Application of Translational Science to Clinical Development - Genomic Biomarkers for Pharmaceutical Development - page 17

1.5 CONCLUSIONS

Genomics research has transformed our understanding of disease and led to tangible
benefits in drug discovery and development. In particular, the landscape of cancer has
changed based on our evolving understanding of driver mutations and heterogeneity of
disease. In turn, this knowledge has led to accelerated drug development timelines as
shown ( Fig. 1.10 ).

BCR-ABL inhibition
(Gleevec)

41 years

1960 1973 1993-1995 1999 2001

Discovery of the
'Philadelphia
chromosome'

Mechanism of action:
translocation of lhe
ABL oncogene

BCR-Abl inhibitors
(patents filed)

Hematological responses in
CML (53 of 54 patients)

ERBB2 inhibition
(Herceptin)

13 years

1985-1987 1996 1998

ERBB2 cloning &
ID of amplification

ERBB2 expression is
predictive of response

PARP inhibition
(olaparib, iniparib,
MK-4827, others)

15 years

1994 2005 2009

ID of the first familial
breast cancer susceptibility
gene BRCA 1/2

Synthetic lethality of
PARP inhibition with
defects in DNA repair

Responses observed
only in confirmed
BRCA -mutant cancer

BRAF inhibition
(PLX-4032)

8 years

2002 2010

ID of BRAF mutations
in cell lines and malignant
melanoma

Responses in
BRAF
mutant tumors

ALK inhibition
(crizotinib)

3 years

2010

2007

ALK fusions
predict
response

Drug repositioning based on
EML4-ALK translocation in NSCLC

FIGURE 1.10 The historical timelines for developing targeted therapies in cancer. Gleevec received FDA
approval 41 years after the discovery of the Philadelphia chromosome mutation and hyperactive BCR-ABL pro-
tein in chronic myelogenous leukemia (CML). By contrast, the more recent discovery of chromosomal rearrange-
ments (translocations) of ALK in NSCLC has rapidly translated into registration trials and approval for crizotinib.
Likewise, the development paradigm for selective BRAF inhibitors, as exemplified by PLX4032, underlines the
much faster pace of translation (8 years, compared with Gleevec or Herceptin) once the driver status (in this case
BRAF mutations) had been established for an indication (malignant melanoma). The FDA approval of Herceptin
and the accompanying diagnostic test for HER2 expression (HercepTest) proved the value of biomarker-driven tri-
als that are informed by mechanistic insights gained from cancer genetics. The functional understanding of DNA-
repair mechanisms, and the role of BRCA1 and BRCA2 mutations in sensitizing tumors to PARP inhibition, inform
current registration trials of PARP inhibitors in BRCA-associated cancer types and patients that carry the BRCA
mutation. Adapted from Chin et al., Courtesy of Nature Medicine.