Alectinib

Introduction 

Alectinib is a second-generation oral drug that selectively inhibits the activity of anaplastic lymphoma kinase (ALK) tyrosine kinase. Experts specifically use it in the treatment of non-small cell lung cancer (NSCLC); expressing the ALK-EML4 (echinoderm microtubule-associated protein-like 4) fusion protein that causes proliferation of NSCLC cells. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced tumour cell viability. 

Approved under accelerated approval in 2015; alectinib is indicated for use in patients who have progressed on or were not tolerant of crizotinib which is associated with the development of resistance. Alectinib’s approval was in Japan in July 2014 for the treatment of ALK fusion-gene positive. The US Food and Drug Administration (FDA) in December 2015 granted it the accelerated approval to treat patients with advanced ALK-positive NSCLC. 

Chemical Formula:

C30H34N4O2

Mechanism of action:

Alectinib is a second-generation oral drug that selectively inhibits the activity of anaplastic lymphoma kinase (ALK) tyrosine kinase. Experts specifically use it in the treatment of non-small cell lung cancer (NSCLC); expressing the ALK-EML4 (echinoderm microtubule-associated protein-like 4) fusion protein that causes proliferation of NSCLC cells. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced tumour cell viability. Both alectinib and its major active metabolite M4 demonstrate similar in vivo and in vitro activity against multiple mutant forms of ALK. Alectinib and its major metabolite M4 are >99% in accordance to human plasma proteins.

Alectinib reached maximal concentrations at 4 hours; following administration of 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC. The absolute bioavailability was 37% in the fed state. A high-fat, high-calorie meal increased the combined exposure of alectinib and its major metabolite M4 by 3.1-fold following oral administration of a single 600 mg dose.

CYP3A4 metabolises Alectinib to its major active metabolite M4. CYP3A4 then further metabolises M4. Both alectinib and M4 demonstrate similar in vivo and in vitro activity. In vitro studies suggest that alectinib is not a substrate for P-gp while M4 is.

When radioactively labelled, 98% of the radioactivity was found in faeces with 84% of that amount excreted as unchanged alectinib and 6% as M4. Less than 0.5% was found to be recovered in urine. The mean elimination half-life is 33 hr for alectinib and 31 hr for M4.

The length of time that you take Alecensa for will depend on your response and how well you tolerate it. Alecensa treatment usually continues until there is disease progression or the patient has unacceptable side effects.

How to take Alecensa?

Alecensa is an oral tablet and one has to take it twice a day.

  • The usual starting dose is 600mg twice daily.
  • The experts can reduce the dose to 450mg twice daily or even 300mg twice daily if the patient is unable to tolerate side effects.
  • If side effects continue to be a problem at the lower dose of 300mg twice daily, then the experts discontinue Alecensa.

Adverse Effects: 

The most common adverse reactions (>5%) associated with alectinib use were fatigue, constipation, edema, and myalgia. Less common effects associated with use were hepatotoxicity, interstitial lung disease (ILD)/pneumonitis, bradycardia, severe myalgia and creatine phosphokinase (CPK) elevation, and embryo-fetal toxicity. Experts advise females of reproductive potential to use effective contraception during treatment with alectinib and for 1 week following the final dose.