one-third of the patients. Overall, the test identified a molecular
alteration in 64% of patients, including 362 NSCLC patients with
no available tumor tissue [62]. In several instances, mutations were
identified after an initial response to a targeted agent that can be
successfully inhibited with additional lines of therapy, emphasizing
the potential clinical significance of repeated assessment of ctDNA
for targetable mutations throughout the disease course. For exam-
ple, EGFR mutations that emerge during the treatment of NSCLC
patients with erlotinib or gefitinib can be successfully targeted with
rociletinib. Similarly, second-generation inhibitors are available for
ALK mutations that emerge after initial ALK blockade. The same
principles apply to other mutations associated with a range of solid
and hematological cancers.4.3.2 ALK TKI ALK is a validated molecular target in several ALK-rearranged
malignancies, including NSCLC cancer, anaplastic large-cell lym-
phoma, and pediatric neuroblastoma. Anaplastic lymphoma kinase
(ALK) gene rearrangements represent the fusion between ALK and
various partner genes, in which the most widely recognized rear-
rangement is the echinoderm microtubule-associated protein-like
4 (EML4)-ALK fusion detected in NSCLC. ALK rearrangements
represent a unique subset of NSCLC patients. ALK inhibitors may
represent a very effective therapeutic strategy, which could be
applied to approximately 5% of NSCLC [63] (Table2).
Patients with ALK rearrangements are resistant to EGFR TKIs
but share many of the clinical features of NSCLC patients likely to
harbor EGFR mutations (e.g., adenocarcinoma histology, never
smokers, light smokers) except they are more likely to be men and
may be younger [64, 65]. However, ALK rearrangements and
EGFR mutations are mutually exclusive [66]. Collaborative efforts
between basic and clinical scientists in academia and pharmaceutical
industry have led to the development of numerous ALK tyrosine
kinase inhibitors (TKIs). Preclinical studies established the poten-
tial of this ALK fusion. Transgenic mice expressing EML4-ALK in
lung alveolar epithelial cells developed innumerable adenocarci-
noma nodules in their lungs soon after birth [67]. So far, three
oral ALK TKIs (crizotinib, ceritinib, and alectinib) have received
the approval by the US FDA for treatment of advanced or meta-
static NSCLC with ALK gene rearrangement. Clinical trials have
demonstrated remarkable responses in this patient population
[68–73].
Although originally developed as a potent MET inhibitor, cri-
zotinib was the first ALK TKI to be applied in the clinical practice
[74]. In 2011, the results of phase I/II trial demonstrated the robust
clinical activity in advanced ALK-rearranged NSCLC. Thus, crizoti-
nib was granted accelerated approval by the FDA [63]. Thereafter,
58 Jun Li et al.