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response. The molecular mechanisms underlying sensitivity to gefi tinib are
unknown. It was considered to be a targeted therapy based on the idea that lung
cancer might produce excess of EGFR, and blocking it might slow growth with less
toxicity than standard chemotherapy. This growth protein contains a little pocket to
capture ATP. Gefi tinib apparently targets that pocket, and when the protein is
mutated, gefi tinib fi ts inside the pocket much better, blocking ATP and thus inhibit-
ing cancer-cell growth. Patients with lung cancer who respond to gefi tinib have been
reported to have somatic mutations consisting of deletions in exon 19 and in exon
21 of the EGFR gene. In addition, a mutation in exon 20 is also associated with
acquired resistance to gefi tinib in initially gefi tinib-sensitive patients.
Laboratory studies of cancer cells show that the mutated receptors are 10 times
more sensitive to gefi tinib than normal receptors. The mutations are more common
in women, nonsmokers, and persons who had a subtype called bronchoalveolar can-
cer. EGFR mutations have been reported in lung cancer samples from patients who
responded to gefi tinib (Eli Lilly & Co’s Iressa) therapy and in a lung adenocarci-
noma cell line that was hypersensitive to growth inhibition by gefi tinib, but not in
gefi tinib-insensitive tumors or cell lines. These results suggest that EGFR mutations
may predict sensitivity to gefi tinib. Increased EGFR gene copy number based on
FISH analysis is a good predictive biomarker for response to EGFR inhibitors, sta-
ble disease, time to progression, and survival in NSCLC. However, EGFR mutation
is a better predictor of clinical outcome in gefi tinib-treated patients than the CNV’s
of EGFR gene. These fi ndings are important as they would enable the development
of personalized treatment of cancer. The EGFR Mutation Assay (Genzyme) detects
EGFR mutations in patients with NSCLC that correlate with clinical response to
Tarceva ® (erlotinib) and Iressa ® (gefi tinib). This would enable treatment of respond-
ers and even at an earlier stage than the current practice of using it as a last resort.
Prospective large scale clinical studies must identify the most optimal paradigm for
selection of patients.
Ficlatuzumab (Aveo Oncology) is a HGF inhibitory antibody in an exploratory
phase II study as fi rst-line treatment of NSCLC patients and VeriStrat (Biodesix), a
commercially available test that helps physicians guide treatment decisions for
NSCLC patients, is being developed as a companion diagnostic under an agreement
between the two fi rms. VeriStrat can gauge prognosis of patients treated with EGFR
inhibitors that are also TKIs and predict which patients would have better
progression- free survival from fi clatuzumab plus a TKI rather than from a TKI
alone. A proof-of-concept trial of fi clatuzumab plus erlotinib (Pfi zer’s Tarceva) will
be conducted in advanced NSCLC. Patients in this study will be selected using
VeriStrat.
Many patients with NSCLC who show radiographic responses to treatment with
EGFR tyrosine kinase inhibitors gefi tinib and erlotinib have somatic mutations in
the EGFR tyrosine kinase domain. Both are known as small-molecule drugs that
can be taken orally and block the part of the EGFR molecule that’s located within
the cell. Combined use of gefi tinib and cetuximab (Erbitux), a MAb for CRC, shows
that although both drugs kill cells containing a normal but overactive EGFR mole-
cule, only gefi tinib kills lung cancer cells containing a mutated EGFR molecule
10 Personalized Therapy of Cancer