Download Development of the Novel Biologically Targeted Anticancer Agent

Vol. 10, 4607– 4613, July 15, 2004
Clinical Cancer Research 4607
Perspective
Development of the Novel Biologically Targeted Anticancer Agent
Gefitinib: Determining the Optimum Dose for Clinical Efficacy
Michael Wolf,1 Helen Swaisland,2 and
Steven Averbuch1
1
Clinical Research, AstraZeneca Pharmaceuticals, Wilmington,
Delaware, and 2AstraZeneca Pharmaceuticals, Macclesfield, Cheshire,
United Kingdom
ABSTRACT
The emergence of novel, biologically targeted anticancer agents such as gefitinib (‘Iressa’, ZD1839) has raised the
question of how the dose for later-stage clinical development
and clinical use is best determined. For cytotoxic drugs,
because toxic effects and antitumor activity often fall within
the same dose range and are dose dependent, the clinically
used dose will depend on the therapeutic window. Therefore,
the maximum tolerated dose identified in Phase I trials is
typically used to determine the dose level for Phase II and
III trials. However, because biologically targeted agents are
expected to provide clinical benefits that are not predicted
by surrogate end points of toxicity to normal replicating
tissue, new Phase I trials have been designed to determine
the optimum biological dose for use in further studies.
A large, multifaceted Phase I program was designed to
evaluate the pharmacokinetics, safety, efficacy, and targeted
biological activity of a once-daily oral dose of gefitinib. The
maximum tolerated dose was >700 mg/day, although doses
as low as 150 mg/day provided (a) plasma concentrations
sufficient for pharmacological activity, (b) evidence of targeted biological effect, and (c) antitumor activity. From
these observations, two large Phase II trials (‘Iressa’ Dose
Evuluation in Advanced Lung Cancer 1 and 2) evaluated
250- and 500-mg/day doses of gefitinib in patients with
advanced non-small cell lung cancer (NSCLC). As predicted
from the Phase I trials, doses >250 mg/day provided no
additional efficacy benefit, whereas adverse effects increased
in a dose-dependent manner. Consequently, the recommended dose of gefitinib in NSCLC is 250 mg/day. The early
clinical trial development of gefitinib provides a model for
the development of novel, noncytotoxic anticancer agents.
Received 1/12/04; revised 4/12/04; accepted 4/19/04.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
Note: S. Averbuch is currently at Merck Pharmaceuticals, Wynnewood,
PA. ‘Iressa’ is a trademark of the AstraZeneca group of companies.
Requests for reprints: Helen Swaisland, AstraZeneca, Alderley Park,
Macclesfield, Cheshire, SK10 4TG, United Kingdom. Phone: 44 (0)
1625 510340; Fax: 44 (0) 1625 585626; E-mail: helen.swaisland@
astrazeneca.com.
INTRODUCTION
In recent years, the search for novel anticancer agents has
moved from cytotoxic agents to biologically targeted agents
(which are primarily antiproliferative) to avoid the traditional
toxic effects of anticancer therapy and to develop more selective
and effective agents. Traditionally, Phase I trials of anticancer
agents aim to identify toxicities, pharmacokinetic (PK) profiles,
and the dose for Phase II trials. For cytotoxic agents, antitumor
activity and toxic effects generally occur within a similar dose
range, and the dose selected is usually the maximum tolerated
dose (MTD; Fig. 1A; Ref. 1). However, for biologically targeted
agents that are cytostatic, the maximum biological effect may
occur at doses lower than the MTD (Fig. 1B) and alternative end
points based on biological and/or clinical activity rather than
toxicity might be more appropriate (2). Alternative end points
may include changes in tumor markers, prolonged disease
stabilization, improvements in disease-related symptoms, pharmacodynamic assessment of the biological activity of the target
molecule, and pharmacokinetic studies.
One promising biological target is the epidermal growth
factor receptor (EGFR), because EGFR activation initiates a
signaling cascade that leads to a number of processes involved
in tumor progression, including increased proliferation, angiogenesis and invasion, and decreased apoptosis (3). In addition, a
variety of tumors express EGFR (4), giving rise to the wide
application of EGFR-targeted agents such as gefitinib (‘Iressa,’
ZD1839), an EGFR tyrosine kinase inhibitor. This review will
discuss how the strategic aim of defining the optimum biological dose (OBD) of gefitinib in the early clinical trial program
was achieved.
DESIGNING A CLINICAL TRIAL
FOR GEFITINIB
Several challenges were present in designing the Phase I
clinical trials of gefitinib, because this agent was expected to be
cytostatic rather than cytotoxic; hence, objective tumor
responses might not be expected. These challenges included a
scarcity of precedents, the way in which “biological activity”
was defined, the integration of outcomes across multiple tumor
types in Phase I trials (because the OBD and clinical activity
may not necessarily be the same for all tumor types), the
relationship between biological activity and clinical outcome,
and unknown PK and pharmacodynamic (PD) relationships.
Thus, four large, multicenter, randomized, oncology-like and
clinical pharmacology-like Phase I trials were designed.
Two conventional oncology-like Phase I trials used dose
escalation to identify the MTD and characterize the PK of
gefitinib in patients; these trials also ascertained whether there
was any evidence of antitumor activity (objective tumor
response and stable disease). Two more sophisticated pharmacology-like Phase I trials were split into Part A (dose escalation)
and Part B (randomized dose response). Up to four doses from
Part A were to be evaluated in Part B, with alternative efficacy
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4608 Gefitinib: Determining the Optimum Dose for Efficacy
Fig. 1 Idealized curves reflecting molecular target effects, antitumor effects, and toxicity as
functions of dose for (A) a typical
cytotoxic agent whose toxicity
occurs at roughly the same dose
as target effects and (B) a hypothetical target-based antiproliferative agent whose target effects
occur at lower doses than do
toxic effects (1). MTD, maximum tolerated dose; OBD, optimum biological dose.
end points used to collate tumor-specific PK/PD data for each
patient (tumor measurements, serum tumor markers, baseline
and day-28 tumor EGFR levels, and cell proliferation indices
from skin and tumor biopsies, where available). Data from these
four trials would enable dose levels for the Phase II/III trials to
be determined.
If a single dose level for Phase II/III trials could not be
determined, a blinded-review panel would assess evaluable
cases using the collated PK/PD data available from Part B of the
two pharmacology-like Phase I trials. The relevance of the data
(magnitude of change, reliability, and methodology) would be
weighed in a prospective algorithm to assign an overall targeted
biological effect (TBE) outcome (yes/no). Regression analysis
from dose-response (for the TBE) and exposure-response relationships would be constructed, from which dose selection could
be derived. Evidence of TBE would be based on tumor shrinkage, changes in tumor EGFR-specific markers [EGFR expression, phosphorylated EGFR, phospho-p44/42 mitogen-activated
protein kinase (pMAPK)], proliferation (Ki67) or apoptosis, and
skin EGFR markers and serum tumor markers.
PHASE I TRIALS OF GEFITINIB
Initial Phase I trials performed in healthy volunteers
showed that oral administration of gefitinib given once on day 1
(50, 100, 250 or 500 mg) or daily for 14 days (100 mg/day) was
feasible, and that PK parameters that were used to assess exposure to gefitinib increased in proportion to dose (5). Four multicenter Phase I trials then evaluated the safety profile of gefitinib (50 –1000 mg/day) in more than 250 patients with a wide
range of solid tumors that were known to express EGFR [e.g.,
non-small cell lung cancer (NSCLC) and head and neck, breast,
colorectal, prostate, and ovarian cancers], although baseline
expression levels were not determined (6 –9). All of the patients
had histologically confirmed advanced or metastatic tumors that
were refractory to conventional chemotherapy or hormone therapy, were aged ⱖ18 years, and had a life expectancy of ⱖ12
weeks and a WHO performance status of 0⫺1.
Oncology-like Trials. Two conventional oncology-like
Phase I monotherapy trials evaluated the safety of gefitinib
(50 –1000 mg/day) given daily for 14 days in 95 patients,
followed by 14 days’ observation (6, 7). Adverse events (AEs)
occurred at doses ⱖ50 mg/day, with the most commonly
reported AEs being mild-to-moderate (grade 1–2) acne-like
rash, diarrhea, nausea, anorexia, vomiting, and asthenia. The
frequency of AEs such as skin rash and diarrhea increased with
dose, and the MTD was identified as 700 mg/day. Exposure to
gefitinib increased with dose; in patients taking 100 –700 mg/
day, Cmax (peak plasma concentrations) and AUC0 –24 (area
under the curve from 0 to 24 h) increased from 105 to 2146
ng/ml and 1860 to 36077 ng䡠h/ml, respectively. Despite a 6 – 8fold interpatient variability at each dose level, biologically relevant plasma concentrations [⬎100 ng/ml, equivalent to the in
vitro IC90 (inhibitory concentration) for KB oral carcinoma cells
(3)] were generally maintained at doses ⬎100 mg/day across the
24-h dosing period. Disease control in these trials was observed
across the whole dose range; objective responses in 9 patients
with NSCLC were seen at 225 mg/day, 300 mg/day, 400 mg/
day, 525 mg/day, and 700 mg/day; and stable disease in 15
patients (5 with NSCLC) was seen at 50 mg/day, 100 mg/day,
225 mg/day, 400 mg/day, 525 mg/day, and 700 mg/day (6, 7).
For those nine patients with objective responses, steady-state
trough plasma concentrations ranged between 63 and 1873
ng/ml (10); interestingly, two patients taking 225 and 300
mg/day had steady-state trough plasma concentrations of gefitinib ⬍100 ng/ml, which suggests that plasma levels ⬍100
ng/ml may result in objective responses in patients with
NSCLC.
Oncology/Pharmacology-like Trials. Two pharmacologylike Phase I trials determined a dose range for gefitinib given
orally on a daily basis and further defined the OBD (8, 9).
Secondary objectives were to (a) monitor gefitinib exposure; (b)
investigate the feasibility and sensitivity of the Functional Assessment of Cancer Therapy (FACT) questionnaire for lung,
head and neck, breast, colorectal, prostate and ovarian cancer;
(c) assess improvements in NSCLC-related symptoms using the
seven-item Lung Cancer Subscale of FACT-Lung (11); and (d)
select tumor types for Phase II/III studies. Up to 14 patients
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Clinical Cancer Research 4609
were enrolled at each planned dose level (150 –1000 mg/day
gefitinib).
A total of 157 patients received 150-1000 mg/day gefitinib
(Table 1), with the MTD identified in one trial as 800 mg/day
(8) and not reached in the other (9). The most commonly
reported AEs (grade 1–2 diarrhea and skin rash) were dose
related across the range studied (150 – 800 mg/day), with dosage
interruptions and reductions generally required only at doses
⬎600 mg/day. There was no clear dose-response relationship
for disease control, which was observed at all doses (Table 2),
with 45 patients receiving gefitinib for ⱖ3 months, 20 patients
receiving gefitinib for ⱖ6 months, and 7 patients receiving
gefitinib for ⬎1 year (1 with a partial response and 6 with stable
disease). Patients with NSCLC who had stable disease for ⱖ6
months also had improvements or stabilization in diseaserelated symptoms, whereas those patients with disease progression had worse Lung Cancer Subscale (LCS) scores (12). Therefore, duration of treatment and the LCS might be useful in
determining clinical activity with gefitinib treatment.
Because the EGFR is present and important for normal skin
homeostasis (13, 14), the biological activity of gefitinib was
assessed using markers of PD effects from skin biopsies (e.g.,
levels of phosphorylated EGFR and activated pMAPK; Ref. 15).
These biopsies showed that EGFR phosphorylation was abolished and that activated pMAPK levels were significantly
reduced in skin biopsies from patients taking ⱖ150 mg/day
gefitinib (Figs. 2A and B, respectively), the lowest dose at which
objective tumor responses were noted. These PD analyses indicate that in the skin, gefitinib was exerting maximum biological
effect at the lowest dose studied.
Table 2
Patients with disease control who received gefitinib for
ⱖ6 monthsa,b
No. of
Time on
Gefitinib dose, mg/day patients Response Tumor study, months
150 (n ⫽ 19)
1
1
PRc
SD
NSCLC
NSCLC
17
15
225 (n ⫽ 7)
1
1
1
1
SD
SD
SD
SD
SCCHN
NSCLC
SCCHN
HRPC
28⫹d
14
8
7e
300 (n ⫽ 27)
1
1
1
1
SD
SD
SD
SD
Ovarian
SCCHN
NSCLC
NSCLC
9f
9
8
6
400 (n ⫽ 27)
1
1
1
1
1
SD
SD
SD
SD
SD
SCCHN
Ovarian
CRC
CRC
NSCLC
14d
7g
6
6
6
600 (n ⫽ 20)
1
1
SD
SD
NSCLC
NSCLC
25⫹d
14d
800 (n ⫽ 20)
1
SD
NSCLC
7
1000 (n ⫽ 17)
1
1
SD
SD
NSCLC
HRPC
8d
6h
DOSE SELECTION FOR PHASE II AND III
CLINICAL TRIALS
ⱖ 6 ⫻ 28-day treatment periods.
References 8 and 9.
PR, partial response; NSCLC, non-small cell lung cancer; SD,
stable disease; SCCHN, squamous cell carcinoma of the head and neck;
HRPC, hormone-refractory prostate cancer; CRC, colorectal carcinoma.
d
Includes time spent on extension compassionate-use trial.
e
Patient had a sustained decrease from baseline prostate-specific
antigen ⬎50% over 4 months.
f
No change in carbohydrate antignen 125 (CA125).
g
Patient had a 48% reduction in serum CA125.
h
Worsening in prostate-specific antigen levels observed.
The gefitinib Phase I trials were designed and planned for
the possibility that results might be unclear, because gefitinib
was anticipated to be cytostatic rather than induce tumor regression. However, the blinded-review panel was not required
because sufficient patients with objective tumor responses and
stable disease were observed across a range of tumors to establish a dose-response curve, supported by PD and PK assessments. The dose:response and dose:toxicity relationships observed are shown in Fig. 3; clinical benefit was not dose related
at doses ⱖ150 mg/day, whereas the most common AEs (skin
rash and acne) increased with gefitinib dose. These Phase I trial
results showed that the OBD for gefitinib is much lower than the
MTD, supporting the hypothetical model in Fig. 1B, and they
suggested that gefitinib had maximum biological and clinical
activity over the dose range 150-1000 mg/day. In addition, PK
a
b
c
Table 1 Patients receiving gefitinib by dose and tumor type in two Phase I pharmacology-like dose-escalation trialsa
Tumor type
b
Gefitinib dose, mg/day
NSCLC
(n ⫽ 61)
Ovarian
(n ⫽ 25)
CRC
(n ⫽ 28)
HRPC
(n ⫽ 17)
SCCHN
(n ⫽ 26)
Total
(n ⫽ 157)
150
225
300
400
600
800
1000
13
11
13
8
4
5
7
1
2
4
6
6
2
4
0
4
3
6
3
9
3
0
4
2
2
3
3
3
5
6
5
5
4
1
0
19
27
27
27
20
20
17
a
References 8 and 9.
NSCLC, non-small cell lung cancer; CRC, colorectal carcinoma; HRPC, hormone-refractory prostate cancer; SCCHN, squamous cell
carcinoma of the head and neck.
b
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4610 Gefitinib: Determining the Optimum Dose for Efficacy
dose related, grade 1–2 diarrhea, skin rash, dry skin, pruritus,
nausea, acne, vomiting, and elevated liver transaminases. Grade
3– 4 AEs were more frequently observed in patients receiving
500 mg/day than in those given 250 mg/day (Table 3), with the
increased incidence accounted for primarily by diarrhea.
Furthermore, fewer patients receiving 250 mg/day withdrew
(1.5% overall) compared with those given 500 mg/day (4.4%).
Consequently, the recommended dose of gefitinib in NSCLC is
now 250 mg/day, the dose at which ⬎40% of patients experienced disease control and a favorable tolerability profile was
maintained.
REACHING THE TARGET: GEFITINIB
TISSUE DISTRIBUTION
Fig. 2 Graphic display of the immunohistochemical evaluation of
paired skin samples taken before (Pre) and during (During) gefitinib
therapy. Percentage of keratinocytes with (A) activated epidermal
growth factor receptor (EGFR) and (B) phospho-p44/42 mitogen-activated protein kinase (MAPK) levels (15). ⴱ, P ⬍ 0.001.
studies indicated that plasma levels of gefitinib over this dose
range were sufficient for effective EGFR inhibition.
The objective tumor responses observed in patients with
NSCLC resulted in two dose levels being selected for Phase II
and III NSCLC trials. Although the lowest dose at which objective tumor responses were observed was 150 mg/day, there
was potential for individuals receiving this dose to have subtherapeutic exposure as a result of interpatient variability in
pharmacokinetics. Accordingly, the slightly higher dose of 250
mg/day was chosen because this dose would ensure adequate
gefitinib drug exposure. The second dose chosen was 500
mg/day, which was the highest dose that was well tolerated by
most patients on a chronic daily dosing schedule. Both doses
were significantly lower than the MTD (approximately onethird and two-thirds of the MTD, respectively), unlike conventional dose selection for chemotherapy agents, which would use
the MTD.
Evidence to support the extensive tissue distribution of
gefitinib has been provided in PK studies involving healthy
volunteers and patients with advanced solid tumors, which
found that gefitinib (50 –100 mg) had a very high volume of
distribution (ⱖ1400 liters; Table 4; Ref. 10). In the Phase I
trials, analysis of PD marker levels in the skin also provided
evidence that sufficient gefitinib was reaching the skin and
inhibiting EGFR signaling (15). Additionally, objective tumor
responses observed across a dosage range of 150-1000 mg/day
in the Phase I trials indicated that these doses resulted in target
inhibition in tumors. These data are supported by preclinical
xenograft (LoVo) data showing that, 8 h after the administration
of radiolabeled [14C]gefitinib, the tumor:plasma gefitinib ratio
was 11:1 (19); radioactivity levels in skin and tumor samples
were similar and considerably higher than those in the plasma.
Thus, gefitinib targets tumors effectively.
DISCUSSION
Although the primary objective of a Phase I trial is to
assess the safety profile of an anticancer agent, some evidence
PHASE II DOSE-EVALUATION TRIALS
IN NSCLC
Two large, dose-randomized, double-blind, parallel-group,
multicenter Phase II trials (‘Iressa’ Dose Evaluation in Advanced Lung Cancer 1 and 2) independently evaluated the
activity of 250 and 500 mg/day gefitinib in 425 patients with
advanced NSCLC (16, 17). These trials allowed a more detailed
evaluation of the doses selected from the Phase I trials and
included symptom improvement as an additional end point.
There was no difference between the doses for any of the
efficacy end points such as objective tumor response rate, disease control rate, time to progression, overall survival, and
symptom improvement. Symptom improvement occurred rapidly in both trials (8 –10 days) and was associated with conventional efficacy end points such as objective tumor response rates
and overall survival (18). However, fewer and less severe AEs
were observed with 250 mg/day than with 500 mg/day in both
trials. The most common AEs were manageable, noncumulative,
Fig. 3 Dose relationship of disease control (partial response plus stable
disease) and skin rash/acne in patients from the Phase I and II (IDEAL)
trials (31). Œ, Phase I rash/acne; 䉬, Phase I disease control; large open
triangle, Phase II rash/acne; large open diamond, Phase II disease
control.
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Clinical Cancer Research 4611
Table 3
IDEAL 1 and 2 drug-related grade 3– 4 adverse events, disease control, symptom improvement, and survivala
IDEAL 1
Drug-related grade 3–4 adverse events (%)
Response rate (%)
Disease control rate (%)
Overall survival (mo)
Symptom improvementd (%)
Patients with partial response experiencing
symptom improvement (%)
Improved quality of lifee (%)
IDEAL 2
250 mg/day
(n ⫽ 103)
500 mg/day
(n ⫽ 106)
250 mg/day
(n ⫽ 102)
500 mg/day
(n ⫽ 114)
8.7b
18.4
54.4
7.6
40.3
69.2
30.2b
19.0
51.4
7.9
37.0
85.7
6.9
11.8
42.2c
7
43
100
17.5
8.8
36.0c
6
35
90
23.9
21.9
34.3f
22.8f
a
References 16 and 17.
Reference 28.
c
Reference 29.
d
Assessed using the seven-item Lung Cancer Subscale (LCS) of Functional Assessment of Cancer Therapy-Lung (FACT-L).
e
Assessed using FACT-L.
f
Reference 30.
b
of antitumor activity is required to justify progression to Phase
II trials. For the evaluation of biologically targeted agents,
conventional clinical end points should be supplemented with
surrogate markers of clinical activity, because these agents
might not be expected to cause tumor regression or normal
tissue toxicity at maximally effective doses. This review has
used the example of gefitinib to show that early clinical trials of
biologically targeted agents should aim to identify the OBD
using clinical end points and one or more PD parameters.
NSCLC objective tumor response data from the Phase I
and II trials, in which objective responses were observed across
a wide dose range (150 –1000 mg/day; Fig. 3), indicate that
these doses of gefitinib were sufficient to inhibit EGFR signaling. However, in the absence of an objective response, how do
we know that relevant levels of biologically targeted agents are
reaching their target tissue? Evidence that gefitinib reaches
target tissues and tumors has been supported by the high tumor:
plasma ratio observed in xenograft models and by the high
volume of distribution of gefitinib (10, 19). Furthermore, PD
analyses of biomarker expression have shown that gefitinib at
250 mg/day and 500 mg/day inhibits EGFR-mediated signaling
in clinical breast and gastric cancer tumor biopsies (20, 21).
The use of surrogate markers has previously been shown to
be feasible in selecting the dose for cetuximab (IMC-C225), a
humanized anti-EGFR monoclonal antibody; 200 mg/m2 was
the lowest dose that saturated the antibody systemic clearance
rate and was significantly lower than the MTD (22). In the
gefitinib example, when conventional clinical end points were
used, doses above a certain threshold did not give better objective tumor responses, whereas AEs were dose-related (Fig. 3).
Surrogate markers (including inhibition of EGFR signaling in
skin biopsies, duration of treatment, and improvements in
disease-related symptoms) were also shown to be feasible for
Phase II dose selection. Indeed, the rapid onset of symptom
improvement in the Phase II trials along with an observed
correlation between symptom improvement and objective tumor
response, suggests that symptom improvement may be a rapid
surrogate marker of objective tumor response, although additional placebo-controlled studies are needed to clarify this.
Although the gefitinib Phase I trials aimed to explore the
OBD in an optimal fashion, there were a number of complications that may also apply in early trials of other novel targeted
agents. These included the fact that the patient population was
heterogeneous, with a variety of EGFR-expressing tumor types.
In addition, there is no certainty that each tumor type will be
equally sensitive to gefitinib or that the OBD will be identical in
all tumors. Such uncertainties meant that two doses (250 and
500 mg/day) were chosen for Phase II/III trials. Finally, much of
the PD data came from skin biopsies rather than tumor biopsies,
and, because biopsies are not easy to obtain for many tumor
types, this is a significant challenge for any approach relying on
tumor PD assessments.
Furhter refinements in the design of Phase I trials for
biologically targeted agents could also be made. One of the
complexities of using a blinded-review panel is in the evaluation
of TBE based on the relevance of each type of data, because
patients will be differently evaluable for specific data of antitumor effects. As such, trials could benefit from cross-validation
between experts to obtain a consensus, with focused discussion
on discordant cases. If all patients are evaluable for at least one
PD parameter (rather than depending on serial biopsies),
evidence of TBE could be measured consistently and more
Table 4
Intravenous pharmacokinetics of gefitiniba
Volume of distribution, liter
Mean
Range
Plasma clearanceb rate, ml/min
Mean
Range
Elimination half-life, h
Mean
Range
a
b
Healthy volunteers
50–100 mg i.v.
(n ⫽ 8)
Patients
50 mg i.v.
(n ⫽ 19)
1610
1230–2540
1400
830–2710
840
471–1250
514
194–1460
34
23–73
48
10–136
Reference 10.
Geometric mean.
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4612 Gefitinib: Determining the Optimum Dose for Efficacy
accurately; and, if there were more than one PD parameter per
patient, the relative merit of that parameter could be prospectively specified (a weighting factor). Potentially, if evidence of
a dose response for TBE is further explored in relation to
specific tumors (e.g., by increasing patient numbers across the
dose range to focus on the most reliable PD measures), a better
dose decision for subsequent trials could be determined.
One major challenge in designing clinical trials for biologically targeted agents and optimizing their use is how to identify
a patient population that is likely to benefit from treatment. In
the case of some novel targeted agents, such as trastuzumab,
high expression of the target itself is used to select the patients
to be treated (23, 24). However, the situation with gefitinib is
not so straightforward. Although clinical trials have recruited
patients with tumor types known to express EGFR, subsequent
retrospective gene expression and immunohistochemical analysis of EGFR expression have shown that tumor EGFR expression levels do not correlate with response to gefitinib (25),
although it remains possible that phosphorylated EGFR may be
more important (26). Thus, sensitivity to gefitinib is likely to be
much more complex and dependent on a number of factors, of
which the EGFR may be but one (27). Some studies have
investigated genes associated with resistance to gefitinib, and
one retrospective analysis found that increased expression of
gefitinib resistant gene 1 (GRG1) correlated with a decreased
probability of responding to gefitinib (25). Such analyses of
molecular factors are being explored in a wide-ranging clinical
trial program to explore more fully the potential to identify those
patients who will benefit from gefitinib treatment.
The clinical trials of gefitinib presented in this review have
shown that efficacy and surrogate end points (duration of treatment, improvements in disease-related symptoms, and PD
effects) have identified 250 mg/day as the OBD in NSCLC,
because higher doses of gefitinib do not give better responses
and cause increased toxicity. This recommended dose is onethird of the MTD and results in a favorable benefit:risk ratio.
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Development of the Novel Biologically Targeted Anticancer
Agent Gefitinib: Determining the Optimum Dose for Clinical
Efficacy
Michael Wolf, Helen Swaisland and Steven Averbuch
Clin Cancer Res 2004;10:4607-4613.
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