Alectinib

Alectinib is a highly selective and potent inhibitor of the anaplastic lymphoma kinase (ALK) and rearranged during transfection (RET) tyrosine kinases. In ALK-positive non-small cell lung cancer (NSCLC), an abnormal ALK fusion protein such as EML4–ALK drives tumour cell proliferation; alectinib blocks that signal.

Mechanism of Action

• ALK inhibition: alectinib blocks ALK tyrosine kinase activity, including the EML4–ALK fusion protein found in some NSCLC. In preclinical studies this shut down signalling through STAT3 and the PI3K/AKT pathway and induced tumour cell death (apoptosis).
• Mutant ALK: it was active in vitro and in vivo against mutant forms of ALK, including mutations that cause resistance to crizotinib.
• Active metabolite: the major metabolite, M4, has similar in vitro potency and activity against ALK.
• Central nervous system: in preclinical data alectinib is not a substrate of the efflux transporters P-gp and BCRP at the blood–brain barrier, so it can distribute into and remain in the central nervous system.

Pharmacokinetics

• Absorption: with food, peak levels are reached after about 4 to 6 hours, and steady state within 7 days (about 6-fold accumulation). Absolute bioavailability is 36.9% with food. A high-fat, high-calorie meal raised alectinib and M4 exposure about 3-fold compared with fasting, which is why the capsules are taken with food.
• Distribution: alectinib and M4 are more than 99% bound to plasma proteins. The steady-state volume of distribution after intravenous dosing was 475 L, indicating extensive tissue distribution.
• Metabolism: CYP3A4 is the main enzyme converting alectinib to M4 (an estimated 40–50% of alectinib metabolism) and metabolising M4 further. Alectinib and M4 are the main circulating compounds.
• Elimination: the mean half-life is about 33 hours for alectinib and 31 hours for M4. After a radiolabelled dose, 98% of the radioactivity was recovered in faeces, mostly as unchanged alectinib (about 84%) with some M4 (about 6%), and less than 0.5% in urine, so renal elimination is negligible.

Alectinib is indicated as monotherapy in adults with ALK-positive non-small cell lung cancer (NSCLC):

• Adjuvant treatment of resected NSCLC: following complete tumour resection, in patients at high risk of recurrence (selection criteria are given in section 5.1 of the SmPC).
• Advanced NSCLC, first line: first-line treatment of ALK-positive advanced NSCLC.
• Advanced NSCLC after crizotinib: ALK-positive advanced NSCLC previously treated with crizotinib.

• Hypersensitivity to alectinib or to any of the excipients.

The safety data come from 533 patients with resected or advanced ALK-positive NSCLC given 600 mg twice daily. Each of the following affected at least 20% of them: constipation, myalgia, oedema, increased bilirubin, increased AST, anaemia, rash and increased ALT.

Very common (≥1/10): anaemia, bradycardia (including sinus bradycardia), diarrhoea, vomiting, constipation, nausea, increased AST, increased ALT, increased bilirubin, increased alkaline phosphatase, rash, myalgia, increased blood creatine phosphokinase, increased blood creatinine, oedema, weight increased.

Common (≥1/100 to <1/10): haemolytic anaemia (reported in the adjuvant trial), dysgeusia, vision disorders (such as blurred vision, floaters, reduced visual acuity, diplopia, photophobia and photopsia), interstitial lung disease or pneumonitis, stomatitis, photosensitivity, acute kidney injury, hyperuricaemia.

Uncommon (≥1/1,000 to <1/100): drug-induced liver injury.

Important serious reactions are interstitial lung disease or pneumonitis, liver injury, severe myalgia with raised creatine phosphokinase, symptomatic bradycardia and haemolytic anaemia.

CYP3A4 is the main enzyme metabolising alectinib and its equally active metabolite M4, so strong CYP3A modulators change their combined exposure only slightly; the SmPC recommends monitoring rather than dose changes.

• Strong CYP3A inducers (carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St John’s wort): rifampicin lowered alectinib exposure (peak by 51%, area under the curve by 73%) but raised M4, so the combined exposure fell by only 4% (peak) and 18% (area under the curve). No dose adjustment; monitor appropriately.
• Strong CYP3A inhibitors (ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, grapefruit, Seville oranges): posaconazole raised alectinib exposure (peak 1.18-fold, area under the curve 1.75-fold) but lowered M4, so the combined peak fell by 7% and the area under the curve rose 1.36-fold. No dose adjustment; monitor appropriately.
• Substrates of P-gp and BCRP: the SmPC gives separate guidance on these transporter substrates (sections 4.4 and 4.5).
• Food: alectinib must be taken with food, which raises exposure about 3-fold compared with fasting.

Treatment should be started and supervised by a physician experienced in the use of anticancer medicines. A validated ALK assay is needed to select patients, and ALK-positive status must be established before treatment starts. The capsules are swallowed whole with food; they must not be opened or dissolved.

Recommended Dose

• 600 mg (four 150 mg capsules) twice daily with food, a total of 1,200 mg per day.
• Adjuvant treatment of resected NSCLC: continue until disease recurrence or unacceptable toxicity, or for 2 years.
• Advanced NSCLC: continue until disease progression or unacceptable toxicity.
• Severe hepatic impairment (Child-Pugh C): starting dose of 450 mg twice daily with food (900 mg per day).

Dose Adjustments for Side Effects

• Reduce in steps of 150 mg twice daily according to tolerability: from 600 mg to 450 mg, then to 300 mg twice daily. Stop permanently if the 300 mg twice daily dose is not tolerated.
• Interstitial lung disease or pneumonitis of any grade: interrupt immediately, and stop permanently if no other cause is identified.
• ALT or AST above 5 times the upper limit of normal (ULN) with bilirubin up to 2 times ULN: withhold until recovery to baseline or ≤3 times ULN, then resume at a reduced dose.
• ALT or AST above 3 times ULN with bilirubin above 2 times ULN, without cholestasis or haemolysis: stop permanently.
• Raised creatine phosphokinase, symptomatic bradycardia and haemolytic anaemia are managed as described under Special Instructions.

Special Populations

• Hepatic impairment: no starting dose adjustment in mild (Child-Pugh A) or moderate (Child-Pugh B) impairment; 450 mg twice daily in severe impairment. Monitor liver function in all patients with hepatic impairment.
• Renal impairment: no dose adjustment in mild or moderate impairment; none is needed in severe impairment either, although it has not been studied, because renal elimination is negligible.
• Elderly (65 years and older): no dose adjustment is suggested by the limited data; there are no data above 80 years.
• Body weight above 130 kg: no data are available.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed or Vomited Dose

A missed dose can be taken unless the next dose is due within 6 hours. Never take two doses at the same time to make up for a missed one. If vomiting occurs after a dose, take the next dose at the scheduled time.

Interstitial Lung Disease and Pneumonitis

Patients should be monitored for pulmonary symptoms suggesting pneumonitis; treatment is interrupted at once if it is diagnosed (see Administration and Dosage).

Hepatotoxicity

ALT and AST rises above 5 times ULN, and bilirubin rises above 3 times ULN, occurred mostly in the first 3 months, and three patients with grade 3 to 4 aminotransferase rises had drug-induced liver injury. ALT, AST and total bilirubin should be checked at baseline, every 2 weeks for the first 3 months and periodically afterwards (more often if they rise), as events can occur later. Treatment is withheld and resumed at a reduced dose, or stopped permanently, according to severity.

Severe Myalgia and Creatine Phosphokinase Elevation

Myalgia and raised creatine phosphokinase (CPK), including grade 3 events, occurred; the median time to a grade 3 or higher CPK rise was 15 days. Patients should report unexplained muscle pain, tenderness or weakness. CPK is assessed every two weeks during the first month and as clinically indicated in patients with symptoms; treatment is withheld, then resumed or reduced according to severity.

Bradycardia

Symptomatic bradycardia can occur. Heart rate and blood pressure should be monitored as clinically indicated. Asymptomatic bradycardia needs no dose change; if it is symptomatic or life-threatening, medicines known to cause bradycardia and antihypertensives should be reviewed and alectinib adjusted as set out in the SmPC.

Haemolytic Anaemia

If the haemoglobin concentration falls below 10 g/dL and haemolytic anaemia is suspected, alectinib is withheld and laboratory tests started. If it is confirmed, treatment is resumed at a reduced dose once the anaemia has resolved.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid pregnancy and use highly effective contraception during treatment and for at least 5 weeks after the last dose. Men with female partners of childbearing potential must use highly effective contraception during treatment and for at least 3 months after the last dose.
• Pregnancy: there are no or limited data. Alectinib may cause foetal harm based on its mechanism of action, and animal studies showed reproductive toxicity. A woman who becomes pregnant during treatment or within 5 weeks of the last dose, or a man whose partner becomes pregnant during treatment or within 3 months of the last dose (the partner should also seek medical advice, given alectinib’s aneugenic potential), must contact their doctor.
• Breastfeeding: it is unknown whether alectinib or its metabolites pass into human milk; a risk to the infant cannot be excluded, so mothers should not breastfeed during treatment.
• Fertility: no animal fertility studies have been performed.

Lactose and Sodium

Each capsule contains 33.7 mg of lactose (as monohydrate) and 6 mg of sodium, so the usual daily dose of eight capsules contains about 270 mg of lactose and 48 mg of sodium. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it; patients on a controlled sodium diet should take the sodium into account.

Effect on Driving

Alectinib has a minor influence on the ability to drive and use machines. Caution is needed because patients may have symptomatic bradycardia (for example syncope, dizziness or low blood pressure) or vision disorders.

Alecensa capsules must be kept in the original package to protect them from moisture, with bottles tightly closed; the SmPC states no temperature limit. They are supplied in aluminium blisters (224 capsules as 4 packs of 56) or in a bottle with an integrated desiccant (240 capsules); not all pack sizes may be marketed. Keep out of the sight and reach of children.

5 years. Do not use after the expiry date stated on the pack.

Prescription only (Rx), subject to restricted medical prescription: treatment is started and supervised by a physician experienced in the use of anticancer medicines. Alectinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.