Download Pharmacologic insights into the future of trastuzumab

Annals of Oncology 12 (Suppl. I): S43-S47, 2001.
© 2001 Kluwer Academic Publishers. Printed in the Netherlands.
Symposium article
Pharmacologic insights into the future of trastuzumab
B. Leyland-Jones,1 A. Arnold, 2 K. Gelmon,3 S.Verma,4 J.-P. Ayoub,1 A. Seidman,5 R. Dias, 6
J. Howell7 &A. Rakhit 8
1
Department of Oncology, McGill University, Montreal; 2Hamilton Regional Cancer Centre, Hamilton; iBCCA Vancouver Centre, Vancouver;
Otta\va Regional Cancer Centre, Ottawa, Canada; 5Memorial Sloan Kettering Cancer Center, New York, USA; 6F. Hoffmann-La Roche Ltd,
Toronto, Canada; 7F. Hoffmann-La Roche Ltd, Welwyn Garden City, UK; SF. Hoffmann-La Roche Ltd, Basel, Switzerland
4
Summary
A combination of factors has been responsible for improvements in cancer survival and cure rates. In addition to new
therapies with novel/genetic targets, these include improvements in drug delivery, new schedules/sequencing of drug
administration and the identification of combination therapies
with greater activity/dose density than existing regimens. The
recognition that such criteria can affect treatment outcome has
led to their incorporation into clinical trials of new drugs.
Furthermore, pharmacokinetic and pharmacodynamic parameters have become increasingly important for the rational
selection of dose, administration route and schedule. The
humanized monoclonal antibody trastuzumab (Herceptin) has
been rationally developed to target the human epidermal
growth factor receptor-2 (HER2), which is overexpressed in
20%-30% of breast cancers and is associated with poor prog-
Introduction
New drug discovery has played a major role in improving
cancer outcome and many new agents for the treatment
of metastatic breast cancer have been developed, including the taxanes [1, 2], vinorelbine [3,4] and trastuzumab
(Herceptin) [5]. However, recent developments in drug
administration and new combination therapy regimens
have also resulted in improvements in treatment outcome. Thus, changing administration route (e.g., the
introduction of i.v. or intra-arterial administration) [6],
changing drug formulation (which includes administering chemotherapeutic drugs encapsulated in liposomes
or bound to polymers) [6], and introducing new drug
combinations (e.g., trastuzumab plus taxanes) [7, 8],
have contributed to the improvement in outcomes. Such
strategies, either alone or in combination, have been
successful in positively impacting cancer survival and
cure rates [9-12].
Based upon these considerations, optimal drug formulation, route of administration and selection of combination therapy have become extremely important factors
in new drug development and are the subject of multiple
clinical trials [6, 13, 14]. Such advances require that
nosis. Trastuzumab when administered i.v. on a weekly schedule
either alone or in combination with taxanes, improves survival
of women with HER2-positive metastatic breast cancer. Based
upon pharmacokinetic considerations, current studies are examining whether trastuzumab can be administered i.v. every
three weeks or by the s.c. route. These regimens would have
advantages for patients and medical staff in terms of acceptability, ease of administration and, potentially, cost effectiveness. Furthermore, various combinations of trastuzumab and
chemotherapeutic agents are being explored with the aim of
identifying the optimal combination regimen for clinical use.
The rationale for these various studies and the studies themselves are described.
Key words: combination therapy, HER2, Herceptin, intravenous, pharmacokinetics, subcutaneous, trastuzumab
the pharmacology of new drugs, in particular their
pharmacokinetics, is well characterized [6, 14]. Drug
physicochemical properties influence bioavailability and
thus optimal formulation, whereas pharmacokinetics
influence drug distribution and serum concentrations,
and contribute to optimal route of administration. Ascertaining the precise mechanism of action of the specific
agent together with pharmacodynamic considerations
of the agent's interaction with its target /receptor are
critically important. An excellent example of the latter
is the inhibition by trastuzumab of the repair of DNA
adducts induced by cisplatin, thus promoting tumor cell
death [15,16].
Trastuzumab is a recently approved humanized monoclonal antibody directed against the extracellular domain
(ECD) of the human epidermal growth factor receptor-2
(HER2) [5]. A HER2-positive status is observed in
20%-30% of breast cancers [17] and is associated with
poor prognosis [18]. Trastuzumab is approved in the
USA for the treatment of HER2-positive metastatic
breast cancer as an initial dose of 4 mg i.v. over 90
minutes followed by weekly doses of 2 mg i.v. over 30
minutes until disease progression, either alone or in
combination with taxanes [19]. However, two clinical
44
Table I. Pharmacokinetics in phase I and II trials using various doses of trastuzumab.
Dose (mg)/regimen
Single-dose studies"
10
50
100
250
500
Multiple-dose study
100b
a
b
Dose (mg/kg)
0.163
0.787
1.433
3.7
7.7
±0.006
±0.124
±0.451
±1.02
±1.31
1.55 ±0.30
Number of patients
Cmax (ug/ml)
Half-life (days)
Clearance (ml/day/kg)
3
3
3
4
3
3.0 ± 0.064
19.0 + 8.6
29.0 ± 7.4
93.0 ±23.0
170.0
1.1
2.8
3.3
130
23.0
38.0
13.0
12.0
6.1
4.1
84
116.0 ±62.0
±0.26
±0.64
±0.28
± 11.0
± 1.9
9.02 ± 9.76
±7.2
± 1.1
±4.2
±1.9
6.26 ± 7.44
Genentech, data on file.
Combined data from studies reported in Baselga et al. [22] and Pegram et al. [23].
tion with cisplatin 100 mg/m2 i.v. administered on a
four-weekly dose schedule (n = 15) (study H0453g)
(data on file, F. Hoffmann-La Roche Ltd). The maximum tolerated dose was not reached in either study and
concomitant administration of cisplatin did not influence
the pharmacokinetic profile of trastuzumab. Furthermore, trough serum concentrations were at or above the
levels associated with anti-proliferative activity in vitro.
Phase II studies in which larger numbers of women
with metastatic breast cancer were treated with trastuzumab 250 mg i.v. followed by weekly doses of 100 mg
Pharmacokinetics of trastuzumab
i.v. until disease progression with (n = 46) or without
Humanization of the murine monoclonal antibody 4D5 cisplatin 75 mg/m2 every four weeks (n = 39) produced
to produce trastuzumab resulted in a molecule with in similar results [22, 23]. In the single-agent trial, > 90%
vitro binding affinity for the HER2 ECD three-fold that of patients had trastuzumab trough levels above the
of the parent antibody (Kd = 0.1 nM) [5]. Trastuzumab target level of 10 ug/ml and the mean serum half-life of
was also shown to be cytostatic and to mediate anti- trastuzumab was 8.3 days [22]. In the combination trial,
body-dependent cellular cytotoxicity against HER2- the mean trough and peak trastuzumab concentrations
were approximately 79 ug/ml and 123 ug/ml, respectively,
positive cells in these and other in vitro studies [5, 20].
Preclinical pharmacokinetic studies of trastuzumab and the mean half-life was 5.8 days [23].
have revealed slow serum clearance (<0.7 ml/kg/hour)
The pharmacokinetic and safety data from these
and a long terminal half-life (less than one week) (data early clinical trials led to the use in pivotal clinical trials
on file, F. Hoffmann-La Roche Ltd). Maximal tumor of a trastuzumab dosing schedule in which the drug was
growth inhibition in preclinical studies was associated administered as a 4 mg/kg i.v. initial dose with subsewith antibody concentrations of between 1 and 23 ug/ml quent weekly doses of 2 mg/kg i.v. [7, 8, 24]. However,
(data on file, F. Hoffmann-La Roche Ltd). A minimum available data also indicate that higher doses of trastuserum trough concentration of 10 ug/ml was considered zumab are likely to be well tolerated and could be
necessary for a therapeutic response in humans and was administered at longer intervals without compromising
therefore targeted in clinical studies [5, 21].
the clinical efficacy of the drug. Furthermore, because
Initial phase I trials evaluating single fixed doses of trastuzumab was administered i.v. in both the early and
trastuzumab of between 10 and 500 mg demonstrated an pivotal clinical trials, other routes of administration
increase in mean half-life from one day to three weeks warrant investigation.
and a decrease in clearance from 38 to 4.1 ml/kg/day
with increasing dose level (Table 1). In other words,
trastuzumab showed dose-related non-linear pharmaco- Phase I/II study of a three-weekly schedule of
kinetics in which clearance was faster and half-life shorter trastuzumab in combination with paclitaxel
at doses < 100 mg (data on file, F. Hoffmann-La Roche
Ltd). This finding was important because it indicated A phase I/II study of trastuzumab in combination with
that it may be possible to administer trastuzumab for paclitaxel administered i.v. every three weeks to women
longer intervals while maintaining serum concentrations with HER2-positive metastatic breast cancer has recently
above the minimum required for therapeutic activity.
started enrolling patients. Women will receive an initial
The tolerability of trastuzumab was assessed in phase trastuzumab dose of 8 mg/kg i.v. followed by 6 mg/kg
I trials of multiple weekly doses of i.v. trastuzumab (10- i.v. every three weeks in combination with paclitaxel 175
500 mg) alone (n = 17) (study H0452g), or in combina- mg/m2 also every three weeks (Figure 1). The primary
trials currently being conducted are examining alternative dose schedules and routes of administration. Other
preclinical and clinical studies are examining various
trastuzumab combination therapy regimens to determine
the most active regimen for clinical use. The pharmacokinetics of trastuzumab in relation to its dosing are
reviewed, and the protocols and aims of studies examining different trastuzumab regimens are described.
45
Week
—I %
0
3
6
•
i
i
Scanning
t
9
12
15
18
21
24
27
30
t
t
t
t
i
I t
t t t
Herceptn* 6 mg/kg i v. + paclitaxel 175 mg/m'
3
,3//
42
45
t
48
t t
52
Follow-up
Herceptin* 6 mg/kg i.v.
Herceptin* 8 mg/kg P.V.
+
paclitaxel 175mg/m"
Figure 1. Design of the clinical trial examining the pharmacokinetics and safety of trastuzumab administered i.v. every three weeks. Women with
HER2-positive metastatic breast cancer are eligible for the trial in which trastuzumab will be administered with paclitaxel to allow its effect on
trastuzumab pharmacokinetics to be studied. Therapy will continue until disease progression.
(a)
Herceptin* 2 mg/kg s.c.
1 I I 1I I I I I I I I 1I I I I i I
2
3 4
i
I
Herceptin*
4 mg/kg i.v.
5 6 ..17 18 19 20 21 22 23 24 25..44 45 46 47 48
7
I
i
//
i
t T
i
i
I
I
I
i
i
i //
i
i
i
i
i
t
Paclitaxel q3 weekly
Herceptin*
4 mg/kg s.c
I ,,\
2
3
4
5
ttttttttt
6 17 18 19 20 21 22 23 24 25 44 45 46 47 48
tttttttttttttt
(b)
Herceptin* 2 mg/kg s.c.
Figure 2. Design of the clinical trial examining the pharmacokinetics and safety of trastuzumab administered s.c. Trastuzumab will be
administered to women with HER2-positive metastatic breast cancer either once (a) or twice (b) weekly in combination with a standard weekly
paclitaxel regimen Therapy will continue until disease progression.
objective of this study is to characterize the pharmacokinetics of trastuzumab on this dose schedule. The trastuzumab continuation phase of the trial will allow the
pharmacokinetics of trastuzumab alone to be compared
with those in combination with paclitaxel in this patient
population. This is of interest because prior studies in
rhesus monkeys and the pivotal phase III clinical trial
have suggested that the serum concentration of trastuzumab increases by 50% in the presence of paclitaxel
(data on file, F. Hoffmann-La Roche Ltd). Secondary
objectives are to evaluate the safety and tolerability of
trastuzumab in combination with paclitaxel administered
every three weeks.
Simulation of the dose regimen of trastuzumab
6 mg/kg every three weeks suggests that the serum
trough concentration will be 40-50 ug/ml. This is above
the minimum trough concentration established as being
required for therapeutic efficacy [5, 21]. Furthermore, it
is similar to the serum trough concentrations observed
in early trials of trastuzumab 2 mg/kg i.v. weekly (data
on file, F. Hoffmann-La Roche Ltd), which is the dose
that has shown clinical efficacy in phase III trials.
The enrolment target of 32 patients was reached on
December 20, 2000.
Subcutaneous administration of trastuzumab
Subcutaneous administration is a relatively simple,
potentially self-administered alternative to i.v. administration, and would be particularly useful for the adjuvant
treatment of women with breast cancer. In studies in
female rhesus monkeys, it has been demonstrated that
the bioavailability of trastuzumab 2 mg/kg administered
s.c. is 54% (data on file, F. Hoffmann-La Roche Ltd).
Furthermore, this method of administration failed to
produce any overt clinical signs or symptoms of toxicity
and there was no evidence of the formation of trastuzumab-neutralizing antibodies.
Based on these data, a clinical study has been designed with the following objectives: to characterize the
pharmacokinetics of trastuzumab following single and
multiple s.c. doses; to define the safety and tolerability of
s.c. trastuzumab in combination with paclitaxel; to obtain preliminary activity data for the trastuzumab plus
paclitaxel combination; and to define the pharmacokinetics of paclitaxel. The study design incorporates
both single-agent trastuzumab and trastuzumab plus
paclitaxel combination therapy to achieve these objectives (Figure 2). The initial dose of single-agent trastuzumab 2 mg/kg s.c. followed by a two-week wash-out
period will allow its pharmacokinetics to be examined.
46
The subsequent trastuzumab plus paclitaxel combination
treatment phase and single-agent trastuzumab continuation phase will allow pharmacokinetics to be examined
further to determine whether the effects of paclitaxel on
trastuzumab concentrations following s.c. administration are similar to those following i.v. administration.
Furthermore, the use of two trastuzumab dose schedules
(2 mg/kg s.c. weekly vs. 2 mg/kg s.c. twice weekly) will
guide the selection of the optimal dose regimen for this
route of administration.
For this trial, 4.4 ml vials for s.c. injection containing
trastuzumab at a concentration of 102 mg/ml will be
used. This means that a 70 kg woman will receive a s.c.
injection of approximately 1.4 ml in volume administered
into the anterior abdominal wall using a 25-gauge needle.
This trial was initiated in March 2000 and the recruitment target is approximately 50 women. It is expected
that results will be available in 2001.
techniques have been introduced and our understanding
of disease pathogenesis has enabled specific therapeutic
targets to be identified. The recognition that formulation
and route of administration influence the effects of drugs
has coincided with this progress. Together, these developments have resulted in a process of rational drug development in which drugs are selected for their efficacy and
tolerability in a given disease, and are formulated and
administered so as to exploit their intrinsic characteristics. This process requires that drugs undergo extensive
pharmacologic characterization and that preclinical
findings are confirmed in clinical trials.
Trastuzumab, a humanized anti-HER2 monoclonal
antibody for the treatment of HER2-overexpressing
metastatic breast cancer, was rationally developed to
target a growth factor receptor (HER2) implicated in
the pathogenesis of breast cancer. This rational development has continued with the application of knowledge
regarding its pharmacokinetics and interactions with
other agents obtained in preclinical and early clinical
Trastuzumab in combination with other agents
trials being applied to the clinical assessment of new
treatment regimens and new routes of administration.
Pietras et al. [15] demonstrated that trastuzumab and Although many of these studies are in their preliminary
cisplatin in combination have synergistic activity against stages, it is probable that they will have a significant
HER2-positive tumor cells in vivo. This is believed to be impact on how trastuzumab is used in the treatment not
due to the effects of trastuzumab on the HER2 receptor, only of breast cancer, but also in a range of tumors in
which inhibit intracellular signal transduction and thus which HER2 is overexpressed, including bladder and
DNA repair, increasing the cytotoxic effects of cisplatin- lung cancer.
induced DNA damage [16]. Pegram et al. [25] have
These investigations are also relevant to the imporshown that this pharmacologic synergy is not restricted tant issue of patient quality of life [29, 30], which is
to the combination of trastuzumab with cisplatin, but is affected by and influences drug selection, formulation
also observed in vitro and in vivo with docetaxel, etopo- and administration. For example, patients have expressed
side and thiotepa. Furthermore, additive effects are seen clear preferences for less invasive routes of administrawhen trastuzumab is administered in combination with tion as long as efficacy is not compromised [31]. Trastuanthracyclines, paclitaxel, methotrexate and vinblastine. zumab is administered once weekly, with many patients
This suggests that trastuzumab in combination with one being treated as out-patients. This is a beneficial feature
or more of these agents is likely to be most effective for of the drug, but the need for i.v. administration, which is
metastatic breast cancer therapy. This work is the basis cited by patients as a source of discomfort [32], indicates
for several European studies examining trastuzumab that further research into the optimal administration
in combination with docetaxel, epirubicin, cyclophos- route and frequency of dosing of trastuzumab is
phamide, carboplatin, gemcitabine and other agents. In warranted. Such research is currently ongoing, with a
addition, other trials have revealed that trastuzumab three-weekly dosing schedule and s.c. administration
plus docetaxel, trastuzumab plus weekly paclitaxel [26, under investigation. Identifying improved dose regimens
27] and trastuzumab plus vinorelbine [28] are active and may also have advantages in terms of cost-effectiveness,
well tolerated combination regimens.
which will likely become an increasingly critical aspect
Interestingly, docetaxel and trastuzumab have been of therapeutic decision-making in cancer chemotherapy
shown to be synergistic at all doses tested [Pegram M, [33]. As administration and nursing costs form a major
Slamon D, unpublished data]. Furthermore, combining component of the total cost of i.v. chemotherapy [34],
trastuzumab, docetaxel and carboplatin has been shown less frequent administration and/or a switch to s.c.
to produce even greater synergy (data on file, F. Hoff- administration may have implications for the cost-effecmann-La Roche Ltd). This combination is the subject of tiveness of trastuzumab.
a Breast Cancer International Research Group (BCIRG)
In summary, preclinical and clinical studies of trastutrial.
zumab have provided important pharmacologic information, which is being used to further optimize the use
of this novel therapy with proven efficacy in metastatic
Discussion and conclusions
breast cancer. Current clinical studies of trastuzumab
are investigating whether the use of different treatment
Progress in new drug development has accelerated, as regimens is feasible. Furthermore, other studies are
the technology available has improved, innovative new examining whether preclinical data regarding the activity
47
of trastuzumab in combination with various chemotherapeutic agents translate into beneficial clinical effects.
Note
Dr Leyland-Jones has reported that he serves on a Roche advisory
board for Herceptin. Drs Dias, Howell and Rakhit are employees of F.
Hoffmann-La Roche Ltd, as indicated.
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Correspondence to:
B. Leyland-Jones, MD
Department of Oncology
McGill University
546 Pine Avenue West
Montreal H2W 1S6
Canada
E-mail: [email protected]