Application of Translational Science to Clinical Development - Genomic Biomarkers for Pharmaceutical Development - page 4

Current

Drugs

Which patients respond best?

Emerging

Determine molecular profile
of the patient's tumor

Determine which drugs
are most appropriate

FIGURE 1.3 Two approaches to drug development: In the past, new molecular entities were tested in a variety
of indications, e.g., cancers of different types, to identify those patients most likely to respond. In the emerging
translational approach, molecular heterogeneity of a disease is analyzed first, and then therapeutics are developed
and tailored to subsets of disease. Adapted from [5] .

1.2.1 Prospective Analysis: The Case of Crizotinib in NSCLC
The crizotinib story started several years ago, when analysis of a cDNA library from a
Japanese patient with lung adenocarcinoma identified a novel fusion between the EML4
and ALK genes with the ability to transform 3T3 fibroblasts [7] . Analysis of a series of biop-
sies from NSCLC patients revealed that ~5% of patients carry this fusion protein.
Soon after the publication of the initial discovery in 2007, it was found that crizotinib, a
small molecule inhibitor of the protein encoded by the ALK gene, was very effective in
NSCLC patients whose tumors harbored the ALK fusion gene. It caused tumors to shrink or
stabilize in 90% of 82 patients carrying the ALK fusion gene, and tumors shrank at least 30%
in 57% of people treated [8] . These promising clinical results led to a Phase II and a Phase III
trial, which selectively enrolled NSCLC patients with ALK fusion genes. Astonishingly, within
four years of the initial publication by Soda et al., the Food and Drug Administration (FDA)
approved crizotinib for the treatment of certain late stage (locally advanced or metastatic)
NSCLC patients whose tumors have ALK fusion genes as identified by a companion diagnos-
tic that was approved simultaneously with the drug [6] .
There are several important lessons to be learned from the development of crizotinib.
First, understanding molecular heterogeneity to identify a mutation or pathway that is caus-
ally linked to the disease is crucial to the eventual success. With this knowledge in hand,
investigators could design small but highly effective trials targeted to those patients more
likely to benefit from the therapy. Such approaches allow drug companies to save both
money and time in drug development. The approval for crizotinib was based on two reg-
istrational trials that enrolled fewer than 150 subjects each. To better illustrate how target-
ing patients can improve the PoS of a clinical trial, we performed simulations to estimate the
sample sizes that would be required if patients had not been selected in trials of a drug like
crizotinib that is targeted to, for instance, only 10% of the population.
Under the assumption of placebo response rates ranging from 6-14% in typical cancer
clinical trials [9] , if patient randomization is conducted requiring the presence of a bio-
marker, or biomarker positive group, the minimum sample size needed at 80% power and
alpha = 0.05 could be as low as N = 33 / arm, with a 30% effect size and 6% response rate in