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Alectinib


Topic Completed: 26 October 2020

Minor changes: 26 October 2020

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PubMed Search: Alectinib[TI] NSCLC with ALK mutation

Y. Albert Yeh, M.D., Ph.D.
Page views in 2020 to date: 51
Cite this page: Yeh YA. Alectinib. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/drugsalectinib.html. Accessed November 23rd, 2020.
Definition / general
  • Alectinib is a therapeutic agent that inhibits the activity of anaplastic lymphoma kinase (ALK)
  • Developed by Hoffmann-La Roche, Inc. and Genentech, Inc.
Trade name
  • Alecensa®
Indications
  • To treat patients with advanced or recurrent ALK positive non small cell lung cancer (NSCLC) or who could not tolerate crizotinib (Xalkori®) - approved by U.S. Food and Drug Administration (FDA) in December 2015
  • First line treatment of patients with ALK positive metastatic NSCLC - approved by U.S. FDA in November 2017
Pathophysiology
  • In normal cells, ALK is activated by dimerization of extracellular ligands and autophosphorylation of intracellular tyrosine kinase, mostly involved in the neurodevelopment of CNS, gut and testes (Figure 1)
  • ALK has been found to fuse with other genes in NSCLC, more commonly with EML4 gene; the resulting EML4-ALK fusion gene occurred in 3 - 6% of lung adenocarcinoma
  • ALK is activated by the 5' fusion partner (e.g. EML4) that serves as a functional promotor and expresses a domain in the fusion protein for dimerization (Figure 1)
  • Dimerized ALK rearranged fusion proteins activate downstream signaling pathways including STAT3, mTOR, PI3K, Ras and MEK to enhance cell survival, angiogenesis and cell cycle progression (Figure 1)
  • Alectinib inhibits ALK tyrosine kinase by binding to its ATP binding site and blocking autophosphorylation of the EML4-ALK fusion protein, thereby inhibiting downstream STAT3, Ras and PI3K signaling pathways (Figure 2)
  • Reference: Semin Cancer Biol 2017;42:81
Diagrams / tables

Images hosted on other servers:
Rearranged ALK signaling in NSCLC

Rearranged ALK signaling in NSCLC

Alectinib binds to tyrosine kinase

Alectinib binds to tyrosine kinase

ALK break apart probe for rearranged ALK

ALK break apart probe for rearranged ALK

Mechanisms of EML4-ALK rearrangement

Mechanisms of EML4-ALK rearrangement

Alectinib interacts with ALK P loop

Alectinib interacts with ALK P loop

Clinical information
  • Hepatotoxicity: monitor liver function tests every 2 weeks for first 3 months, then monthly
  • Not recommended in patients with moderate to severe hepatic impairment
  • Withhold the drug if patients develop interstitial lung disease
  • Withhold the drug if patients develop renal impairment
  • Bradycardia: monitor heart rate and blood pressure regularly
  • Myalgia: monitor creatine phosphokinase (CPK) every 2 weeks in first month
  • Embryo fetal toxicity: advise females to use elective contraception
  • Pharmacokinetics (Drug Saf 2019;42:199)
    • Bioavailability: 37% (taken with a meal)
    • Protein binding: > 99%
    • Metabolism: CYP3A4 and other CYP enzymes and aldehyde dehydrogenase
    • Plasma half life: 32.5 hours
    • Excretion: mainly via feces (98%), minor fraction in urine (< 1%)
    • Steady states: reached within 7 days
  • Reference: FDA: Highlights of Prescribing Information [Accessed 8 October 2020]
Uses by pathologists
  • ALK immunohistochemistry: cytoplasmic staining for altered ALK protein expression (N Engl J Med 2010;363:1693, Mod Pathol 2013;26:1545)
    • Clone ALK1, Dako mouse monoclonal ALK1 antibody CD246, sensitivity 100%, specificity 99%
    • Clone 5A4, Novocastra mouse monoclonal antibody p80 ALK, sensitivity 100%, specificity 98%
    • Clone D5F3, Cell Signaling Technology rabbit monoclonal ALK XP, sensitivity 100%, specificity 99%
    • Clone 1A4, Zeta mouse monoclonal anti-ALK antibody
  • ALK FISH: gold standard for evaluating ALK rearrangement
    • ALK 2p23 dual color break apart FISH probe for detecting ALK gene rearrangement (Figure 3)
    • ALK / EML4 tricolor FISH probe for detecting EML4-ALK gene fusion
  • ALK RT-PCR and next generation sequencing
Side effects
  • Fatigue (> 20%)
  • Constipation (> 20%)
  • Anemia (20%)
  • Peripheral edema (17%)
  • Myalgia (16%)
  • Increased blood bilirubin (15%)
  • Increased ALT (15%)
  • Increased AST (14%)
  • Nausea (14%)
  • Diarrhea (12%)
  • Increased weight (10%)
  • Dizziness (8%)
  • Musculoskeletal pain (7%)
  • Vomiting (7%)
  • Photosensitivity reaction (5%)
  • Dysgeusia (3%)
  • Blurred vision (2%)
  • Visual impairment (1%)
  • Alopecia (1%)
  • Increased γ glutamyltransferase (1%)
  • References: N Engl J Med 2017;377:829, FDA: Highlights of Prescribing Information [Accessed 8 October 2020]
Drug administration
Molecular theory
  • ALK is located at chromosome 2p21 and EML4 at 2p23.1-23.2
  • EML4-ALK fusion gene can be caused by chromosomal inversion or a complicated chromosomal translocation (chromothripsis) (Figure 4) (J Thorac Oncol 2014;9:1638)
  • Alectinib weakly interacts with the P loop of rearranged ALK protein shown in the cocrystal structures (Figure 5) (Lung Cancer 2017;110:32)
Board review style question #1
Which of the following lung primary tumors could be treated with alectinib?

  1. Adenocarcinoma with ALK rearrangement
  2. Adenocarcinoma with c-MET rearrangement
  3. Adenocarcinoma with EGFR mutations
  4. Small cell carcinoma with MYC rearrangement
Board review answer #1
A. Adenocarcinoma with ALK rearrangement

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Reference: Alectinib
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