O
ver 1.8 million people were diagnosed with lung
cancer in 2012, making it the most common form of
cancer worldwide. It is the leading cause of cancer
deaths in men, the second in women and 1.59 million people
die annually from the disease (1).
Although there have been significant advances in imaging to
detect the presence of tumours and testing procedures to
determine pathology (2, 3), lung cancer continues to carry a
significant mortality and over 60% of patients die within a year
of diagnosis (4).
New therapeutic approaches
Since the 1990s, the success rates for drug development have
fallen significantly across all therapeutic areas, including
oncology. However, there is clear evidence of innovative new
medicines making it successfully through the pharmaceutical
industry pipelines. An increasing proportion of novel cancer
medicines are targeted to patient populations where cancer
growth is driven by a pathway specifically inhibited by the
drug. Another exciting emerging trend is the understanding of
the mechanisms or "checkpoints" controlling the development
of an immunosuppressive environment within tumours. Novel
medicines are being developed which can affect these
"checkpoints" and induce prolonged responses based on
reactivation of immune-driven tumour cell killing (5, 6).
However, these same opportunities also present challenges
which require adaptation of the "traditional" drug
development route starting from phase I. Success is indeed
possible, and it requires good understanding of the driving
biology, the right preclinical models, understanding of the
limitations of these models, and close collaboration between
drug developers, diagnostic developers, academic
investigators and regulatory bodies.
Defining the success factors
At AstraZeneca, we undertook a comprehensive review of our
drug projects from 2005-2010. The analysis allowed us to
establish a framework based on the five most important
technical determinants of project success and pipeline quality,
which we describe as the five "R"s: the right target, the right
patient, the right tissue, the right safety and the right
commercial potential (Figure 1). A sixth factor - the right
culture - is also crucial in encouraging effective decisionmaking
based on these technical determinants.
This framework is now being used by AstraZeneca's R&D
teams, although it is too early to evaluate the full impact of the
5R approach on oncology drug development. However, there
are some interesting differences in the development paths of
gefitinib, the first personalised drug for non-small cell lung
cancer (NSCLC) and AZD9291, an oral, potent, selective,
irreversible inhibitor of both epidermal growth factor
receptor (EGFR) tyrosine kinase inhibitor (TKI) sensitising and
resistance mutations in development for the treatment of
advanced NSCLC. By examining each approach in more detail,
we can see the improved application of emerging knowledge
and early signs of the impact of the 5R framework.
Before 5R
Gefitinib entered phase I clinical trials in 1998 (7, 8) where
evidence of major tumour regression was seen in a small
proportion of NSCLC patients. Two doses were selected for
investigation in phase II and phase III trials in an unselected
patient population in NSCLC. The phase II trial demonstrated
an encouraging response rate of 18-19% (9). However, the
phase III trials adding gefitinib on to standard of care
chemotherapy subsequently failed to show an improvement in
overall survival or substantive improvement in progression
free survival (PFS) in the unselected patient population (10, 11).
In 2004, it was discovered that "super-responders" to
gefitinib had a mutation in the EGFR ATP binding pocket
which was shown to be a tumour "driver" (12, 13). When
patients are selected based on the presence of a sensitizing
mutation in EGFR, the response rates to gefitinib are
approximately 70% with median PFS of 9 to 12 months (14).
The IPASS trial demonstrated a statistically significant
improvement in PFS in the sub-group with EGFR mutations
SPONSORED FEATURE: ASTRAZENECA
28 CANCER CONTROL 2015 ONCOLOGY DRUG DEVELOPMENT -
ACTIVATING THE 5R FACTORS
SUSAN GALBRAITH, PHD, VP AND HEAD OF ONCOLOGY INNOVATIVE MEDICINES UNIT, ASTRAZENECA