bilirubin and AST within ULN). In aclinical study investigating the effect of severe hepatic impairment on the pharmacokinetics ofavapritinib following administration of a single oral dose of 100 mg avapritinib, the mean unbound

AUC was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) as comparedto matched healthy subjects with normal hepatic function. A lower starting dose is recommended inpatients with severe hepatic impairment (see section 4.2).

Based on a population pharmacokinetic analysis, avapritinib exposures were similar among136 subjects with mild renal impairment (CLcr 60-89 mL/min), 52 subjects with moderate renalimpairment (CLcr 30-59 mL/min) and 298 subjects with normal renal function (CLcr ≥90 mL/min),suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment.

The pharmacokinetics of avapritinib in patients with severe renal impairment (CLcr 15-29 mL/min) orend-stage renal disease (CLcr <15 mL/min) has not been studied.

Repeat dose toxicology studies

Haemorrhage in the brain and spinal cord occurred in dogs at doses greater than or equal to15 mg/kg/day (approximately 9.0, 1.8 and 0.8 times the human exposure based on AUC at 25 mg,200 mg and 300 mg dose once daily, respectively) and choroid plexus oedema in the brain occurred indogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1.0 and 0.4 times the humanexposure based on AUC at the clinical dose of 25 mg, 200 mg and 300 mg once daily, respectively).

Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemicexposures ≥96, 12 and ≥8-fold higher than the exposure in patients at the clinical dose of 25 mg,200 mg and 300 mg once daily.

In a 6 month repeat dose toxicology study in rats, rats manifested haemorrhagic and cysticdegeneration of the ovarian corpus lutea and vaginal mucification at dose levels greater or equal to3 mg/kg/day with exposure margins of 15, 3 and 1.3 times the human exposure based on AUC at25 mg, 200 mg and 300 mg, respectively. In a 9 month repeat dose toxicology study in dogs,hypospermatogenesis (3/4 males) was observed at the highest dose tested, 5 mg/kg/day (5.7, 1.2 and<1 times the human exposure (AUC) at 25 mg, 200 mg and 300 mg dose, respectively).

Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). It waspositive in the in vitro chromosome aberration test in cultured human peripheral blood lymphocytesbut negative in the rats for both the bone marrow micronucleus test and for the chromosomal damageliver comet assays, and thus, overall non-genotoxic. The carcinogenic potential of avapritinib wasevaluated in a 6 month transgenic mouse study where higher incidences of lower thymic corticalcellularity were noted at 10 and 20 mg/kg/day doses. A long-term carcinogenicity study withavapritinib is ongoing.

Toxicity to reproduction and development

A dedicated combined male and female fertility and early embryonic development study wasconducted in rats at oral avapritinib doses of 3, 10, and 30 mg/kg/day for males, and 3, 10, and20 mg/kg/day for females. No direct effects on male or female fertility were noted at the highest doselevels tested in this study (100.8 and 62.6 times the human exposure (AUC) at 25 mg, 20.3 and9.5 times the human exposure (AUC) at 200 mg and 8.7 and 4.1 times the human exposure (AUC) at300 mg).

Avapritinib partitioned into seminal fluids up to 0.1 times the concentration found in human plasma at25 mg. There was an increase in pre-implantation loss and in early resorptions with exposure marginsof 15, 3 and 1.3 times the human exposure (AUC) at the clinical doses of 25 mg, 200 mg and 300 mg,respectively. Reduction in sperm production and relative testicular weight were observed in male ratsadministered avapritinib at exposures of 7 and 30 times, 1 and 5 times, and 0.6 and 3 times the 25 mg,200 mg, and 300 mg human doses, respectively.

In an embryo-foetal development toxicity study in rats, avapritinib showed embryotoxic andteratogenic effects (decreases in foetal weights and viability, and increases in visceral and skeletalmalformations). Oral administration of avapritinib during the period of organogenesis was teratogenicand embryotoxic in rats at exposures approximately 31.4, 6.3 and 2.7 times the human exposure(AUC) at the 25 mg, 200 mg, and 300 mg dose, respectively.

Phototoxicity studies

An in vitro phototoxicity study in 3T3 mouse fibroblasts as well as a phototoxicity study in pigmentedrats demonstrated that avapritinib has a slight potential for phototoxicity.

Microcrystalline cellulose

Copovidone

Croscarmellose sodium

Magnesium stearate

Talc

Macrogol 3350

Poly(vinyl alcohol)

Titanium dioxide (E171)

Printing ink (for 100 mg, 200 mg and 300 mg film-coated tablets only)

Shellac glaze 45% (20% esterified) in ethanol

Brilliant blue FCF (E133)

Titanium dioxide (E171)

Black iron oxide (E172)

Not applicable.

4 years

This medicinal product does not require any special storage conditions.

High-density polyethylene (HDPE) bottle with child-resistant cap (polypropylene) with foiledinduction seal liner (pulp backed heat induction foil) and a desiccant in canister.

Each carton contains one bottle with 30 film-coated tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Blueprint Medicines (Netherlands) B.V.

Gustav Mahlerplein 21082 MA Amsterdam

Netherlands

AYVAKYT 25 mg film-coated tablets

EU/1/20/1473/004

AYVAKYT 50 mg film-coated tablets

EU/1/20/1473/005

AYVAKYT 100 mg film-coated tablets

EU/1/20/1473/001

AYVAKYT 200 mg film-coated tablets

EU/1/20/1473/002

AYVAKYT 300 mg film-coated tablets

EU/1/20/1473/003

Date of first authorisation: 24 September 2020

Date of latest renewal: 24 July 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.