2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 1. Response Rates in Expanded Cohorts of Recent Phase I Trials of Targeted Drugs in Selected Patient Populations
Response
Response
Tumor Mutation Drug No. Patients Complete Partial Rate (%) Ref.
Basal Cell Cancer smoothed in hedgehog pathway GDC-0449 33 2 16 54 15
NSCLC EML4-ALK translocation Crizotinib 82 1 46 57 4
Melanoma BRAF (V600E) Vemurafenib 32 2 24 81 5
progression. The endpoint for the latter trial was response
rate, time to progression (TTP), and survival (despite the
crossover design).
Crizotinib received accelerated approval in August of
2011, 3 years after the first patient with EML-4/ALK
NSCLC entered the phase I trial, based on the results of the
82 patient expansion cohort of the phase I trial and the
confirmation of response rates and safety in the 173 phase II
trial. The phase III trial of crizotinib versus chemotherapy
has completed enrollment but has not yet been analyzed.
For vemurafenib, the strategy for obtaining drug approval
was somewhat different. The key registration trial was a
phase III comparing the new agent to a standard, but
ineffective drug, DTIC, which has a response rate of 10 percent.
7 In fact, DTIC is the only approved chemotherapy
agent for metastatic melanoma but does not prolong survival.
The endpoint was overall survival, and crossover to
the experimental drug at the time of progression was not
allowed. Vemurafenib was approved in September of 2011,
4 years after the first patient with BRAF V600E melanoma
entered the phase I trial for that drug; full marketing
approval for first-line treatment of metastatic melanoma
was based on a survival advantage versus DTIC in the
randomized phase III trial, which reached an early conclusion
1 year after receiving its first patient. The rapid
appreciation of success of the experimental drug in the
phase III trial led to amendment to allow crossover of
patients on the DTIC arm midway through the trial. The
decision to conduct a phase III trial of vemurafenib, without
crossover, provoked substantial criticism in the lay press
and editorial comment in leading medical journals, where
the ethics of comparing a clearly active agent with a drug of
minimal activity (basically a placebo) were questioned. The
decision to do so was attributed to the sponsor, which wished
to obtain exclusivity for first-line use of its drug. Interestingly,
crizotinib’s accelerated approval specified its use for
both first-line or later treatment of patients with stage III
(not the subject of a trial) or stage IV disease.
What are we to conclude from these recent decisions and
e2
KEY POINTS
● A patient selection strategy is essential to rapid drug
approval.
● Expansion phases of phase I trials allow early establishment
of disease response rates.
● Biomarkers for patient selection can be validated in
expanded phase I.
● One confirmatory phase II may be sufficient for
accelerated approval.
● Postapproval trials may refine the dose, schedule,
sequence, and combination therapies.
BRUCE CHABNER
strategies? It seems apparent that with a valid biomarker
test in hand and appropriate patient selection, an appropriately
targeted therapy can provide strong indications of its
ultimate value in an expanded cohort of subjects during a
phase I trial. A confirmatory phase II trial, which need not
be randomized if an active control is not available, can
provide sufficient evidence to convince regulatory authorities
to grant accelerated approval, and the process can be
completed in three years or less. In many types of cancer, a
strong indication of activity, such as a 50 percent or greater
partial and complete response rate coupled with a time to
progression of 4 to 6 months or greater, would represent a
significant step forward and need not require preapproval
confirmation in a phase III trial, particularly if no standard
therapy provides benefit. 8 One can imagine many such disease
entities, including grade glioblastomas, metastatic pancreatic
cancer, metastatic cholangiocarcinoma, hepatoma, and various
subsets of soft tissue sarcoma, in which standard therapies
are minimally active and significantly toxic. Given the
modest toxicity of most targeted agents, if a new agent
demonstrates impressive activity in its early trials, there is
minimal safety risk in granting accelerated approval for these
agents. Confirmatory trials postapproval would be required
and might take the form of randomized comparison of two
dose levels, intermittent compared with continuous therapy,
randomized discontinuation in patients with stable disease,
or randomization to continued therapy beyond progression
in combination with an alternative therapy. Such trials
would provide a better definition of safety, and survival
benefit, although in most cases, it would not be ethical to
deny the new agent to patients on any arm of the trial.
As an example of the potential strategy for a new targeted
agent, we might consider the development of a new drug for
patients with IDH 1 or IDH 2 mutations (Fig. 1). IDH is a
key enzyme in the intermediary metabolism of glucose in the
Krebs cycle, in which isocitrate to alpha ketoglutarate
(AKG). AKG is further utilized as a substrate for the Krebs
cycle and for more than 60 dioxygenase reactions. 9,10 The
dioxygenases require AKG as a substrate in reactions that
hydroxylate methylated bases, such as methyl cytosine
residues in DNA, and methyl groups in the histones that
control gene expression; hydroxylation of these sites leads to
demethylation and changes in gene expression. Dioxygenases
have other important functions. They participate in
the repair of DNA alkylation through removal of methyl or
ethyl adducts. Recent work has shown that mutations in
IDH 1 and 2 reduce AKG to a new enzymatic product,
2 hydroxyglutarate (2HG), the isomers of which function
either as potent inhibitors of dioxygenases or, in the case of
the R-isomer, activators of the same enzymes. 11 Inhibition
of dioxygenase function leads to hypermethylation of DNA
and of histone H3K27. 9,10 The IDH mutations, and their
product, 2HG, have transforming activity in preclinical
systems. Experimental and human tumors with underlying