Personalized Health Care (PHC) in Cancer - Genomic Biomarkers for Pharmaceutical Development - page 30

TABLE 2.3 EGFR Tkis Compared to Chemotherapy in Unselected and selected Patient

Populations

EGFR TKIs Platinum Doublets

TTP or PFS
(months)

OS
(months)

TTP or PFS
(months)

OS
(months) Patient Selection RR (%) RR (%)

Unselected 20-23 3-4.4 13.9-14.7 17-21 3.1-4.2 7.4-8.1

Molecularly
Selected*

62-71 9.2-13.1 28.0 32-47 5-6 23.6

(Adapted from Lopez-Chavez and Giaccone [43] .)
Abbreviations: OS = overall survival; PFS = progression free survival; RR = response rate; TTP = time to progression.
* EGFR TKI sensitizing mutation positive.

group, the EGFR TKI gefitinib was shown to be superior to conventional chemotherapy
for the first line treatment of NSCLC with sensitizing EGFR mutations [47] . In this study,
gefitinib with cisplatin plus docataxel was given to 172 chemotherapy-naïve patients with
stage IIIB / IV NSCLC who had EGFR mutations that were either exon 19 deletions or L858R
point mutations. Patients treated with gefitinib had a longer progression-free survival than
chemotherapy-treated patients and the objective response rate was 62.1% in the gefitinib
group compared to 32.2% in the chemotherapy group [47] . Prior to this trial, EGFR TKIs
had been tested in unselected patient populations with a frequency of EGFR mutations at
12-15% and these patients achieved a response rate of 20-23%. This is substantially lower
than that observed in patients selected for EGFR mutations, highlighting the value of this
predictive marker. Table 2.3 illustrates the difference in response rate and overall survival
achievable with EGFR TKIs when targeting the appropriate patient population.

BCR / ABL TRANSLOCATION, ALK FUSIONS, AND PML-RARA FUSION
Chronic myeloid leukemia accounts for 15% of newly diagnosed cases of leukemia
in adults [51] . Most CML cases are associated with a translocation between the Abelson
murine leukemia (ABL) gene on chromosome 9 with the breakpoint cluster region (BCR)
gene on chromosome 22, resulting in the fusion protein BCR-ABL acting as a constitutively
active tyrosine kinase found only in cancer cells [2,3] . Small molecule TKIs were developed
to target this abnormally expressed BCR-ABL protein in CML cells, leading to a dramatic
change in the management of this disease, and improving the 10-year overall survival from
approximately 20% to 80-90% [52] . Measurement of the BCR-ABL protein can be accom-
plished by measuring the co-localization of genomic probes specific to the BCR and ABL
genes using FISH or by amplifying the region around the splice junction between BCR
and ABL using polymerase chain reaction (PCR) [51] . The existence of BCR-ABL predicts
response to imatinib, a selective TKI of this fusion protein that has demonstrated substantial
and durable responses in CML, leading to FDA approval in 2001 [2,3,53] .
Crizotinib is a small molecule TKI originally synthesized to inhibit activated HGFR
(c-Met); however, studies also showed that it could inhibit anaplastic lymphoma kinase
(ALK) [54-56] . This is clinically significant due to the role of ALK in a subtype of non-
Hodgkin's lymphoma (fusion of the ALK gene with the NPM gene leads to constitutively