Avapritinib

Avapritinib is a Type 1 kinase inhibitor with strong activity against the PDGFRA D842V and KIT D816V mutants, which are associated with resistance to imatinib, sunitinib and regorafenib. The PDGFRA D842V mutation defines its GIST indication. It is taken by mouth once daily, and its dose depends on the disease treated.

Mechanism of Action

• Kinase inhibition: in biochemical tests avapritinib inhibited the PDGFRA D842V and KIT D816V mutants, which are associated with resistance to imatinib, sunitinib and regorafenib, with IC50 values of 0.24 and 0.27 nM. It was also more potent against clinically relevant KIT exon 11, exon 11/17 and exon 17 mutants than against wild-type KIT.
• Cellular effects: in cell assays it blocked autophosphorylation of KIT D816V and PDGFRA D842V (IC50 4 and 30 nM) and the proliferation of KIT-mutant cell lines, including a murine mastocytoma line and a human mast cell leukaemia line. It also inhibited the growth of a murine mastocytoma xenograft with a KIT exon 17 mutation.
• Cardiac electrophysiology: in 27 GIST patients taking 300 or 400 mg daily, the mean change in QTcF from baseline was 6.55 ms (90% CI 1.80 to 11.29) at the observed steady-state geometric mean peak concentration of 899 ng/mL. Heart rate and the PR, QRS and RR intervals were not affected.

Pharmacokinetics

• Absorption: median time to peak concentration is 2–4 hours after single oral doses of 25–400 mg; absolute bioavailability has not been determined. Steady state is reached by about 15 days, and exposure rises in proportion to dose. Steady-state geometric mean Cmax and AUC were 813 ng/mL and 15,400 h·ng/mL at 300 mg (GIST), 377 ng/mL and 6,600 h·ng/mL at 200 mg (advanced systemic mastocytosis) and 70.2 ng/mL and 1,330 h·ng/mL at 25 mg (indolent systemic mastocytosis). Estimated oral bioavailability is 16% lower in GIST and 47% lower in advanced disease than in indolent systemic mastocytosis.
• Food: a high-fat meal raised Cmax by 59% and AUC by 29% in healthy subjects compared with fasting, which is why the tablets are taken on an empty stomach.
• Distribution: 98.8% bound to human plasma proteins in vitro, independent of concentration; blood-to-plasma ratio 0.95; apparent central volume of distribution about 971 L at a median lean body weight of 54 kg.
• Metabolism: mainly by CYP3A4 and CYP2C9 in vitro.
• Elimination: half-life about 32–57 hours and apparent oral clearance about 19.5 L/h. After a radiolabelled dose, about 70% was recovered in faeces (11% unchanged) and 18% in urine (0.23% unchanged).
• Special populations: severe hepatic impairment calls for a lower starting dose, and severe renal impairment has not been studied (see Administration and Dosage). The SmPC gives further detail.

• Unresectable or metastatic GIST: monotherapy in adults with unresectable or metastatic gastrointestinal stromal tumours harbouring the platelet-derived growth factor receptor alpha (PDGFRA) D842V mutation.
• Advanced systemic mastocytosis (AdvSM): monotherapy in adults with aggressive systemic mastocytosis (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): adults with indolent systemic mastocytosis with moderate to severe symptoms inadequately controlled on symptomatic treatment.

• Hypersensitivity to avapritinib or to any of the excipients.

The safety database covers 585 patients with GIST, 193 with advanced systemic mastocytosis and 246 with indolent systemic mastocytosis. The most common reactions differ by indication:

• GIST (300 or 400 mg starting dose): nausea (45%), fatigue (40%), anaemia (39%), periorbital oedema (33%), hyperbilirubinaemia (28%), face oedema (27%), diarrhoea (26%), vomiting (24%), peripheral oedema (23%), increased lacrimation (22%), decreased appetite (21%) and memory impairment (20%). Serious reactions occurred in 23% of patients, most often anaemia (6%) and pleural effusion (1%).
• Advanced systemic mastocytosis (200 mg): periorbital oedema (38%), thrombocytopenia (37%), peripheral oedema (33%) and anaemia (22%). Serious reactions occurred in 12%, most often subdural haematoma, anaemia and haemorrhage (2% each).
• Indolent systemic mastocytosis (25 mg): peripheral oedema (12%), mostly grade 1. No serious or fatal reactions occurred in the 141 patients treated at 25 mg in the pivotal part of the PIONEER study.

The SmPC tables list reactions seen in at least 1% (GIST), 3% (advanced systemic mastocytosis) or 5% (indolent systemic mastocytosis) of patients, plus those named in its warnings whatever their frequency, and give percentages and severity grades. Combined by frequency group:

Very common (≥1/10): anaemia (GIST, advanced); decreased white cell and neutrophil counts, decreased appetite, memory impairment, dizziness, increased lacrimation, vomiting, abdominal pain, gastro-oesophageal reflux, hyperbilirubinaemia, raised transaminases and rash (GIST); thrombocytopenia and neutropenia (advanced); cognitive disorder, taste effects, nausea, diarrhoea, hair colour changes, oedema and fatigue (GIST, advanced); peripheral oedema (indolent).

Common (≥1/100 to <1/10): thrombocytopenia, conjunctivitis, decreased lymphocyte count, low phosphate, potassium, magnesium, sodium, calcium or albumin, dehydration, confusional state, depression, anxiety, insomnia, mental impairment, peripheral neuropathy, somnolence, headache, aphasia, speech disorder, tremor, balance disorder, hypokinesia, intracranial haemorrhage, ocular and conjunctival haemorrhage, blurred vision, photophobia, vertigo, hypertension, pleural effusion, dyspnoea, cough, nasal congestion, gastrointestinal haemorrhage, ascites, constipation, dysphagia, stomatitis, flatulence, salivary hypersecretion, palmar-plantar erythrodysaesthesia syndrome, photosensitivity reaction, pruritus, alopecia, skin hypopigmentation, myalgia, arthralgia, back pain, muscle spasms, acute kidney injury, raised creatinine, haematuria, asthenia, pyrexia, malaise, feeling cold, QT prolongation on the ECG, raised creatine phosphokinase and lactate dehydrogenase and weight change (GIST); leukopenia, epistaxis, contusion, pain and raised alkaline phosphatase (advanced); flushing, face oedema, insomnia, photosensitivity reaction and raised alkaline phosphatase (indolent). In advanced systemic mastocytosis, QT prolongation on the ECG also falls in this group, as do several reactions that are very common in GIST (memory impairment, dizziness, increased lacrimation, vomiting, abdominal pain, gastro-oesophageal reflux, hyperbilirubinaemia, raised transaminases and rash).

Uncommon (≥1/1,000 to <1/100): tumour haemorrhage, hepatic haemorrhage, encephalopathy and pericardial effusion (GIST); pericardial effusion, photosensitivity reaction and acute kidney injury (advanced).

Intracranial haemorrhage is the most serious reaction. It occurred in 1.7% of 585 GIST patients and in 3.2% of 126 patients with advanced systemic mastocytosis at 200 mg; it was more frequent with platelet counts below 50 × 10⁹/L and with starting doses of 300 mg or more, and fatal events occurred in under 1% of advanced systemic mastocytosis patients. None occurred in the 141 patients with indolent systemic mastocytosis in the pivotal part of PIONEER. Cognitive effects occurred in 33% of GIST patients, 18% of advanced systemic mastocytosis patients at 200 mg and 2.8% of indolent systemic mastocytosis patients, mostly grade 1 and generally reversible with dose interruption or reduction. In GIST, patients aged 65 or over had more reactions leading to dose reduction or discontinuation.

Avapritinib is cleared mainly by CYP3A, so strong and moderate modulators of this enzyme change its exposure.

• Strong and moderate CYP3A inhibitors (for example ketoconazole, itraconazole, posaconazole, voriconazole; erythromycin, clarithromycin, telithromycin; cobicistat, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir; conivaptan; boceprevir): itraconazole raised avapritinib Cmax 1.4-fold and AUC 4.2-fold. Avoid them. If a moderate inhibitor cannot be avoided in GIST or advanced systemic mastocytosis, the starting dose is reduced (see Administration and Dosage); in indolent systemic mastocytosis they must be avoided.
• Strong and moderate CYP3A inducers: rifampicin cut avapritinib Cmax by 74% and AUC by 92% after a single 400 mg dose, which may reduce efficacy. They should be avoided; St John’s wort, which induces CYP3A, is among them.
• Grapefruit and grapefruit juice: they inhibit CYP3A and should be avoided.
• Anticoagulants and other medicines that raise bleeding risk (for example warfarin, phenprocoumon): monitor blood counts and coagulation parameters closely, and weigh the risk of intracranial haemorrhage before starting.
• QT-prolonging medicines: consider interval ECG assessments of QT when avapritinib is taken with them.
• Food: a high-fat meal increases exposure, so the tablets are taken on an empty stomach.

Section 4.5 of the SmPC gives the complete interaction information.

Treatment should be started by a healthcare professional experienced in the diagnosis and treatment of the conditions for which avapritinib is indicated. For GIST, patient selection for the PDGFRA D842V mutation should rest on a validated test method. The tablets are taken once daily on an empty stomach, at least 1 hour before or at least 2 hours after a meal, and swallowed whole with a glass of water.

Recommended Dose

• GIST: 300 mg once daily, continued until disease progression or unacceptable toxicity.
• Advanced systemic mastocytosis: 200 mg once daily, continued until disease progression or unacceptable toxicity. This is also the maximum dose and must not be exceeded. Treatment is not recommended with a platelet count below 50 × 10⁹/L.
• Indolent systemic mastocytosis: 25 mg once daily, continued until disease progression or unacceptable toxicity. This is also the maximum dose.

Dose Adjustments for Side Effects

Interruption, with or without dose reduction, may be used to manage adverse reactions according to severity and presentation.

• Dose reduction steps: GIST 300 mg → 200 mg → 100 mg once daily. Advanced systemic mastocytosis 200 mg → 100 mg → 50 mg → 25 mg once daily. Indolent systemic mastocytosis 25 mg once daily → 25 mg every other day; below that, treatment is stopped.
• Intracranial haemorrhage of any grade: permanent discontinuation.
• Cognitive effects: grade 1, continue at the same dose or reduce or interrupt until improvement; grade 2 or 3, interrupt until improved to baseline, grade 1 or resolution, then resume at the same or a reduced dose; grade 4, permanent discontinuation.
• Other grade 3 or 4 reactions: interrupt until grade 2 or lower, then resume at the same dose or a reduced dose if warranted.
• Thrombocytopenia in advanced systemic mastocytosis: with platelets below 50 × 10⁹/L, interrupt until the count is at least 50 × 10⁹/L, then resume at a reduced dose; consider platelet support if it does not recover.

With CYP3A Inhibitors

If a moderate CYP3A inhibitor cannot be avoided, the starting dose is reduced from 300 mg to 100 mg once daily in GIST and from 200 mg to 50 mg once daily in advanced systemic mastocytosis. Strong inhibitors, and in indolent systemic mastocytosis any strong or moderate inhibitor, must be avoided.

Special Populations

• Elderly: no dose adjustment from age 65; clinical data in indolent systemic mastocytosis patients aged 75 or over are limited.
• Hepatic impairment: no adjustment in mild or moderate impairment. In severe impairment (Child-Pugh C) the starting dose is reduced: GIST 300 mg to 200 mg, advanced systemic mastocytosis 200 mg to 100 mg, indolent systemic mastocytosis 25 mg daily to 25 mg every other day.
• Renal impairment: no adjustment in mild or moderate impairment (creatinine clearance 30–89 mL/min). Not studied in severe impairment or end-stage renal disease, so use there cannot be recommended.
• Children and adolescents: safety and efficacy under 18 years have not been established; no data are available.

Missed or Vomited Dose

A missed dose is made up unless the next scheduled dose is due within 8 hours, in which case it is skipped. After vomiting, no extra dose is taken; treatment continues with the next scheduled dose.

Haemorrhage and Intracranial Haemorrhage

Avapritinib is associated with more haemorrhagic reactions, including serious gastrointestinal and intracranial bleeding, in GIST and advanced systemic mastocytosis; hepatic and tumour haemorrhage also occurred in GIST. Surveillance includes physical examination, complete blood counts with platelets and coagulation parameters, particularly in patients predisposed to bleeding or taking anticoagulants.

• Before starting at any dose, weigh the risk of intracranial haemorrhage in patients with a history of vascular aneurysm, intracranial haemorrhage or cerebrovascular accident within the prior year, concomitant anticoagulants or thrombocytopenia.
• Patients with relevant neurological signs (severe headache, vision problems, somnolence, focal weakness) must interrupt dosing and tell their healthcare professional at once. MRI or CT may be performed at the physician’s discretion.
• Any intracranial haemorrhage, of any grade, means permanent discontinuation.
• There is no clinical study experience in patients with brain metastases.
• In advanced systemic mastocytosis, a platelet count is taken before starting and avapritinib is not recommended below 50 × 10⁹/L. Platelets are then counted every 2 weeks for the first 8 weeks regardless of baseline; after that every 2 weeks if below 75 × 10⁹/L, every 4 weeks if 75–100 × 10⁹/L and as clinically indicated above 100 × 10⁹/L.

Cognitive Effects

Memory impairment, cognitive disorder, confusional state and encephalopathy can occur; the mechanism is unknown. Patients with GIST or advanced systemic mastocytosis are monitored for new or increased forgetfulness, confusion or difficulty with cognitive functioning and must report new or worsening symptoms at once. In indolent systemic mastocytosis, cognitive symptoms can be part of the disease, and patients should still report new or worsening ones.

Fluid Retention

Localised oedema (facial, periorbital, peripheral) or pleural effusion, and generalised oedema, occurred at least commonly in GIST. In advanced systemic mastocytosis, pulmonary oedema, pericardial effusion and ascites were also seen. Laryngeal oedema and pericardial effusion are uncommon. Weight and respiratory symptoms are assessed regularly; rapid unexpected weight gain or breathing symptoms need investigation and supportive care such as diuretics. Ascites should be investigated for its cause.

QT Prolongation

QT prolongation has been seen in GIST and advanced systemic mastocytosis and can raise the risk of ventricular arrhythmias, including torsade de pointes. Use caution in patients with known or possible QT prolongation (concomitant medicines, heart disease, electrolyte disturbances) and avoid strong or moderate CYP3A inhibitors. ECG assessment should be considered with QT-prolonging medicines, and in indolent systemic mastocytosis in patients with other QT risk factors such as age or rhythm disorders.

Gastrointestinal Effects, Blood Counts and Liver Function

Diarrhoea, nausea and vomiting are the most common gastrointestinal reactions; disease-related causes should be excluded, hydration monitored and antiemetic, antidiarrhoeal or antacid treatment used as needed. In GIST and advanced systemic mastocytosis, complete blood counts are performed regularly because of anaemia, neutropenia and thrombocytopenia, and transaminases and bilirubin are monitored regularly.

Photosensitivity

Direct sunlight should be avoided or minimised because of the risk of phototoxicity. Patients should use protective clothing and a high-SPF sunscreen.

Pregnancy, Breastfeeding and Fertility

• Contraception: pregnancy status is verified before starting. Women of childbearing potential must use effective contraception during treatment and for 6 weeks after the last dose; men with female partners of childbearing potential, during treatment and for 2 weeks after. Patients must contact their healthcare professional at once if pregnancy occurs or is suspected.
• Pregnancy: no data in pregnant women; animal studies showed reproductive toxicity. Avapritinib is not recommended in pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: it is unknown whether avapritinib or its metabolites pass into milk, so a risk to the infant cannot be excluded. Breastfeeding must stop during treatment and for 2 weeks after the last dose.
• Fertility: no human data; animal findings suggest male and female fertility may be compromised.

Sodium

Each tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Avapritinib can cause reactions such as cognitive effects that may affect the ability to drive and use machines. Patients who notice difficulty concentrating or reacting should take special care.

Ayvakyt tablets need no special storage conditions. They are supplied in a bottle of 30 tablets with a child-resistant cap, an induction-sealed liner and a desiccant.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B of the marketing authorisation), with treatment started by a healthcare professional experienced in diagnosing and treating GIST or systemic mastocytosis. Avapritinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.