Alectinib

In the European Union, alectinib is indicated for the first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC); ==Contraindications==

There are no reported contraindications. ==Side effects==

Apart from unspecific gastrointestinal effects such as constipation (in 34% of patients) and nausea (22%), common adverse effects in studies included oedema (swelling; 34%), myalgia (muscle pain; 31%), anaemia (low red blood cell count), sight disorders, light sensitivity and rashes (all below 20%). Serious side effects occurred in 19% of patients; fatal ones in 2.8%. == Interactions ==

Alectinib has a low potential for interactions. While it is metabolised by the liver enzyme CYP3A4, and blockers of this enzyme accordingly increase its concentrations in the body, they also decrease concentrations of the active metabolite M4, resulting in only a small overall effect. Conversely, CYP3A4 inducers decrease alectinib concentrations and increase M4 concentrations. Interactions via other CYP enzymes and transporter proteins cannot be excluded but are unlikely to be of clinical significance. ==Pharmacology==

Mechanism of action The substance potently and selectively blocks two receptor tyrosine kinase enzymes: anaplastic lymphoma kinase (ALK) and the RET proto-oncogene. The active metabolite M4 has similar activity against ALK. Inhibition of ALK subsequently blocks cell signalling pathways, including STAT3 and the PI3K/AKT/mTOR pathway, and induces death (apoptosis) of tumour cells. Pharmacokinetics of alectinib. Alectinib itself and the active metabolite M4 are the main compounds found in the circulation, while the others are minor metabolites. Plasma half-life of alectinib is 32.5 hours, and that of M4 is 30.7 hours. 98% are excreted via the faeces, of which 84% are unchanged alectinib and 6% are M4. Less than 1% are found in the urine. == Chemistry ==

Alectinib has a pKa of 7.05. It is used in form of the hydrochloride, which is a white to yellow-white lumpy powder. == History ==

The approvals were based mainly on two trials: In a Japanese Phase I–II trial, after approximately 2 years, 19.6% of patients had achieved a complete response, and the 2-year progression-free survival rate was 76%. In November 2017, the FDA approved alectinib for the first-line treatment of people with ALK-positive metastatic non-small cell lung cancer. This based on the phase 3 ALEX trial comparing it with crizotinib. This was based on the Phase III ALINA study [NCT03456076]. In April 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion for the use of alectinib for adjuvant treatment of resected non‑small cell lung cancer (NSCLC). In June 2024, the EU approved alectinib as an adjuvant treatment for people in the EU with ALK-positive early-stage lung cancer. This was based on the Phase III ALINA study [NCT03456076]. In October 2024, the UK`s NICE recommended alectinib as an adjuvant treatment for adults for the treatment of stage 1B to 3A ALK-positive non-small-cell lung cancer. == Society and culture ==

Legal status Alectinib was approved in Japan in July 2014, for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small-cell lung cancer (NSCLC). The approval was upgraded from conditional to full approval in December 2017. == References ==