Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Clinical Applications of Pharmacogenomics in Cancer Therapy
169
The presence of an EGFR-activating mutation in advanced stages of NSCLC
treated with gefitinib or erlotinib increases the median survival from 10 up to 27
months. In the absence of such EGFR-activating mutations, gefitinib therapy is
not superior to conventional chemotherapy. The presence of the T790M resistance
mutation at presentation, together with an EGFR-activating mutation, predicts a
shorter time to progression of the disease. Whereas the absence of EGFR-activating
mutations is clearly associated with the nonresponse to gefitinib, it has been described
that patients without EGFR-activating mutations seem to have a slightly better outcome
with erlotinib compared with a placebo. In the EURTAC trial, erlotinib was
compared to platinum doublet chemotherapy; in patients with EGFR mutation positive,
PFS was higher in erlotinib compared with the platinum doublet chemotherapy.
Additionally, when erlotinib was compared with gemcitabine and carboplatin in
OPTIMAL trial, it yielded a higher PFS. 97
All EGFR inhibitors share similar toxicities that are important to patients, which
are diarrhea, uncommon interstitial pneumonitis, and acneiform rash. Acneiform
rash is a characteristic of EGFR inhibitors as there are high levels of EGFR in the
basal layer of epidermis. 96
CRIZOTINIB AND CERITINIB
A small fraction of patients with NSCLC (4–8%) may have EML4-ALK mutation
that can produce an inversion of chromosomes that results in fusion of oncogenes.
Tumors that contain these EML4-ALK fusion oncogenes are associated with specific
clinical features, such as little or no smoking history, younger age of patients,
and adenocarcinoma subtype. 98
EML4-ALK fusion oncogene provides a potential target for therapeutic intervention.
Small molecule inhibitors that can target the ALK tyrosine kinase may be able
to block ALK receptor, thus producing an anticancer effect on these tumor cells.
Crizotinib (Xalkori ® ) is a TKI that targets the ALK. Crizotinib is approved for
the treatment of locally advanced or metastatic NSCLC with ALK-positive mutation
that is detected by an FDA-approved test. 99 Crizotinib targets the ALK gene,
which results in expression of oncogenic fusion proteins. These proteins function in
activating and dysregulating a gene’s expression, ultimately causing increased cell
proliferation and survivals of the tumor cells that express these proteins. Crizotinib
inhibits the activities from these proteins, thus reducing the cell proliferation and
promoting apoptosis of the tumor cells that express these ALK mutations. 100
Ceritinib is the newly approved ALK inhibitor. It is indicated for the treatment
of patients with anaplastic lymphoma kinase (ALK)–positive metastatic
NSCLC who have progressed on or are intolerant to crizotinib. This indication is
approved under accelerated approval based on tumor response rate and duration
of response. 101 There are currently two phase III trials studying ceritinib compared
to single-agent chemotherapy and comparing ceritinib with platinum-based
doublet in the first-line setting. 102,103 With the success of its first ALK inhibitors,
several second-generation ALK inhibitors are currently under development
to provide more potent and more selective inhibitors that will be paved for the
future of NSCLC therapy (LDK378, alectinib). 104