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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. 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Leyland-Jones, MD Department of Oncology McGill University 546 Pine Avenue West Montreal H2W 1S6 Canada E-mail: [email protected]