Biomedical Engineering Reference
In-Depth Information
Mutations in the
gene are associated with gastrointestinal stro-
mal tumors (GIST) and other types of tumors (Chapter 9). Most pa-
tients with gain-of-function mutations respond to imatinib, which is
indicated for patients with c-Kit-positive unresectable and/or meta-
static malignant GIST.
Kit
35
Crizotinib, a small-molecule inhibitor of the receptor tyrosine
kinases c-Met and an anaplastic lymphoma kinase (ALK), has
been recently developed for the treatment of several cancer types
(Chapter 16).
36,37
It has significant anti-tumor activity in non-small
cell lung cancer (NSCLC) with the
echinoderm microtubule-associated
protein-like 4 anaplastic lymphoma kinase (EML4-ALK)
fusion gene
38
demonstrated by early clinical trials.
fusion gene
is detected for up to 6% of NSCLC, which likely represents a valid
therapeutic biomarker for a subset of NSCLC patients with
The
EML4-ALK
EML4-
ALK
fusion gene. Another signaling kinase inhibitor vemurafenib
(PLX4032), which selectively targets the activating BRAF
V600E
mutation, has been shown to have dramatic anti-tumor activity in
metastatic melanoma.
A recent Phase III study (known as the
BRIM3 trial) demonstrated that patients with metastatic melanoma
treated with vemurafenib had an improved overall survival (OS)
and progression-free survival (PFS) compared with those treated
with dacarbazine.
39,40
41
V600E
mutation is present
in about 50% of melanoma, and accordingly represents a promising
therapeutic biomarker for patients with melanoma (Chapter 17).
The oncogenic BRAF
42
As anticipated, in August 2011, the FDA approved vemurafenib
tablets (ZELBORAF
TM
, Hoffmann-La Roche Inc.) for the treatment
of patients with unresectable or metastatic melanoma with the
BRAF V600E mutation.
The mutation is detected by the approved
companion diagnostic―the COBAS
43
®
4800 BRAF V600E Mutation
Test (Roche Molecular Systems, Inc.). Also in August 2011, the FDA
granted accelerated approval to crizotinib (XALKORI
®
Capsules,
Pfizer, Inc.) for the treatment of patients with locally advanced or
metastatic NSCLC that is ALK-positive. Concurrently with the drug
approval, the FDA approved its companion diagnostic test―the Vysis
ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.).
The epidermal growth factor receptor (EGFR) tyrosine kinase
inhibitor erlotinib is prescribed for patients with advanced-stage
NSCLC whose tumors have not progressed after initial treatment
with certain types of chemotherapy or as second-line and third-line
treatment after failure of at least one prior chemotherapy regimen.
44
