Page 0030

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

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