Phase II Study of Efficacy, Safety, and Pharmacokinetics of Trastuzumab Monotherapy Administered on a 3-Weekly Schedule
http://www.100md.com
《临床肿瘤学》
the Vall d'Hebron, University Hospital, Barcelona
Hospital Arnau de Vilanova, Lleida, Spain
Instituto Nacional De Cancerologia, Tialpan, Mexico
Mutterhaus der Borromaeerinnen, Trier, Germany
Royal Melbourne Hospital, Melbourne, Australia
Auckland Hospital, Auckland, New Zealand
Roche Products Ltd, Welwyn Garden City, United Kingdom
ABSTRACT
PURPOSE: This phase II study investigated the efficacy, safety, and pharmacokinetics of trastuzumab monotherapy given as first-line treatment once every 3 weeks (3-weekly) in women with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC).
PATIENTS AND METHODS: Patients with previously untreated HER2-positive MBC received a loading dose of trastuzumab, 8 mg/kg intravenously (IV) and then 6 mg/kg IV at 3-week intervals until disease progression or patient withdrawal.
RESULTS: In total, 105 patients received a median of five cycles of therapy (range, 1 to 35+). The overall response rate was 19% (23% in patients with measurable centrally confirmed immunohistochemistry [IHC] 3+ and/or fluorescence in situ hybridization [FISH] -positive disease) and clinical benefit rate (complete and partial responses plus stable disease for at least 6 months) was 33% (36% in patients with measurable centrally confirmed IHC 3+ and/or FISH-positive disease). Median time to progression was 3.4 months (range, 0.6 to 23.6 months). The most common treatment-related adverse events were rigors, pyrexia, headache, nausea, and fatigue. Median baseline left ventricular ejection fraction was 63%; this did not significantly change over the course of the study. The average exposure to trastuzumab observed in this study was similar to that in previous studies of the weekly regimen. However, as expected, mean trough trastuzumab concentrations were lower and peak levels were higher with 3-weekly trastuzumab compared with weekly treatments.
CONCLUSION: Administering higher doses on a 3-weekly schedule did not compromise the efficacy and safety of trastuzumab in women with HER2-positive MBC, and average exposure was similar to that observed with weekly therapy. Three-weekly trastuzumab may represent a convenient alternative to weekly administration.
INTRODUCTION
Overexpression or amplification of the human epidermal growth factor receptor-2 (HER2) occurs in approximately 15% to 25% of patients with metastatic breast cancer (MBC), and is associated with aggressive disease and decreased survival.1,2 HER2 overexpression or amplification is an early event in the pathogenesis of breast cancer,3 and evidence that it causes malignant transformation,4,5 stimulated interest in HER2 as a target for therapy. This led to the development of trastuzumab (Herceptin; F. Hoffmann-La Roche Ltd, Basel, Switzerland), a humanized monoclonal antibody that specifically targets the extracellular domain (ECD) of HER2.6
Trastuzumab has been extensively investigated in the clinical setting, both as monotherapy and in combination with standard chemotherapeutic drugs. In combination with doxorubicin/cyclophosphamide (AC) or paclitaxel, trastuzumab has been shown to prolong survival in women with HER2-positive MBC.7 Trials of weekly trastuzumab monotherapy as first-line8 and second- or third-line therapy9 have shown it to be active and well tolerated in women with HER2-positive MBC. Trastuzumab is not associated with the typical adverse effects of standard cytotoxic chemotherapeutic drugs. The most common adverse effects of trastuzumab are mild-to-moderate infusion-related reactions (IRRs), which are usually noted with the first infusion and decrease in frequency thereafter. The most clinically significant adverse event is symptomatic cardiac dysfunction, which occurred in 2.0% to 4.7% of patients in trials of trastuzumab monotherapy.8,9 However, cardiotoxicity is usually reversible and manageable even with continued trastuzumab therapy.10
In the trials that led to the approval of trastuzumab as treatment for patients with HER2-positive MBC, trastuzumab was administered as a loading dose of 4 mg/kg intravenously (IV) followed by a weekly dose of 2 mg/kg, which is now the standard schedule.7–9 However, pharmacokinetic (PK) and safety data indicate that administration of higher doses at longer intervals might be feasible and potentially more convenient.11 Retrospective analysis of population PK data for weekly trastuzumab using a two-compartment model indicated that the half-life of trastuzumab is approximately 28.5 days,12 which supports less frequent dosing. A previous study8 in which an alternative schedule of trastuzumab monotherapy was administered (8 mg/kg loading dose followed by 4 mg/kg weekly) showed that larger doses of trastuzumab administered every week do not result in undue toxicity. Furthermore, administration of trastuzumab once every 3 weeks (3-weekly; 8 mg/kg loading dose followed by 6 mg/kg 3-weekly) plus paclitaxel produced favorable response rates, with no new or unexpected toxicity,13 and produced serum trastuzumab trough levels similar to those achieved with the standard weekly trastuzumab regimen.12,14,15 Finally, simulation of the PK of trastuzumab 6 mg/kg once every 3 weeks and of the standard weekly regimen demonstrates that exposure to trastuzumab would be similar for the weekly and 3-weekly regimens, despite higher end of infusion and lower predose serum concentrations with the 3-weekly regimen.13,16
In the metastatic setting, excellent results have been achieved with the addition of trastuzumab to chemotherapy.7,17 However, there will always be patients who are not eligible for, do not want to receive, or wish to delay receiving chemotherapy. For these patients, alternative options that provide palliative treatment with few adverse effects need to be found. The clinical benefits of trastuzumab monotherapy given on the standard schedule were shown in trials H0650g8 and H0649g.9 A 3-weekly schedule may provide additional benefits in terms of patient convenience.
This multicenter, single-arm, open-label phase II study was designed to investigate the efficacy and safety of 3-weekly single-agent trastuzumab (8 mg/kg loading dose followed by 6 mg/kg, at 3 week intervals) in women with HER2-positive MBC. Secondary aims were to assess PK parameters in a subgroup of patients; to assess all patients for shed HER2 ECD levels; and to compare and correlate levels of HER2 overexpression with efficacy.
PATIENTS AND METHODS
Study Design
This was a single-arm, multicenter, open-label phase II study conducted in 35 centers. Of these, 24 centers were selected to undertake PK assessments in addition to safety and efficacy assessments.
Patients
Women aged 18 years with histologically or cytologically proven HER2-positive MBC, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease according to WHO criteria18 were enrolled. The study was approved by the institutional ethics committees of the participating centers, and written informed consent was obtained from all patients.
Pregnant or lactating women were excluded. All women of child-bearing potential were required to have a negative pregnancy test and had to be using effective contraception. Patients receiving any investigational drug within 30 days before starting trastuzumab or who had received prior anti-HER2 or antigrowth-factor receptor therapy at any time were excluded, as were patients with the following criteria: uncontrolled serious illness; uncontrolled CNS metastases; invasive malignancy other than breast cancer or nonmelanoma skin cancer (unless free of disease for > 5 years); previous chemotherapy or hormonal therapy for MBC; previous treatment with a cumulative dose of doxorubicin more than 480 mg/m2 or epirubicin more than 800 mg/m2; radiotherapy within 2 weeks of the start of trastuzumab treatment; dyspnea at rest as a result of complications of malignancy or requiring supplementary oxygen therapy; and New York Heart Association (NYHA) class III/IV congestive heart failure (CHF), or a left ventricular ejection fraction (LVEF) less than 50% assessed by a multigated radionuclide angiography (MUGA) scan or echocardiography.
In addition, patients demonstrating the following hematologic and laboratory abnormalities at baseline were excluded: hemoglobin less than 10 g/dL; neutrophils less than 1.5 x 109/L; platelets less than 100 x 109/L; serum total bilirubin more than 1.5 x the upper limit of normal (ULN; except for patients with clearly documented Gilbert's syndrome); ALT or AST more than 2.5 x ULN (> 5.0 x ULN with liver metastases); alkaline phosphatase more than 2.5 x ULN (> 4.0 x ULN with liver or bone metastases); and/or serum creatinine more than 1.5 x ULN.
HER2 Status
Patients with HER2 receptor overexpression at the 3+ level (HercepTest, DakoCytomation, Carpinteria, CA) and/or HER2 gene amplification by fluorescence in situ hybridization (FISH) were eligible for inclusion. HER2 testing was performed on a sample of the primary tumor or a biopsy of a metastatic site. For patients with bilateral breast cancer, HER2 testing results for both tumors were required, unless the first tumor was diagnosed more than 5 years before the second tumor and the second tumor was HER2 positive.
At the start of the trial, discrepancy between local versus central testing results had not been recognized as a potential problem.19,20 However, after enrollment of approximately 50 patients, HER2 testing entry criteria were modified because of a relatively high level of false-positive results with local testing. Thereafter, immunohistochemistry (IHC) 3+ tumors on local testing were required to have central confirmation of HER2 status; central testing was conducted at the Pathology Institute in Kassel, Germany. Tumors that were FISH-positive according to local laboratory testing did not require central confirmation before enrollment.
Treatment
Trastuzumab was administered as a loading dose of 8 mg/kg IV followed by 6 mg/kg every 3 weeks, starting 21 days after the loading dose (day 22), until disease progression, unmanageable toxicity, or patient request. All doses were given as an infusion for a period of 90 minutes. This is the recommended infusion time for the first (4 mg/kg) loading dose in the approved weekly regimen. However, other studies have successfully used a 30-minute infusion duration, if the first 90-minute infusion was well tolerated.8 Any medication, other than chemotherapy or immunotherapy, that was deemed necessary for patient management was permitted. Patients at increased risk of IRRs because of extensive pulmonary disease (eg, lymphangitis, multiple metastases, and so on), and those who experienced mild or moderate IRRs with the first dose, could be treated with acetaminophen and diphenhydramine. Before the start of the study, patients could start on bisphosphonates or receive localized radiotherapy to sites of disease (eg, bone) that were not utilized in the evaluation of tumor response.
Efficacy Assessments
Objective response of measurable disease was evaluated by the investigator using WHO criteria.18 Tumor assessments were performed every two cycles and patients with disease progression were withdrawn from the study. Following withdrawal, patients were treated at the investigator's discretion.
Safety Assessments
Adverse events were assessed at each cycle and graded using the Common Toxicity Criteria (CTC) version 2.0. Cardiac failure was graded according to the NYHA classification system. LVEF was assessed using MUGA scans or echocardiography at baseline, after every four cycles of treatment, and as clinically indicated thereafter. Withdrawal from treatment was not mandatory for prespecified LVEF changes. If LVEF was to fall by 15 absolute percentage points, or a patient was to develop symptomatic CHF, the risks and benefits of continuing trastuzumab therapy were to be carefully considered on a case-by-case basis. If treatment was continued, patients would receive more frequent LVEF monitoring, once every 6 weeks (once every two cycles). Patients who experienced a life-threatening IRR to the first dose (eg, tachypnea, bronchospasm, hypotension, or hypoxia) were withdrawn from the study.
PK and Pharmacodynamic Assessments
Serum samples were taken from all patients for measurement of trough trastuzumab concentrations and shed HER2 ECD before trastuzumab infusion on day 1 of each treatment cycle. In addition, a full PK profile was obtained at cycle 6 in a subgroup of 20 patients (planned number). This sample size was chosen for practical reasons and aimed to include the maximum number of patients from as few centers as possible. The rationale for assessment at cycle 6 was based on the observations of a previous trial of 3-weekly trastuzumab,11 in which the majority of patients had withdrawn/discontinued after cycle 6. Therefore, although longer duration of treatment is required to reach steady-state, subset analyses were performed at cycle 6 to ensure adequate patient numbers. To predict the trend for mean predose concentrations over time, a Hill equation was used.
In the PK substudy, blood samples were collected during cycle 6 only via a cannula from a forearm vein predose (0 hours), and at 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 hours and at 1, 4, 7, and 14 days after infusion of trastuzumab. Noncompartmental PK analysis was performed and the following PK parameters were derived using WINNonlin (Scientific Consultant, Apex, NC) Professional version 3.0: minimum serum concentration (Cmin), maximum serum concentration (Cmax), time to Cmax (tmax), terminal half-life (t1/2), area under the serum concentration-time curve (AUC), and clearance (Clss).
Serum trastuzumab and HER2 ECD concentrations were determined using an enzyme-linked immunosorbent assay (ELISA; Genentech Inc, South San Francisco, CA) with a limit of quantification of 150 ng/mL, and inter- and intra-assay variability of 3% and less than 1%, respectively. Trastuzumab serum trough concentration values were related to the number of metastatic sites and tumor bulk at baseline. The relationship between serum trastuzumab and HER2 ECD levels was also investigated.
Statistical Analyses
No formal testing of hypotheses was planned and the statistical analysis was descriptive. A greater number of patients than usual for a phase II trial were planned to generate more robust results and ensure adequate PK assessments. It was assumed that with a response rate of 35%, enrollment of 80 patients would give a lower 80% confidence limit (one-sided) of 30.08%. Response rates and 95% CIs were calculated according to the Pearson-Clopper method. PK parameters were analyzed descriptively and Kaplan-Meier curves were calculated for time-to-event end points.
RESULTS
Patient Demographics
Table 1 lists baseline patient characteristics. At the time of data cutoff, 18 months after the last patient enrolled, patients had received a median of five cycles of trastuzumab therapy (range, 1 to 35+), and eleven patients had completed 24 or more cycles (18 months) of trastuzumab therapy. Eighty-seven patients (83%) had centrally confirmed IHC 3+ or FISH-positive MBC. Twenty-two patients were excluded from the per protocol subset (PPS) because they did not have confirmed HER2 overexpression or amplification (ie, centrally tested IHC 3+ and/or locally/centrally tested FISH-positive disease [n = 17]), measurable disease according to WHO criteria, or adequate tumor assessment at baseline (n = 8). Detailed analysis of HER2 status will be published in another article.
Efficacy
The overall response rate (ORR) was 19% in all patients in the intent-to-treat (ITT) population (two complete responses [CR] and 18 partial responses [PR]; n = 105), and 23% (two CRs and 17 PRs) in the PPS (n = 83; Tables 2 and 3 ). Stable disease (SD) was the best response in fifty-one percent of the full study population and of the PPS. The clinical benefit rate (CBR; CR + PR + SD > 6 months) was 33% in all patients, and 36% in the PPS. Median time to progression (TTP) was 3.4 months (range, 0.6 to 23.6 months) in all patients, and 3.5 months (range, 0.6 to 23.5 months) in the PPS (15 patients in the full analysis set and 13 patients in the PPS were censored due to lack of documented disease progression at the time of data cutoff). The median time to response was 1.4 months for both groups of patients and the median duration of response was 8.3 months (range, 2.8 to 22.5 months) in all patients, and 10.1 months (range, 2.8 to 22.5 months) in the PPS. Median overall survival was not reached during the observed study period but this was mainly because of loss to follow-up (only 15 deaths were reported at the time of data cutoff).
Safety
Trastuzumab monotherapy was generally well tolerated and no unexpected toxicities were noted. Overall, 599 adverse events were reported in 94 patients (regardless of causality) but only 37 adverse events were CTC grade 3, and three adverse events were CTC grade 4. Twenty-nine percent of adverse events were considered by the investigator to be treatment related. Only six serious adverse events were considered to be related to trastuzumab. The most common treatment-related adverse events were mild-to-moderate rigors, pyrexia, headaches, nausea, and fatigue (Table 4).
Fifty-four percent of patients had at least one symptom associated with their first infusion (defined as an adverse event experienced on the day of, or the day after, the infusion), but the frequency decreased with subsequent infusions: 29% with the second infusion and 20% with the third. The most common IRRs were rigors, pyrexia, and headache. Only three patients experienced serious IRRs. Two of these IRRs resolved and the patients continued to receive trastuzumab; the third patient was withdrawn from treatment on day 6 of the study. A total of 15 deaths have been reported, of which 14 were as a result of progressive disease, and one to a cerebral vascular accident considered unrelated to trastuzumab therapy. There were few significant changes in biochemical or hematologic laboratory parameters, and those that did occur were thought to be disease related.
Cardiac Safety
Median baseline LVEF was 63% (range, 49% to 84%; n = 103); this did not change significantly over the course of the study. Only one patient in this study experienced symptomatic cardiac failure. This patient was a 74-year-old woman with a baseline LVEF of 59% and a history of hypertension, obesity, and prior epirubicin therapy (total cumulative dose, 450 mg/m2). At cycle 4, she was hospitalized with dyspnea and cardiac insufficiency (NYHA class II), at which time her LVEF was 33%. Trastuzumab was stopped, she was treated with furosemide and enalapril, and her symptoms resolved after 9 days. Approximately 6 months later, her LVEF had increased to 53% and she was no longer taking cardiac medication. Other trastuzumab-related cardiac events were hypertension (n = 3) and tachycardia (n = 1); these were infusion-related, mild to moderate in severity and rapidly resolved after completion of the infusion. One other patient experienced more severe dyspnea and chest tightness following her first infusion, and required overnight administration and treatment with oxygen and tramadol. This patient did not have a baseline LVEF assessment before treatment, and though the breathlessness and chest tightness resolved, she continued to experience exertional dyspnea. She was withdrawn from the study on day 19. Six patients experienced cardiac events that were considered to be unrelated to trastuzumab (palpitations, hypertension, tachycardia, cardiac tamponade, and pericardial effusion).
In addition, isolated drops in LVEF of uncertain significance were not uncommon. Changes in LVEF among all patients and in those with or without previous exposure to anthracyclines are listed in Table 5. Decreases in LVEF were more frequent and more severe among patients who had a history of anthracycline therapy. Eight of 11 patients whose worst change in LVEF was a reduction of 15%, and six of nine patients with a worst LVEF measurement of less than 50%, had previously received anthracyclines. Overall, a total of 16 patients had an absolute drop in LVEF of 15% and/or an LVEF of less than 50%. Of these 16 patients, two withdrew from the study as a result of the LVEF change, nine withdrew due to disease progression, and one for unspecified reasons. The remaining four patients were still receiving trastuzumab at data cutoff. There was no change in the incidence of decreased LVEF in the 12-month additional follow-up period.
PK and Pharmacodynamics
The individual variability in predose serum trough concentrations of trastuzumab showed an almost 10-fold range before the administration of dose 6, when the PK substudy was performed. However, this may not represent the total variability because patients who had the lowest exposure to trastuzumab had already withdrawn from the study, largely due to progressive disease (19 patients at or before cycle 3). The mean trough concentration profile for trastuzumab revealed that accumulation occurred with a mean increase of 94%, ranging across 13 cycles from 27.3 μg/mL at cycle 2 to 52.7 μg/mL at cycle 15 (Fig 1). The cumulative dose during a 3-week interval was identical between the 3-weekly regimen arm and the weekly regimen arm. As expected, mean trough trastuzumab concentrations were approximately 20% lower at the end of each cycle than those concentration levels at the same timepoint using weekly dosing in the pivotal trastuzumab monotherapy trial (Fig 1). Also as expected, Cmax values were approximately 70% higher than using the weekly regimen (Fig 2 and data not shown), and serum concentrations exceeded or equaled those observed using the weekly regimen for approximately half the 3-week dose interval (Fig 2). As a result, average exposure at any time during the treatment is comparable between the two regimens (Fig 2). It has been necessary to use simulations to compare Cmax and exposure at common timepoints, as the sampling schemes employed in investigating the two regimens were different. The results of the validation of these simulations using observed data are shown in Figure 3 (weekly regimen)9 and Figure 4 (3-weekly regimen).
Further analysis using the Hill equation (steady-state trough concentration x time/constant + time) estimated the concentration at steady-state to be 65.47 μg/mL, and the time taken to reach steady-state to be approximately 14 weeks. These data indicate that mean trough concentrations remained within 20% of the predicted plateau between cycles 11 and 13.
PK profiles were obtained for 23 patients at cycle 6 and PK data for all these patients are included in the analysis. The mean trough concentration before dosing for cycle 6 was significantly above zero (mean trough concentration, 49.1 μg/mL; n = 48, which included predose values from those patients not included in the PK substudy). PK parameters for patients in the PK substudy are listed in Table 6. In this study, the mean estimated terminal half-life for 3-weekly trastuzumab was 16.4 days. This value is in agreement with data obtained from previous studies of weekly (ie, estimated terminal half-life approximately 16 days) trastuzumab based on noncompartmental PK methods.9 Sampling within a single dosing interval (ie, limited sampling period) is known to result in an underestimation of terminal half-life. Trastuzumab has a PK profile of at least two elimination phases after infusion. The first phase has a shorter half-life of about 4 days, and the second phase, which starts approximately 1 week after the end of infusion, has a longer half-life. A short sampling period within a dosing interval (ie, 3 weeks) will capture data mostly from the first phase. Estimation of half-life using a noncompartmental analysis method (ie, without modeling the PK data) will yield an underestimation of the half-life. Two separate population PK analyses (using pooled data across a number of studies, one of which was the data set from this study), derived a mean half-life (CV%) for the second phase of elimination that was 28.5 ± 5.0 days.12,21
Inter-individual variability in trastuzumab serum trough concentrations was wide. To determine the cause of this variability, several indicators of disease burden were investigated. A weak inverse relationship was found between serum trastuzumab concentrations and each of the following: disease burden at baseline, number of metastatic sites, and best response (data not shown).
An inverse relationship between serum HER2 ECD and serum trastuzumab concentrations was noted, particularly at ECD concentrations of more than 100 ng/mL (Fig 5). However, no clear relationship was observed when baseline ECD levels were compared with best response (Fig 6), or when the maximum change in ECD level from baseline was compared with best response (data not shown).
DISCUSSION
This study evaluated the efficacy, safety, and PK of a 3-weekly trastuzumab monotherapy regimen in which three times the standard weekly dose are given.
A previous study13 that evaluated the same 3-weekly trastuzumab regimen in combination with paclitaxel (n = 32) demonstrated a response rate of 59%, no unexpected toxicities, and no PK interactions between the two drugs. These findings indicated that trastuzumab could be administered at higher individual doses given less frequently without compromising efficacy or tolerability. In the present trial, clinical efficacy was within the range expected based on studies of weekly trastuzumab monotherapy.8,9 The ORR of 19% (95% CI, 12.04 to 27.87; 23% in the PPS group; 95% CI, 14.38 to 33.42) was lower than in the previous study of first-line weekly trastuzumab monotherapy (all, 26%; IHC 3+, 35%)8 but higher than in the study of second and third-line trastuzumab (all, 15%; IHC 3+, 18%).9 This may have been because of differences in the prognosis of the patient populations at baseline,8,9 though no striking differences are apparent. The CBR in the two first-line studies were in a similar range; with 3-weekly trastuzumab the CBR was 33% in all patients and 36% (95% CI, 26% to 47%) in the PPS group, compared with 38% in all patients and 48% in patients with IHC 3+ disease in the first-line weekly trastuzumab monotherapy study.8 Median TTP was also similar for the 3-weekly and first-line weekly regimens (3.4 months v 3.5 and 3.8 months, respectively).8 It is of note that almost 30% of patients in the present study progressed at or before the first tumor assessment at 6 weeks. Because response to trastuzumab was rapid (median time to response was 1.4 months, similar to that for chemotherapy), this suggests that these patients had rapidly progressing disease and a poor prognosis. In an analysis of patient demographics in the ITT group, patients with a best response of progressive disease had a higher incidence of lung metastases (64%) at baseline compared with those patients who did not exhibit rapid disease progression (42%). With the benefit of hindsight, it might have been better if these patients had been treated with trastuzumab in combination with chemotherapy. In general, this suggests that clinicians should select patients carefully, and perhaps reserve trastuzumab monotherapy for those with less advanced or more indolent disease. Alternatively, patients with more aggressive disease could be checked more frequently (eg, at week 3, before cycle 2), for possible early disease progression.
Weekly trastuzumab therapy has a favorable safety profile.7–10,22,23 Our findings indicate that 3-weekly single-agent trastuzumab is also well tolerated. The majority of adverse events were mild-to-moderate IRRs, occurring predominantly with the first infusion. Although the absolute percentage of patients experiencing IRRs in this study (54% with the first infusion) seems to be higher than in other studies of weekly trastuzumab, the definition of an IRR (ie, any adverse event occurring on the day of, or day after, the infusion) was probably more inclusive than that used in many other studies. The incidence of severe IRRs (4%) is not higher than expected.
In the pivotal trastuzumab combination trial (H0648g), trastuzumab was associated with cardiotoxicity, especially when given with anthracyclines.24 Trastuzumab trials since then have included cardiac eligibility criteria and prospective cardiac monitoring. The incidence of CHF in a pooled analysis of six recent trials (including this trial) was 2.7%.25 In our study, CHF occurred in one patient (< 1% of all patients); she stopped trastuzumab therapy and was treated with standard cardiac medication and the event resolved. These data suggest that the incidence of cardiac events is no higher with the 3-weekly compared with the weekly trastuzumab schedule. As described in other studies,25 isolated drops in LVEF of uncertain significance were common in this study, especially in patients previously exposed to anthracyclines.
Analysis of population PK data has indicated that the half-life of trastuzumab is significantly longer than previously believed, at 28.5 days rather than 8.3 days.12 Based on the PK parameters from the population PK analysis,12 simulations were performed to construct full concentration-time profiles for the 3-weekly and weekly regimens. Simulations were employed given that direct comparison of full PK profiles between the two regimens was not possible because of differences in the study design and sampling schedules. The data from these simulations show that the PK profiles observed for the 3-weekly regimen in this study compare favorably with the simulated data for 3-weekly trastuzumab (Fig 4); the simulated profile for the weekly regimen is also consistent with previously observed data (Fig 3).9 Of note, comparison of the full concentration-time profiles (Fig 2) shows that though peaks are higher (by 50% to 70%) and troughs are lower (by up to 22%) for the 3-weekly regimen compared with the weekly regimen, the average exposure for the two regimens is similar. These differences are not considered to be of clinical importance because trastuzumab does not exhibit dose-dependent toxicity, and efficacy is likely to be related to average exposure rather than peak or trough levels. The efficacy results reported support the relevance of drug exposure rather than the per dose concentration as a measure of the comparability of regimens.13,16 Moreover, the differences in peaks or troughs between the two regimens are small compared with the high degree of inter-individual variability (approximately 10-fold) observed in clinical trials.16 Although the 3-weekly and weekly regimens have similar efficacy, safety, and exposure, in patients with life-threatening disease there may be a role for a more aggressive approach with both regimens. More intensive loading, for example, could be used to reach steady-state more quickly.
Examination of ECD and serum trastuzumab concentrations at each study cycle showed that an inverse relationship exists between these two variables at ECD concentrations exceeding approximately 100 ng/mL. Although some recent studies have reported a relationship between HER2 ECD levels and response to trastuzumab therapy,26–28 this relationship was not found in this study. Further analyses are ongoing in order to determine the clinical relevance of ECD levels to response.29 These results will be published separately.
In conclusion, trastuzumab monotherapy given on a 3-weekly schedule at three times the standard weekly dose was well tolerated with efficacy in the expected range, in women with HER2-positive MBC. The incidence and severity of cardiotoxicity was low and no higher than that reported for weekly trastuzumab. No new or unexpected adverse events were noted. PK analysis demonstrated that trastuzumab exposure using the 3-weekly regimen was similar to that reported for standard weekly trastuzumab therapy. Additional analyses performed after 12 months of further follow-up (30 months after the last patient entered; data not shown) show that long-term administration of trastuzumab monotherapy is well tolerated. Thus, the 3-weekly trastuzumab regimen might represent a convenient alternative to weekly administration. The findings of our trial provide support for further investigation of the 3-weekly trastuzumab monotherapy regimen, and this is being pursued in several large ongoing adjuvant trials.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Claire Barton, Roche Products Ltd; Parviz Ghahramani, AstraZeneca, Roche Products Ltd. Consultant/Advisory Role: Jose Baselga, Hoffman-La Roche; Claire Barton, Roche. Stock Ownership: Claire Barton, Roche. Honoraria: Jose Baselga, Hoffman-La Roche. Research Funding: Michael Clemens, Roche. Expert Testimony: Vernon Harvey, Roche. Other Remuneration: Vernon Harvey, Roche. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
The authors would like to acknowledge the Pathology Institute in Kassel, Germany, headed by J. Rueschoff, PhD, who performed central testing on tumor samples for this study. The authors would also like to thank Sian Lennon for her thoughtful contributions to this manuscript.
NOTES
Supported by F. Hoffmann-La Roche Ltd.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Baselga J, Tripathy D, Mendelsohn J, et al: Phase II study of a weekly intravenous recombinant anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14:737-744, 1996
Ghahramani P, Barton C, Leyland-Jones B: Pharmacokinetics of Herceptin administered three-weekly compared to weekly: A simulation based on data from the clinical studies. The Breast 12:S40, 2003 (suppl 2; abstr P89)
Extra JM, Cognetti F, Maraninchi D, et al: Trastuzumab (Herceptin) plus docetaxel versus docetaxel alone as first-line treatment of HER2-positive metastatic breast cancer (MBC): Results of a randomised multicentre trial. Eur J Cancer 2:125, 2004 (suppl 3)
World Health Organization: WHO handbook for reporting results of cancer treatment. Geneva, Switzerland, World Health Organization, 1979
Paik S, Bryant J, Tan-Chiu E, et al: Real-world performance of HER2 testing: National Surgical Adjuvant Breast and Bowel Project experience. J Natl Cancer Inst 94:852-854, 2002
Roche PC, Suman VJ, Jenkins RB, et al: Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst 94:855-857, 2002
Charoin JE, Jacqmin P, Banken L, et al: Population pharmacokinetic analysis of trastuzumab (Herceptin) following long-term administration using different regimens. Uppsala, Sweden, Population Approach Group (PAGE), 2004 (abstr) http://www.page-meeting.org
Burstein HJ, Kuter I, Campos SM, et al: Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 19:2722-2730, 2001
Esteva FJ, Valero V, Booser D, et al: Phase II study of weekly docetaxel and trastuzumab for patients with HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:1800-1808, 2002
Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215-1221, 2002
Marty M, Baselga J, Gatzemeier U, et al: Pooled analysis of six trials of trastuzumab (Herceptin): Exploratory analysis of changes in left ventricular ejection fraction (LVEF) as a surrogate for clinical cardiac events. Breast Cancer Res Treat 82:S48, 2003 (abstr 218)
Pichon MF, Neumann R, Guepratte S, et al: Serum Her-2/neu extracellular domain parallels response to trastuzumab treatment of recurrent breast cancer. Breast Cancer Res Treat 76: S110, 2002 (abstr 426)
Brown-Shimer S, Schwartz MK, Lin D, et al: Monitoring serum HER-2/neu levels in metastatic breast cancer patients undergoing Herceptin therapy regimens. Breast Cancer Res Treat 76:S111, 2002 (abstr 432)
Carney WP, Neumann R, Lipton A, et al: Potential clinical utility of serum HER-2/neu oncoprotein concentrations in patients with breast cancer. Clin Chem 49:1579-1598, 2003
Leyland-Jones B, Marty M, Baselga J, et al: Effects of trastuzumab (Herceptin, H) and chemotherapy on circulating HER2 extracellular domain (ECD) in patients with metastatic breast cancer (MBC) and non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 23:19, 2004 (abstr 507)(Jose Baselga, Xavier Carb)
Hospital Arnau de Vilanova, Lleida, Spain
Instituto Nacional De Cancerologia, Tialpan, Mexico
Mutterhaus der Borromaeerinnen, Trier, Germany
Royal Melbourne Hospital, Melbourne, Australia
Auckland Hospital, Auckland, New Zealand
Roche Products Ltd, Welwyn Garden City, United Kingdom
ABSTRACT
PURPOSE: This phase II study investigated the efficacy, safety, and pharmacokinetics of trastuzumab monotherapy given as first-line treatment once every 3 weeks (3-weekly) in women with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC).
PATIENTS AND METHODS: Patients with previously untreated HER2-positive MBC received a loading dose of trastuzumab, 8 mg/kg intravenously (IV) and then 6 mg/kg IV at 3-week intervals until disease progression or patient withdrawal.
RESULTS: In total, 105 patients received a median of five cycles of therapy (range, 1 to 35+). The overall response rate was 19% (23% in patients with measurable centrally confirmed immunohistochemistry [IHC] 3+ and/or fluorescence in situ hybridization [FISH] -positive disease) and clinical benefit rate (complete and partial responses plus stable disease for at least 6 months) was 33% (36% in patients with measurable centrally confirmed IHC 3+ and/or FISH-positive disease). Median time to progression was 3.4 months (range, 0.6 to 23.6 months). The most common treatment-related adverse events were rigors, pyrexia, headache, nausea, and fatigue. Median baseline left ventricular ejection fraction was 63%; this did not significantly change over the course of the study. The average exposure to trastuzumab observed in this study was similar to that in previous studies of the weekly regimen. However, as expected, mean trough trastuzumab concentrations were lower and peak levels were higher with 3-weekly trastuzumab compared with weekly treatments.
CONCLUSION: Administering higher doses on a 3-weekly schedule did not compromise the efficacy and safety of trastuzumab in women with HER2-positive MBC, and average exposure was similar to that observed with weekly therapy. Three-weekly trastuzumab may represent a convenient alternative to weekly administration.
INTRODUCTION
Overexpression or amplification of the human epidermal growth factor receptor-2 (HER2) occurs in approximately 15% to 25% of patients with metastatic breast cancer (MBC), and is associated with aggressive disease and decreased survival.1,2 HER2 overexpression or amplification is an early event in the pathogenesis of breast cancer,3 and evidence that it causes malignant transformation,4,5 stimulated interest in HER2 as a target for therapy. This led to the development of trastuzumab (Herceptin; F. Hoffmann-La Roche Ltd, Basel, Switzerland), a humanized monoclonal antibody that specifically targets the extracellular domain (ECD) of HER2.6
Trastuzumab has been extensively investigated in the clinical setting, both as monotherapy and in combination with standard chemotherapeutic drugs. In combination with doxorubicin/cyclophosphamide (AC) or paclitaxel, trastuzumab has been shown to prolong survival in women with HER2-positive MBC.7 Trials of weekly trastuzumab monotherapy as first-line8 and second- or third-line therapy9 have shown it to be active and well tolerated in women with HER2-positive MBC. Trastuzumab is not associated with the typical adverse effects of standard cytotoxic chemotherapeutic drugs. The most common adverse effects of trastuzumab are mild-to-moderate infusion-related reactions (IRRs), which are usually noted with the first infusion and decrease in frequency thereafter. The most clinically significant adverse event is symptomatic cardiac dysfunction, which occurred in 2.0% to 4.7% of patients in trials of trastuzumab monotherapy.8,9 However, cardiotoxicity is usually reversible and manageable even with continued trastuzumab therapy.10
In the trials that led to the approval of trastuzumab as treatment for patients with HER2-positive MBC, trastuzumab was administered as a loading dose of 4 mg/kg intravenously (IV) followed by a weekly dose of 2 mg/kg, which is now the standard schedule.7–9 However, pharmacokinetic (PK) and safety data indicate that administration of higher doses at longer intervals might be feasible and potentially more convenient.11 Retrospective analysis of population PK data for weekly trastuzumab using a two-compartment model indicated that the half-life of trastuzumab is approximately 28.5 days,12 which supports less frequent dosing. A previous study8 in which an alternative schedule of trastuzumab monotherapy was administered (8 mg/kg loading dose followed by 4 mg/kg weekly) showed that larger doses of trastuzumab administered every week do not result in undue toxicity. Furthermore, administration of trastuzumab once every 3 weeks (3-weekly; 8 mg/kg loading dose followed by 6 mg/kg 3-weekly) plus paclitaxel produced favorable response rates, with no new or unexpected toxicity,13 and produced serum trastuzumab trough levels similar to those achieved with the standard weekly trastuzumab regimen.12,14,15 Finally, simulation of the PK of trastuzumab 6 mg/kg once every 3 weeks and of the standard weekly regimen demonstrates that exposure to trastuzumab would be similar for the weekly and 3-weekly regimens, despite higher end of infusion and lower predose serum concentrations with the 3-weekly regimen.13,16
In the metastatic setting, excellent results have been achieved with the addition of trastuzumab to chemotherapy.7,17 However, there will always be patients who are not eligible for, do not want to receive, or wish to delay receiving chemotherapy. For these patients, alternative options that provide palliative treatment with few adverse effects need to be found. The clinical benefits of trastuzumab monotherapy given on the standard schedule were shown in trials H0650g8 and H0649g.9 A 3-weekly schedule may provide additional benefits in terms of patient convenience.
This multicenter, single-arm, open-label phase II study was designed to investigate the efficacy and safety of 3-weekly single-agent trastuzumab (8 mg/kg loading dose followed by 6 mg/kg, at 3 week intervals) in women with HER2-positive MBC. Secondary aims were to assess PK parameters in a subgroup of patients; to assess all patients for shed HER2 ECD levels; and to compare and correlate levels of HER2 overexpression with efficacy.
PATIENTS AND METHODS
Study Design
This was a single-arm, multicenter, open-label phase II study conducted in 35 centers. Of these, 24 centers were selected to undertake PK assessments in addition to safety and efficacy assessments.
Patients
Women aged 18 years with histologically or cytologically proven HER2-positive MBC, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease according to WHO criteria18 were enrolled. The study was approved by the institutional ethics committees of the participating centers, and written informed consent was obtained from all patients.
Pregnant or lactating women were excluded. All women of child-bearing potential were required to have a negative pregnancy test and had to be using effective contraception. Patients receiving any investigational drug within 30 days before starting trastuzumab or who had received prior anti-HER2 or antigrowth-factor receptor therapy at any time were excluded, as were patients with the following criteria: uncontrolled serious illness; uncontrolled CNS metastases; invasive malignancy other than breast cancer or nonmelanoma skin cancer (unless free of disease for > 5 years); previous chemotherapy or hormonal therapy for MBC; previous treatment with a cumulative dose of doxorubicin more than 480 mg/m2 or epirubicin more than 800 mg/m2; radiotherapy within 2 weeks of the start of trastuzumab treatment; dyspnea at rest as a result of complications of malignancy or requiring supplementary oxygen therapy; and New York Heart Association (NYHA) class III/IV congestive heart failure (CHF), or a left ventricular ejection fraction (LVEF) less than 50% assessed by a multigated radionuclide angiography (MUGA) scan or echocardiography.
In addition, patients demonstrating the following hematologic and laboratory abnormalities at baseline were excluded: hemoglobin less than 10 g/dL; neutrophils less than 1.5 x 109/L; platelets less than 100 x 109/L; serum total bilirubin more than 1.5 x the upper limit of normal (ULN; except for patients with clearly documented Gilbert's syndrome); ALT or AST more than 2.5 x ULN (> 5.0 x ULN with liver metastases); alkaline phosphatase more than 2.5 x ULN (> 4.0 x ULN with liver or bone metastases); and/or serum creatinine more than 1.5 x ULN.
HER2 Status
Patients with HER2 receptor overexpression at the 3+ level (HercepTest, DakoCytomation, Carpinteria, CA) and/or HER2 gene amplification by fluorescence in situ hybridization (FISH) were eligible for inclusion. HER2 testing was performed on a sample of the primary tumor or a biopsy of a metastatic site. For patients with bilateral breast cancer, HER2 testing results for both tumors were required, unless the first tumor was diagnosed more than 5 years before the second tumor and the second tumor was HER2 positive.
At the start of the trial, discrepancy between local versus central testing results had not been recognized as a potential problem.19,20 However, after enrollment of approximately 50 patients, HER2 testing entry criteria were modified because of a relatively high level of false-positive results with local testing. Thereafter, immunohistochemistry (IHC) 3+ tumors on local testing were required to have central confirmation of HER2 status; central testing was conducted at the Pathology Institute in Kassel, Germany. Tumors that were FISH-positive according to local laboratory testing did not require central confirmation before enrollment.
Treatment
Trastuzumab was administered as a loading dose of 8 mg/kg IV followed by 6 mg/kg every 3 weeks, starting 21 days after the loading dose (day 22), until disease progression, unmanageable toxicity, or patient request. All doses were given as an infusion for a period of 90 minutes. This is the recommended infusion time for the first (4 mg/kg) loading dose in the approved weekly regimen. However, other studies have successfully used a 30-minute infusion duration, if the first 90-minute infusion was well tolerated.8 Any medication, other than chemotherapy or immunotherapy, that was deemed necessary for patient management was permitted. Patients at increased risk of IRRs because of extensive pulmonary disease (eg, lymphangitis, multiple metastases, and so on), and those who experienced mild or moderate IRRs with the first dose, could be treated with acetaminophen and diphenhydramine. Before the start of the study, patients could start on bisphosphonates or receive localized radiotherapy to sites of disease (eg, bone) that were not utilized in the evaluation of tumor response.
Efficacy Assessments
Objective response of measurable disease was evaluated by the investigator using WHO criteria.18 Tumor assessments were performed every two cycles and patients with disease progression were withdrawn from the study. Following withdrawal, patients were treated at the investigator's discretion.
Safety Assessments
Adverse events were assessed at each cycle and graded using the Common Toxicity Criteria (CTC) version 2.0. Cardiac failure was graded according to the NYHA classification system. LVEF was assessed using MUGA scans or echocardiography at baseline, after every four cycles of treatment, and as clinically indicated thereafter. Withdrawal from treatment was not mandatory for prespecified LVEF changes. If LVEF was to fall by 15 absolute percentage points, or a patient was to develop symptomatic CHF, the risks and benefits of continuing trastuzumab therapy were to be carefully considered on a case-by-case basis. If treatment was continued, patients would receive more frequent LVEF monitoring, once every 6 weeks (once every two cycles). Patients who experienced a life-threatening IRR to the first dose (eg, tachypnea, bronchospasm, hypotension, or hypoxia) were withdrawn from the study.
PK and Pharmacodynamic Assessments
Serum samples were taken from all patients for measurement of trough trastuzumab concentrations and shed HER2 ECD before trastuzumab infusion on day 1 of each treatment cycle. In addition, a full PK profile was obtained at cycle 6 in a subgroup of 20 patients (planned number). This sample size was chosen for practical reasons and aimed to include the maximum number of patients from as few centers as possible. The rationale for assessment at cycle 6 was based on the observations of a previous trial of 3-weekly trastuzumab,11 in which the majority of patients had withdrawn/discontinued after cycle 6. Therefore, although longer duration of treatment is required to reach steady-state, subset analyses were performed at cycle 6 to ensure adequate patient numbers. To predict the trend for mean predose concentrations over time, a Hill equation was used.
In the PK substudy, blood samples were collected during cycle 6 only via a cannula from a forearm vein predose (0 hours), and at 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 hours and at 1, 4, 7, and 14 days after infusion of trastuzumab. Noncompartmental PK analysis was performed and the following PK parameters were derived using WINNonlin (Scientific Consultant, Apex, NC) Professional version 3.0: minimum serum concentration (Cmin), maximum serum concentration (Cmax), time to Cmax (tmax), terminal half-life (t1/2), area under the serum concentration-time curve (AUC), and clearance (Clss).
Serum trastuzumab and HER2 ECD concentrations were determined using an enzyme-linked immunosorbent assay (ELISA; Genentech Inc, South San Francisco, CA) with a limit of quantification of 150 ng/mL, and inter- and intra-assay variability of 3% and less than 1%, respectively. Trastuzumab serum trough concentration values were related to the number of metastatic sites and tumor bulk at baseline. The relationship between serum trastuzumab and HER2 ECD levels was also investigated.
Statistical Analyses
No formal testing of hypotheses was planned and the statistical analysis was descriptive. A greater number of patients than usual for a phase II trial were planned to generate more robust results and ensure adequate PK assessments. It was assumed that with a response rate of 35%, enrollment of 80 patients would give a lower 80% confidence limit (one-sided) of 30.08%. Response rates and 95% CIs were calculated according to the Pearson-Clopper method. PK parameters were analyzed descriptively and Kaplan-Meier curves were calculated for time-to-event end points.
RESULTS
Patient Demographics
Table 1 lists baseline patient characteristics. At the time of data cutoff, 18 months after the last patient enrolled, patients had received a median of five cycles of trastuzumab therapy (range, 1 to 35+), and eleven patients had completed 24 or more cycles (18 months) of trastuzumab therapy. Eighty-seven patients (83%) had centrally confirmed IHC 3+ or FISH-positive MBC. Twenty-two patients were excluded from the per protocol subset (PPS) because they did not have confirmed HER2 overexpression or amplification (ie, centrally tested IHC 3+ and/or locally/centrally tested FISH-positive disease [n = 17]), measurable disease according to WHO criteria, or adequate tumor assessment at baseline (n = 8). Detailed analysis of HER2 status will be published in another article.
Efficacy
The overall response rate (ORR) was 19% in all patients in the intent-to-treat (ITT) population (two complete responses [CR] and 18 partial responses [PR]; n = 105), and 23% (two CRs and 17 PRs) in the PPS (n = 83; Tables 2 and 3 ). Stable disease (SD) was the best response in fifty-one percent of the full study population and of the PPS. The clinical benefit rate (CBR; CR + PR + SD > 6 months) was 33% in all patients, and 36% in the PPS. Median time to progression (TTP) was 3.4 months (range, 0.6 to 23.6 months) in all patients, and 3.5 months (range, 0.6 to 23.5 months) in the PPS (15 patients in the full analysis set and 13 patients in the PPS were censored due to lack of documented disease progression at the time of data cutoff). The median time to response was 1.4 months for both groups of patients and the median duration of response was 8.3 months (range, 2.8 to 22.5 months) in all patients, and 10.1 months (range, 2.8 to 22.5 months) in the PPS. Median overall survival was not reached during the observed study period but this was mainly because of loss to follow-up (only 15 deaths were reported at the time of data cutoff).
Safety
Trastuzumab monotherapy was generally well tolerated and no unexpected toxicities were noted. Overall, 599 adverse events were reported in 94 patients (regardless of causality) but only 37 adverse events were CTC grade 3, and three adverse events were CTC grade 4. Twenty-nine percent of adverse events were considered by the investigator to be treatment related. Only six serious adverse events were considered to be related to trastuzumab. The most common treatment-related adverse events were mild-to-moderate rigors, pyrexia, headaches, nausea, and fatigue (Table 4).
Fifty-four percent of patients had at least one symptom associated with their first infusion (defined as an adverse event experienced on the day of, or the day after, the infusion), but the frequency decreased with subsequent infusions: 29% with the second infusion and 20% with the third. The most common IRRs were rigors, pyrexia, and headache. Only three patients experienced serious IRRs. Two of these IRRs resolved and the patients continued to receive trastuzumab; the third patient was withdrawn from treatment on day 6 of the study. A total of 15 deaths have been reported, of which 14 were as a result of progressive disease, and one to a cerebral vascular accident considered unrelated to trastuzumab therapy. There were few significant changes in biochemical or hematologic laboratory parameters, and those that did occur were thought to be disease related.
Cardiac Safety
Median baseline LVEF was 63% (range, 49% to 84%; n = 103); this did not change significantly over the course of the study. Only one patient in this study experienced symptomatic cardiac failure. This patient was a 74-year-old woman with a baseline LVEF of 59% and a history of hypertension, obesity, and prior epirubicin therapy (total cumulative dose, 450 mg/m2). At cycle 4, she was hospitalized with dyspnea and cardiac insufficiency (NYHA class II), at which time her LVEF was 33%. Trastuzumab was stopped, she was treated with furosemide and enalapril, and her symptoms resolved after 9 days. Approximately 6 months later, her LVEF had increased to 53% and she was no longer taking cardiac medication. Other trastuzumab-related cardiac events were hypertension (n = 3) and tachycardia (n = 1); these were infusion-related, mild to moderate in severity and rapidly resolved after completion of the infusion. One other patient experienced more severe dyspnea and chest tightness following her first infusion, and required overnight administration and treatment with oxygen and tramadol. This patient did not have a baseline LVEF assessment before treatment, and though the breathlessness and chest tightness resolved, she continued to experience exertional dyspnea. She was withdrawn from the study on day 19. Six patients experienced cardiac events that were considered to be unrelated to trastuzumab (palpitations, hypertension, tachycardia, cardiac tamponade, and pericardial effusion).
In addition, isolated drops in LVEF of uncertain significance were not uncommon. Changes in LVEF among all patients and in those with or without previous exposure to anthracyclines are listed in Table 5. Decreases in LVEF were more frequent and more severe among patients who had a history of anthracycline therapy. Eight of 11 patients whose worst change in LVEF was a reduction of 15%, and six of nine patients with a worst LVEF measurement of less than 50%, had previously received anthracyclines. Overall, a total of 16 patients had an absolute drop in LVEF of 15% and/or an LVEF of less than 50%. Of these 16 patients, two withdrew from the study as a result of the LVEF change, nine withdrew due to disease progression, and one for unspecified reasons. The remaining four patients were still receiving trastuzumab at data cutoff. There was no change in the incidence of decreased LVEF in the 12-month additional follow-up period.
PK and Pharmacodynamics
The individual variability in predose serum trough concentrations of trastuzumab showed an almost 10-fold range before the administration of dose 6, when the PK substudy was performed. However, this may not represent the total variability because patients who had the lowest exposure to trastuzumab had already withdrawn from the study, largely due to progressive disease (19 patients at or before cycle 3). The mean trough concentration profile for trastuzumab revealed that accumulation occurred with a mean increase of 94%, ranging across 13 cycles from 27.3 μg/mL at cycle 2 to 52.7 μg/mL at cycle 15 (Fig 1). The cumulative dose during a 3-week interval was identical between the 3-weekly regimen arm and the weekly regimen arm. As expected, mean trough trastuzumab concentrations were approximately 20% lower at the end of each cycle than those concentration levels at the same timepoint using weekly dosing in the pivotal trastuzumab monotherapy trial (Fig 1). Also as expected, Cmax values were approximately 70% higher than using the weekly regimen (Fig 2 and data not shown), and serum concentrations exceeded or equaled those observed using the weekly regimen for approximately half the 3-week dose interval (Fig 2). As a result, average exposure at any time during the treatment is comparable between the two regimens (Fig 2). It has been necessary to use simulations to compare Cmax and exposure at common timepoints, as the sampling schemes employed in investigating the two regimens were different. The results of the validation of these simulations using observed data are shown in Figure 3 (weekly regimen)9 and Figure 4 (3-weekly regimen).
Further analysis using the Hill equation (steady-state trough concentration x time/constant + time) estimated the concentration at steady-state to be 65.47 μg/mL, and the time taken to reach steady-state to be approximately 14 weeks. These data indicate that mean trough concentrations remained within 20% of the predicted plateau between cycles 11 and 13.
PK profiles were obtained for 23 patients at cycle 6 and PK data for all these patients are included in the analysis. The mean trough concentration before dosing for cycle 6 was significantly above zero (mean trough concentration, 49.1 μg/mL; n = 48, which included predose values from those patients not included in the PK substudy). PK parameters for patients in the PK substudy are listed in Table 6. In this study, the mean estimated terminal half-life for 3-weekly trastuzumab was 16.4 days. This value is in agreement with data obtained from previous studies of weekly (ie, estimated terminal half-life approximately 16 days) trastuzumab based on noncompartmental PK methods.9 Sampling within a single dosing interval (ie, limited sampling period) is known to result in an underestimation of terminal half-life. Trastuzumab has a PK profile of at least two elimination phases after infusion. The first phase has a shorter half-life of about 4 days, and the second phase, which starts approximately 1 week after the end of infusion, has a longer half-life. A short sampling period within a dosing interval (ie, 3 weeks) will capture data mostly from the first phase. Estimation of half-life using a noncompartmental analysis method (ie, without modeling the PK data) will yield an underestimation of the half-life. Two separate population PK analyses (using pooled data across a number of studies, one of which was the data set from this study), derived a mean half-life (CV%) for the second phase of elimination that was 28.5 ± 5.0 days.12,21
Inter-individual variability in trastuzumab serum trough concentrations was wide. To determine the cause of this variability, several indicators of disease burden were investigated. A weak inverse relationship was found between serum trastuzumab concentrations and each of the following: disease burden at baseline, number of metastatic sites, and best response (data not shown).
An inverse relationship between serum HER2 ECD and serum trastuzumab concentrations was noted, particularly at ECD concentrations of more than 100 ng/mL (Fig 5). However, no clear relationship was observed when baseline ECD levels were compared with best response (Fig 6), or when the maximum change in ECD level from baseline was compared with best response (data not shown).
DISCUSSION
This study evaluated the efficacy, safety, and PK of a 3-weekly trastuzumab monotherapy regimen in which three times the standard weekly dose are given.
A previous study13 that evaluated the same 3-weekly trastuzumab regimen in combination with paclitaxel (n = 32) demonstrated a response rate of 59%, no unexpected toxicities, and no PK interactions between the two drugs. These findings indicated that trastuzumab could be administered at higher individual doses given less frequently without compromising efficacy or tolerability. In the present trial, clinical efficacy was within the range expected based on studies of weekly trastuzumab monotherapy.8,9 The ORR of 19% (95% CI, 12.04 to 27.87; 23% in the PPS group; 95% CI, 14.38 to 33.42) was lower than in the previous study of first-line weekly trastuzumab monotherapy (all, 26%; IHC 3+, 35%)8 but higher than in the study of second and third-line trastuzumab (all, 15%; IHC 3+, 18%).9 This may have been because of differences in the prognosis of the patient populations at baseline,8,9 though no striking differences are apparent. The CBR in the two first-line studies were in a similar range; with 3-weekly trastuzumab the CBR was 33% in all patients and 36% (95% CI, 26% to 47%) in the PPS group, compared with 38% in all patients and 48% in patients with IHC 3+ disease in the first-line weekly trastuzumab monotherapy study.8 Median TTP was also similar for the 3-weekly and first-line weekly regimens (3.4 months v 3.5 and 3.8 months, respectively).8 It is of note that almost 30% of patients in the present study progressed at or before the first tumor assessment at 6 weeks. Because response to trastuzumab was rapid (median time to response was 1.4 months, similar to that for chemotherapy), this suggests that these patients had rapidly progressing disease and a poor prognosis. In an analysis of patient demographics in the ITT group, patients with a best response of progressive disease had a higher incidence of lung metastases (64%) at baseline compared with those patients who did not exhibit rapid disease progression (42%). With the benefit of hindsight, it might have been better if these patients had been treated with trastuzumab in combination with chemotherapy. In general, this suggests that clinicians should select patients carefully, and perhaps reserve trastuzumab monotherapy for those with less advanced or more indolent disease. Alternatively, patients with more aggressive disease could be checked more frequently (eg, at week 3, before cycle 2), for possible early disease progression.
Weekly trastuzumab therapy has a favorable safety profile.7–10,22,23 Our findings indicate that 3-weekly single-agent trastuzumab is also well tolerated. The majority of adverse events were mild-to-moderate IRRs, occurring predominantly with the first infusion. Although the absolute percentage of patients experiencing IRRs in this study (54% with the first infusion) seems to be higher than in other studies of weekly trastuzumab, the definition of an IRR (ie, any adverse event occurring on the day of, or day after, the infusion) was probably more inclusive than that used in many other studies. The incidence of severe IRRs (4%) is not higher than expected.
In the pivotal trastuzumab combination trial (H0648g), trastuzumab was associated with cardiotoxicity, especially when given with anthracyclines.24 Trastuzumab trials since then have included cardiac eligibility criteria and prospective cardiac monitoring. The incidence of CHF in a pooled analysis of six recent trials (including this trial) was 2.7%.25 In our study, CHF occurred in one patient (< 1% of all patients); she stopped trastuzumab therapy and was treated with standard cardiac medication and the event resolved. These data suggest that the incidence of cardiac events is no higher with the 3-weekly compared with the weekly trastuzumab schedule. As described in other studies,25 isolated drops in LVEF of uncertain significance were common in this study, especially in patients previously exposed to anthracyclines.
Analysis of population PK data has indicated that the half-life of trastuzumab is significantly longer than previously believed, at 28.5 days rather than 8.3 days.12 Based on the PK parameters from the population PK analysis,12 simulations were performed to construct full concentration-time profiles for the 3-weekly and weekly regimens. Simulations were employed given that direct comparison of full PK profiles between the two regimens was not possible because of differences in the study design and sampling schedules. The data from these simulations show that the PK profiles observed for the 3-weekly regimen in this study compare favorably with the simulated data for 3-weekly trastuzumab (Fig 4); the simulated profile for the weekly regimen is also consistent with previously observed data (Fig 3).9 Of note, comparison of the full concentration-time profiles (Fig 2) shows that though peaks are higher (by 50% to 70%) and troughs are lower (by up to 22%) for the 3-weekly regimen compared with the weekly regimen, the average exposure for the two regimens is similar. These differences are not considered to be of clinical importance because trastuzumab does not exhibit dose-dependent toxicity, and efficacy is likely to be related to average exposure rather than peak or trough levels. The efficacy results reported support the relevance of drug exposure rather than the per dose concentration as a measure of the comparability of regimens.13,16 Moreover, the differences in peaks or troughs between the two regimens are small compared with the high degree of inter-individual variability (approximately 10-fold) observed in clinical trials.16 Although the 3-weekly and weekly regimens have similar efficacy, safety, and exposure, in patients with life-threatening disease there may be a role for a more aggressive approach with both regimens. More intensive loading, for example, could be used to reach steady-state more quickly.
Examination of ECD and serum trastuzumab concentrations at each study cycle showed that an inverse relationship exists between these two variables at ECD concentrations exceeding approximately 100 ng/mL. Although some recent studies have reported a relationship between HER2 ECD levels and response to trastuzumab therapy,26–28 this relationship was not found in this study. Further analyses are ongoing in order to determine the clinical relevance of ECD levels to response.29 These results will be published separately.
In conclusion, trastuzumab monotherapy given on a 3-weekly schedule at three times the standard weekly dose was well tolerated with efficacy in the expected range, in women with HER2-positive MBC. The incidence and severity of cardiotoxicity was low and no higher than that reported for weekly trastuzumab. No new or unexpected adverse events were noted. PK analysis demonstrated that trastuzumab exposure using the 3-weekly regimen was similar to that reported for standard weekly trastuzumab therapy. Additional analyses performed after 12 months of further follow-up (30 months after the last patient entered; data not shown) show that long-term administration of trastuzumab monotherapy is well tolerated. Thus, the 3-weekly trastuzumab regimen might represent a convenient alternative to weekly administration. The findings of our trial provide support for further investigation of the 3-weekly trastuzumab monotherapy regimen, and this is being pursued in several large ongoing adjuvant trials.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Claire Barton, Roche Products Ltd; Parviz Ghahramani, AstraZeneca, Roche Products Ltd. Consultant/Advisory Role: Jose Baselga, Hoffman-La Roche; Claire Barton, Roche. Stock Ownership: Claire Barton, Roche. Honoraria: Jose Baselga, Hoffman-La Roche. Research Funding: Michael Clemens, Roche. Expert Testimony: Vernon Harvey, Roche. Other Remuneration: Vernon Harvey, Roche. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
The authors would like to acknowledge the Pathology Institute in Kassel, Germany, headed by J. Rueschoff, PhD, who performed central testing on tumor samples for this study. The authors would also like to thank Sian Lennon for her thoughtful contributions to this manuscript.
NOTES
Supported by F. Hoffmann-La Roche Ltd.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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