347Crizotinib for Personalized Management of NSCLC
Crizotinib (Pfi zer’s Xalkori) is an orally available small molecule that blocks fusion
proteins of anaplastic lymphoma kinase (ALK). This fusion, EML4 (echinoderm
microtubule associated protein like 4)-ALK is a tyrosine kinase like BCR-ABL, and
its formation drives tumor formation; therefore, blocking it should halt tumor
growth. In a study of 1,500 patients with NSCLC, 5.5 % had a fusion containing
ALK, and 57 % of them responded well to crizotinib (Kwak et al. 2010 ). The FDA
has cleared for marketing Abbott’s companion diagnostic kit, Vysis ALK Break
Apart FISH Probe, for use with crizotinib to detect rearrangements of the anaplastic
lymphoma kinase gene in NSCLC. The kit uses FISH technology to detect rear-
rangements on the ALK gene on the 2p23 chromosome, providing clinicians a stan-
dardized, clinically validated method to identify those patients who may benefi t the
most from Pfi zer’s drug. The test is designed to identify the 3–5 % of all NSCLC
patients who would be candidates for Xalkori, and this is expected to change how
patients with NSCLC are diagnosed and treated.
Despite these remarkable initial responses, cancers eventually develop resistance
to crizotinib, usually within 1 year, thereby limiting the potential clinical benefi t. A
study enumerates the mutations in EML4-ALK that confer resistance to crizotinib
(Choi et al. 2010 ). Using a model of acquired resistance to ALK inhibitors, it was
shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treat-
ing crizotinib-resistant tumors harboring secondary gatekeeper mutations (Katayama
et al. 2011 ).
Ceritinib
Ceritinib (LDK378, Novartis) is a new ALK inhibitor that has shown greater antitu-
mor potency than crizotinib in preclinical studies. NSCLC harboring ALK gene
rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably
develops. In a phase I clinical trial, ceritinib was highly active in patients with
advanced, ALK-rearranged NSCLC, including those who had had disease progres-
sion during crizotinib treatment, regardless of the presence of resistance mutations
in ALK (Shaw et al. 2014 ). Responses were observed in patients with various resis-
tance mutations in ALK and in patients without detectable mutations. Among
patients with NSCLC who received at least 400 mg of ceritinib per day, the median
progression-free survival was 7 months.
EGFR Tyrosine Kinase Inhibitor Treatment
The tyrosine kinase inhibitor (TKI) gefi tinib (Iressa), which targets the epidermal
growth factor receptor (EGFR), is approved for late cases of non-small-cell lung
cancer (NSCLC) as a last resort treatment. Most of NSCLC patients do not respond
to gefi tinib but about 10 % of patients have a rapid and often dramatic clinical
Personalized Management of Cancers of Various Organs