Avapritinib

Avapritinib should be used with caution in GIST or AdvSM patients with known QT interval prolongation 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 or moderate CYP3A4 inhibitors should be avoided due to the increased risk of adverse reactions, including QT prolongation and related arrhythmias. If concomitant use of moderate CYP3A4 inhibitors cannot be avoided, see dose modification instructions.

In patients with GIST or AdvSM, interval assessments of QT by electrocardiogram (ECG) should be considered 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 patients with concurrent factors that could prolong QT (e.g. age, pre-existing heart rhythm disorders, etc.).

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

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

Co-administration of avapritinib with a strong CYP3A inhibitor increased avapritinib plasma concentrations 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 dose of avapritinib on Day 4 in healthy subjects increased avapritinib C_max by 1.4-fold and AUC_0-inf by 4.2-fold, relative to a 200 mg dose of avapritinib administered alone.

Concomitant use of avapritinib with strong or moderate CYP3A inhibitors (such as antifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin; active substances to treat human immunodeficiency virus infections/acquired immunodeficiency syndrome (HIV/AIDS) such as cobicistat, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir; as well as conivaptan for hyponatremia and boceprevir to treat hepatitis) including grapefruit or grapefruit juice should be avoided. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinib should be reduced from 300 mg to 100 mg orally once daily for patients with GIST, and from 200 mg to 50 mg orally once daily for patients with AdvSM. For patients with ISM, concomitant use of avapritinib with strong or moderate CYP3A inhibitors must be avoided.

Co-administration of avapritinib with a strong CYP3A inducer decreased avapritinib plasma concentrations 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 subjects decreased avapritinib C_max by 74% and AUC_0-inf by 92%, relative to a 400 mg dose of avapritinib administered 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.

Avapritinib has not been studied in patients 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 disease cannot be recommended.

A modified starting dose of avapritinib is recommended for patients with severe hepatic impairment (Child-Pugh Class C). The starting dose of avapritinib should be reduced from 300 mg to 200 mg orally once daily for patients with GIST, from 200 mg to 100 mg orally once daily for patients with AdvSM, and from 25 mg orally once daily to 25 mg orally every other day for patients with ISM.

There are no data on the effect of avapritinib on human fertility. However, based on nonclinical findings in animals, male and female fertility may be compromised by treatment with avapritinib.

There are no data from the use of avapritinib in pregnant women. Studies in animals have shown reproductive toxicity.

Avapritinib is not recommended during pregnancy and in women of childbearing potential not using contraception.

If avapritinib is used during pregnancy or if the patient becomes pregnant while taking avapritinib, 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 avapritinib and for 2 weeks following the final dose.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential must be informed that avapritinib may cause foetal harm.

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

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

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

Fertility

There are no data on the effect of avapritinib on human fertility. However, based on nonclinical findings in animals, male and female fertility may be compromised by treatment with avapritinib.

Avapritinib may cause adverse reactions such as cognitive effects that may influence the ability to drive and use machines.

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

Summary of the safety profile

The safety database includes a total of 585 patients with GIST (all doses), of which 550 patients received 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, and 246 patients with ISM (doses 25 mg – 100 mg), of which 141 patients received avapritinib at the recommended dose of 25 mg in Part 2, pivotal part of the PIONEER study.

Unresectable or metastatic GIST

The most common adverse reactions of any grade during treatment with avapritinib at a starting dose of 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 serious adverse 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 dose reduction included anaemia, fatigue, neutrophil count decreased, blood bilirubin increased, memory impairment, 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 dose of 200 mg were periorbital oedema (38%), thrombocytopenia (37%), oedema peripheral (33%), and anaemia (22%).

Serious adverse reactions occurred in 12% of patients receiving avapritinib. The most common serious adverse 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 treatment discontinuation. In two patients (1.6%), subdural haematoma occurred. Cognitive disorder, depressed mood, diarrhoea, disturbance in attention, haemoglobin decreased, hair colour changes, libido decreased, 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 count decreased, anaemia, asthenia, fatigue, arthralgia, blood alkaline phosphatase increased, blood bilirubin increased, and white blood cell count decreased.

Indolent systemic mastocytosis

In Part 2 of PIONEER, the most common adverse reaction during treatment with avapritinib at the recommended dose of 25 mg was peripheral oedema (12%). Overall, the majority of oedema adverse reactions 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 at the recommended dose of 25 mg in Part 2 of PIONEER. Treatment discontinuation due to adverse reactions occurred in <1% of patients receiving avapritinib.

Tabulated list of adverse reactions

Adverse reactions that were reported in clinical studies in ≥1% of patients with GIST are listed below (Table 1), 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 2). For patients with ISM, adverse reactions reported in Part 2 of the PIONEER study in ≥5% of patients are listed in Table 3.

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 1. Adverse reactions reported in clinical studies in patients with unresectable or metastatic GIST treated with avapritinib:

¹ Intracranial haemorrhage (including Cerebral haemorrhage, Haemorrhage intracranial, Subdural haematoma, Cerebral haematoma)
² Mental impairment (including Disturbance in attention, Mental impairment, Mental status changes, Dementia)
³ Ocular haemorrhage (including Eye haemorrhage, Retinal haemorrhage, Vitreous haemorrhage)
⁴ Gastrointestinal haemorrhage (including Gastric haemorrhage, Gastrointestinal haemorrhage, Upper gastrointestinal haemorrhage, Rectal haemorrhage, Melaena)
⁵ Oedema (including Periorbital oedema, Oedema peripheral, Face oedema, Eyelid oedema, Fluid retention, Generalised oedema, Orbital oedema, Eye oedema, Oedema, Peripheral swelling, Swelling face, Eye swelling, Conjunctival oedema, Laryngeal oedema, Localised oedema, Lip swelling)
-: no adverse reactions reported with Grades ≥3

Advanced systemic mastocytosis

Table 2. Adverse reactions reported in clinical studies in patients with advanced systemic mastocytosis treated with avapritinib starting at 200 mg:

¹ Neuropathy peripheral (including Paraesthesia, Neuropathy peripheral, Hypoaesthesia)
² Intracranial haemorrhage (including Haemorrhage intracranial, Subdural haematoma)
³ Gastrointestinal haemorrhage (including Gastric haemorrhage, Gastrointestinal haemorrhage, Melaena)
⁴ Oedema (including Periorbital oedema, Oedema peripheral, Face oedema, Eyelid oedema, Fluid retention, 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 3. Adverse reactions reported in clinical studies in patients with indolent systemic mastocytosis:

¹ Peripheral oedema (including oedema peripheral and peripheral swelling)
-: no adverse reactions reported

Description of selected adverse reactions

Intracranial haemorrhage

Unresectable or metastatic GIST

Intracranial haemorrhage occurred in 10 (1.7%) of the 585 patients with GIST (all doses) and in 9 (1.6%) of the 550 patients with GIST who received avapritinib at a starting dose of 300 mg or 400 mg once daily.

Events of intracranial haemorrhage (all grades) occurred in a range from 8 weeks to 84 weeks after initiating avapritinib, with a median time to onset of 22 weeks. The median time to improvement and resolution 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 patients with AdvSM who received avapritinib at a starting dose of 200 mg once daily regardless of platelet count prior to initiation of therapy. In 3 of these 4 patients, the event was assessed as related to avapritinib (2.4%). The risk of intracranial haemorrhagic events is higher in patients with platelet counts <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 platelet count ≥50 x 10⁹/L prior to initiation of therapy. In 2 of the 3 patients, the event was assessed as related to avapritinib (1.7 %). Of 126 patients treated with the recommended starting dose of 200 mg once daily, 5 had platelet counts <50 x 10⁹/L prior to initiation of therapy, of which one patient experienced an intracranial haemorrhage.

Events of intracranial haemorrhage (all grades) occurred in a range from 12.0 weeks to 15.0 weeks after 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 patients who received a starting dose of ≥300 mg once daily, as compared to patients who received the recommended 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 bleeding regardless of platelet count prior to initiation of therapy. In 6 of the 8 patients, the event was assessed as related to avapritinib (12.0%). Of these 50 patients, 7 had platelet counts <50 x 10⁹/L prior to initiation of therapy, of which 4 patients experienced an intracranial haemorrhage, that were assessed as related to avapritinib in 3 of 4 cases. Four of 43 patients with platelet counts ≥50 x 10⁹/L prior to initiation of therapy experienced an intracranial haemorrhage, which were assessed as related to avapritinib in 3 of 4 cases.

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

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 avapritinib during 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 in patients 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%) of the 550 patients with GIST who received avapritinib at starting doses of either 300 or 400 mg once daily. In the patients who had an event (any grade), the median time to onset was 8 weeks.

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

Memory impairment occurred in 20% of patients, <1% of these events were Grade 3. Cognitive disorder occurred in 12% of patients; <1% of these events were Grade 3. Confusional state occurred in 5% 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 either 300 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%) of the 126 patients with AdvSM who received avapritinib at a starting dose of 200 mg. In the patients with AdvSM treated at a starting dose of 200 mg who had an event (any grade), the median 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 a starting dose of 200 mg. Among patients who experienced a cognitive effect of Grade ≥2 (impacting activities 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% of patients, memory impairment occurred in 6% of patients and confusional state occurred in 2% of patients. None of these events were Grade 4.

Serious adverse reactions of cognitive effects were reported for 1 of 193 (<1%) AdvSM patients (all doses), 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 a cognitive 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 mg once daily.

Indolent systemic mastocytosis

In Part 2 of the PIONEER study, cognitive effects occurred in 2.8% of patients with ISM who received 25 mg of avapritinib; all cognitive effects were Grade 1 or 2. Overall, none of the patients who received avapritinib in Part 2 of PIONEER required permanent treatment discontinuation for cognitive effects.

Anaphylactic adverse reactions

Indolent systemic mastocytosis

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

Elderly

Unresectable or metastatic GIST

In NAVIGATOR and VOYAGER (N=550), 39% of patients were 65 years of age and older, and 9% were 75 years of age and older. Compared with younger patients (<65), more patients ≥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 similar regardless of age. Older patients reported more Grade 3 or higher adverse reactions compared to younger patients (63% versus 50%).

Advanced systemic mastocytosis

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

Indolent systemic mastocytosis

In Part 2 of PIONEER (N=141), 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, no meaningful differences in safety were observed between patients ≥65 years and those <65 years.