- © 2010 by American Society of Clinical Oncology
Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) –Positive Breast Cancer After Prior HER2-Directed Therapy
- Howard A. Burris III⇑,
- Hope S. Rugo,
- Svetislava J. Vukelja,
- Charles L. Vogel,
- Rachel A. Borson,
- Steven Limentani,
- Elizabeth Tan-Chiu,
- Ian E. Krop,
- Richard A. Michaelson,
- Sandhya Girish,
- Lukas Amler,
- Maoxia Zheng,
- Yu-Waye Chu,
- Barbara Klencke and
- Joyce A. O'Shaughnessy
- From the Sarah Cannon Research Institute, Nashville, TN; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco; Genentech, South San Francisco, CA; Tyler Cancer Center, Texas Oncology, US Oncology, Tyler; Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX; Lynn Cancer Institute, Boca Raton; Florida Cancer Care, Davie, FL; St Louis Cancer and Breast Institute, St Louis, MO; University of North Carolina, Blumenthal Cancer Center, Charlotte, NC; Dana-Farber Cancer Institute, Boston, MA; and St Barnabas Medical Center, Livingston, NJ.
- Corresponding author: Howard A. Burris III, MD, Sarah Cannon Research Institute, 250 25th Ave North, Ste 110, Nashville, TN 37203-1632; e-mail: howard.burris{at}scresearch.net.
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Presented in part at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL; and the 34th Annual Meeting of the European Society for Medical Oncology, September 20-24, 2009, Berlin, Germany.
Abstract
Purpose The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2) –overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population.
Patients and Methods This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy.
Results With a follow-up of ≥ 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%).
Conclusion T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose.
INTRODUCTION
Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in 15% to 25% of all breast cancers and is associated with poor prognosis.1,2 The humanized anti-HER2 antibody trastuzumab (Herceptin; Genentech, South San Francisco, CA), in combination with chemotherapy, prolongs survival of patients with HER2-positive breast cancer in metastatic and adjuvant settings.3–6 However, most patients with HER2-positive metastatic breast cancer (MBC) eventually develop progressive disease on available therapies, including the HER2-targeted therapies trastuzumab and lapatinib.7 Consequently, the development of additional therapeutic options for this patient population is strongly warranted.
Trastuzumab-DM1 (T-DM1) is a novel anti-HER2 antibody-drug conjugate (ADC) in development for treatment of patients with HER2-positive breast cancer.8 T-DM1 combines the HER2-targeting properties of trastuzumab with intracellular delivery of DM1, a highly potent derivative of the antimicrotubule agent maytansine.9–11 DM1 binds to tubulin and inhibits microtubule assembly with greater potency than vincristine or vinblastine.11 In T-DM1, trastuzumab and DM1 are covalently linked via the thioether linker (N-maleimidomethyl)cyclohexane-1-carboxylate (MCC). The stability of MCC, compared with disulfide linkers, was shown to strongly contribute to the favorable activity and toxicity profiles of T-DM1 in preclinical testing (data on file, Genentech, South San Francisco, CA)12; exposure of HER2-positive tumors to DM1 is maximized, whereas exposure of normal tissue is minimized. Additionally, T-DM1 seems to retain the antitumor properties of trastuzumab, including flagging HER2-positive tumor cells for destruction by antibody-dependent cellular cytotoxicity and inhibiting HER2 signaling (data on file, Genentech, South San Francisco, CA).12,13
A phase I dose-escalation study evaluated dosing schedules of T-DM1 in patients with HER2-positive MBC who had experienced progression on trastuzumab-based therapy.8 Most adverse events (AEs) attributed to T-DM1 were ≤ grade 2. The maximum-tolerated dose of T-DM1 was 3.6 mg/kg every 3 weeks, based on the dose-limiting toxicity of grade 4 thrombocytopenia at 4.8 mg/kg. For the 15 patients treated at the maximum-tolerated dose, median progression-free survival (PFS) was 10.4 months, and four (44%) of nine patients with measurable disease had an objective response. The pharmacokinetics of T-DM1 were characterized by relatively slow clearance, a small volume of distribution (limited to plasma volume), and a half-life of approximately 4 days. Systemic DM1 exposure was low (average of approximately 5 ng/mL maximum plasma levels). On the basis of these results, a phase II study (TDM4258g) was initiated to evaluate T-DM1 treatment in patients with HER2-positive MBC who experienced progression on HER2-directed therapy.
PATIENTS AND METHODS
Patients
Eligibility criteria included HER2-positive disease by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC; 3+) assessment at a local laboratory. All patients received ≥ one prior HER2-targeted therapy and had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0).14 All patients also had prior tumor progression while receiving HER2-directed therapy or ≤ 60 days after the last dose of trastuzumab.
Additional eligibility criteria included the following: prior treatment with ≥ one chemotherapy agent for MBC; no history of significant cardiac disease; left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram or multigated acquisition scans; no history of ≥ grade 3 hypersensitivity to trastuzumab or toxicity requiring discontinuation; no ≥ grade 3 peripheral neuropathy; no untreated or symptomatic brain metastases; and no treatment for brain metastases ≤ 3 months before first T-DM1 dose.
Study Design and Objectives
In this single-arm study, T-DM1 was administered intravenously at 3.6 mg/kg every 3 weeks for up to 1 year, with the option of continued treatment in an extension study. The primary end points were objective response rate (ORR) by independent radiologic facility (IRF) review, safety, and tolerability. Secondary objectives included ORR by investigator review, duration of objective response (DOR), PFS by IRF and investigator, and characterization of pharmacokinetics. Correlation of efficacy with HER2 status as a biomarker was an exploratory objective.
All patients provided written informed consent. The study was reviewed and approved by the institutional review board at each site, according to local clinical guidelines. The study is in accordance with assurances filed with and approved by the Department of Health and Human Services.
Assessments and Data Collection
Tumor assessments per RECIST were conducted every other cycle by investigator and retrospectively by single-reader IRF. Echocardiograms or multigated acquisition scans were obtained after cycles 1 and 2 and then every two cycles thereafter until study termination. Serum cardiac troponin I levels were assessed on day 8 of every other cycle.
Serum and plasma samples were obtained from all patients before dosing and 30 minutes after treatment infusion to determine T-DM1 and total trastuzumab and DM1 levels. Additional samples were obtained on days 8 and 15 of cycles 1 and 4. T-DM1 and total trastuzumab levels (conjugated and unconjugated T-DM1) in serum were quantitated using a validated enzyme-linked immunosorbent assay.8 DM1 concentrations in plasma were determined by Xendo Drug Development B.V. (Groningen, the Netherlands) using a validated liquid chromatography–tandem mass spectrometry method. Pre- and postdose serum samples (day 1 of cycles 1 and 4) were assessed for anti–T-DM1 antibodies using a bridging-antibody electrochemiluminescent assay.8
HER2 Testing
Archival tumor tissue blocks from tumors obtained at initial diagnosis were retrospectively assessed for HER2 overexpression by central laboratory using IHC (HercepTest kit; DAKO, Glostrup, Denmark) and/or FISH (Vysis PathVysion HER2 FISH kit; Abbott Molecular, Abbott Park, IL). By central retesting, patients were defined as HER2-positive based on a score of 3+ by IHC (strong, complete membrane staining in > 10% of the tumor cells) and/or an HER2/CEP17 ratio of ≥ 2.0 by FISH.
HER2 and glucose-6-phosphate dehydrogenase expression were measured by real-time, reverse transcriptase polymerase chain reaction (RT-PCR); methods and primer and probe sequences have been previously described.15,16 RNA was extracted from tumor material using commercially available reagents (Roche Diagnostics, Mannheim, Germany). HER2 expression was expressed as normalized ratio to glucose-6-phosphate dehydrogenase mRNA expression. The kit to conduct these assays is not approved by the US Food and Drug Administration but is technically validated; the laboratory setting was in compliance with Clinical Laboratory Improvement Amendments standards.
Statistics
Statistical analyses were conducted after all patients had completed 1 year of treatment and/or discontinued from study (approximately 12 months of minimum follow-up). Primary and secondary efficacy and safety end points were analyzed on the treated population, which was defined as patients who received ≥ one dose of T-DM1. Objective response was defined as complete or partial response on two consecutive tumor assessments ≥ 4 weeks apart; the 95% CI for ORR was calculated using Blythe-Still-Casella methodology. The Kaplan-Meier method was used to calculate median PFS and DOR with 95% CIs by Greenwood's formula. For patients who experienced no disease progression and did not die while on study, data were censored at the date of last tumor assessment.
Exploratory diagnostic analyses based on central HER2 testing and RT-PCR expression levels were also conducted. Exploratory analyses of efficacy in relation to HER2 testing were conducted on the efficacy-evaluable population, which was defined as patients who received ≥ one dose of T-DM1 and had ≥ one postbaseline tumor assessment or died ≤ 30 days after last study treatment. For patients with evaluable pharmacokinetics data, standard noncompartmental modeling was used to calculate parameters at cycles 1 and 4, using WinNonLin 5.2.1 in the Pharsight Knowledgebase Server (Pharsight, Mountain View, CA).
RESULTS
Patient Demographics and Characteristics
One hundred twelve patients were enrolled onto the study and received at least one dose of T-DM1 (Table 1). Patients received a median of eight prior anticancer agents in all disease settings, including taxanes (84%), anthracycline (71%), capecitabine (66%), and carboplatin (42%). All patients received prior trastuzumab (median exposure, 17.6 months). In a post hoc exploratory analysis, 75 patients reported discontinuation of a trastuzumab-containing chemotherapy regimen as a result of progressive disease. Sixty-seven patients (60%) also received prior lapatinib (median exposure, 6.0 months).
Baseline Patient Demographics and Clinical Characteristics
Efficacy
Among treated patients, 29 patients had an objective tumor response (all partial responses) by IRF assessment, corresponding to an ORR of 25.9% (Table 2). By investigator assessment, there were 42 objective responses (37.5%), including four complete responses (3.6%). There was 82% agreement between IRF and investigator assessments. The primary reasons for differences between the IRF- and investigator-determined ORR were the independent selection of different lesions by the reviewers and alternative interpretations of nontarget lesions. Among the 75 treated patients who reported discontinuation of a prior trastuzumab-containing regimen as a result of progressive disease, 21 patients had objective responses, for an ORR of 28.0% (95% CI, 18.2% to 38.9%).
Objective Responses
The median DOR was not reached (95% CI, 6.2 months to not estimable [NE]) by IRF assessment and was 9.4 months (95% CI, 7.0 months to NE) by investigator assessment (Fig 1A). Median PFS for efficacy-evaluable patients was 4.6 months by both IRF (Figure 1B) and investigator (Figure 1C) assessment (95% CI, 3.9 to 8.6 months and 4.1 to 6.0 months, respectively).
Progression-free response (PFS) and duration of objective response. (A) Kaplan-Meier plot of duration of objective response by IRF assessment. (B) Kaplan-Meier plot of PFS by IRF assessment. (C) Kaplan-Meier plot of PFS by INV assessment. T-DM1, trastuzumab-DM1.
Among efficacy-evaluable patients with prior lapatinib treatment (n = 66), the ORR was 24.2% (95% CI, 14.5% to 36.0%) by IRF and 34.8% (95% CI, 23.5% to 46.8%) by investigator. Median PFS times were 5.3 months (95% CI, 3.6 to 8.9 months) and 4.2 months (95% CI, 2.8 to 6.8 months) per IRF and investigator, respectively.
Exploratory HER2 Testing Analyses
Ninety-five efficacy-evaluable patients had HER2 status reassessed on archival primary tumor by a central laboratory using IHC or FISH. Seventy-four of 95 patients were confirmed as having HER2-positive tumors, and 21 patients had HER2-normal tumors. By IRF assessment, ORR was 33.8% (95% CI, 23.2% to 44.9%) in patients with confirmed HER2-positive tumors and 4.8% (95% CI, < 1.0% to 21.8%) in patients with HER2-normal tumors by central retesting (Table 2). Median PFS was 8.2 months (95% CI, 4.4 months to NE) among patients with confirmed HER2-positive tumors and 2.6 months (95% CI, 1.4 to 3.9 months) among patients with confirmed HER2-normal tumors (Fig 2A).
Efficacy based on centrally assessed human epidermal growth factor receptor 2 (HER2) status and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) expression levels of HER2. (A) Kaplan-Meier plot of progression-free survival (PFS) per independent radiologic facility (IRF) assessment, by centrally assessed HER2 status (HER2 positive or HER2 normal). (B) HER2 qRT-PCR levels by retrospectively confirmed HER2 status are shown in box plots as the levels of HER2 mRNA normalized to glucose-6-phosphate dehydrogenase mRNA expression, for centrally assessed tumor samples that were found to be HER2 positive (left) and HER2 normal (right). The upper and lower limits within the box represent the 75th and 25th percentiles, respectively. Open circles represent HER2 expression levels from individual tumor samples. (C) Kaplan-Meier plot of PFS per IRF assessment for centrally confirmed HER2-normal patients and HER2-positive patients based on expression of HER2 measured by qRT-PCR (≥ and < median). PFS results presented are based on IRF assessment. INV, investigator.
Patients with retrospectively confirmed HER2-positive disease were grouped according to HER2 expression levels (≥ or < median) determined by quantitative RT-PCR. Distributions and ranges of HER2 levels assessed by quantitative RT-PCR are shown in Figure 2B. With available data from 50 patients, ORR per IRF in patients with ≥ median HER2 expression (n = 25) was 36% (95% CI, 18.5% to 56.9%; Table 2); median PFS was not reached (95% CI, 4.6 months to NE; Fig 2C). ORR in patients who had tumors with less than median HER2 expression (n = 25) was 28.0% (95% CI, 12.1% to 47.5%), and median PFS was 4.2 months (95% CI, 2.7 to 6.8 months). Similar trends were observed by investigator assessment (data not shown).
Safety
The 112 treated patients received a median of seven doses (range, one to 17 doses) of T-DM1 on study, with a median duration of exposure of 4.2 months. Twenty-one patients completed 1 year of study treatment, of whom 19 continued therapy in an extension study.
The most common AEs (any grade) were fatigue, nausea, and headache (Table 3). The most frequently observed grade 3 or 4 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). hypokalemia was not associated with vomiting, diarrhea, or diuretic use. No single serious AE occurred in more than three patients.
Adverse Events Occurring in ≥ 20% of Patients
Three patients died within 30 days of receiving T-DM1. Disease progression was documented before death in two patients; the third patient was discontinued because of clinical deterioration as a result of underlying MBC. Four patients (3.6%) discontinued T-DM1 for the following reasons: concurrent thrombocytopenia and hepatotoxicity (n = 1); thrombocytopenia (n = 1); concurrent asthenia and failure to thrive (n = 1); and secondary malignancy with onset retrospectively determined to occur before T-DM1 dosing (n = 1). Six patients had T-DM1 dose reductions as a result of thrombocytopenia (n = 2), peripheral neuropathy, concurrent thrombocytopenia and neutropenia, back pain, epistaxis, and unknown reason. Five patients had T-DM1 doses reduced to 3.0 mg/kg; one patient had a further dose reduction to 2.4 mg/kg.
thrombocytopenia, which was defined as the dose-limiting toxicity in phase I,8 was not associated with serious hemorrhage. The most commonly reported hemorrhagic AE was grade 1 or 2 epistaxis, which occurred in 34% of treated patients. There were six reported grade 3 hemorrhagic AEs, including epistaxis (n = 2), hematochezia (n = 1), hemorrhoidal hemorrhage (n = 1), subdural hemorrhage (n = 1), and upper gi hemorrhage (n = 1). No patients discontinued treatment as a result of hemorrhage. Concurrent grade 3 thrombocytopenia was reported in one patient with grade 3 epistaxis. Episodic platelet transfusions were administered to four patients for thrombocytopenia; no patient required chronic platelet transfusions.
AEs associated with eye disorders were reported in 35 patients (31.3%), mostly grades 1 and 2 (commonly dry eye, increased lacrimation, vision blurred/visual impairment, and conjunctivitis). One patient with a history of glaucoma had grade 3 glaucoma and transient grade 4 reduced visual acuity, reported as unrelated to T-DM1; the patient remained on therapy without recurrence.
Characterization of the cardiotoxicity profile of T-DM1 was of interest, given the well-documented association of cardiotoxicity with trastuzumab treatment.17 No cases of grade 3 LVEF decline or symptomatic congestive heart failure were observed; no patients discontinued treatment as a result of cardiac toxicity. Two patients had LVEF declines to 40% to 45%. No elevations in serum troponin I levels were observed.
Pharmacokinetics
Pharmacokinetic parameter values for T-DM1 from all patients evaluable for pharmacokinetics are shown in Table A1. T-DM1 maximum serum concentration and area under the curve in cycles 1 and 4 were comparable, indicating no accumulation of T-DM1 with a dosing schedule of every 3 weeks (Table A1). As observed in phase I,8 total trastuzumab had a higher maximum serum concentration, area under the curve, and longer terminal half-life than T-DM1 (Figure 3). Systemic exposure to DM1 was consistently low (Fig 3); maximum DM1 levels averaged 5.35 ± 2.03 ng/mL in cycle 1. The highest reportable concentration of DM1 was less than 17 ng/mL. No formal pharmacokinetic analysis was possible because DM1 was only measurable immediately after T-DM1 administration. Repeated T-DM1 administration did not result in DM1 accumulation. Forty-four percent of patients had measurable total serum trastuzumab (0.044 to 66.9 μg/mL) before receiving T-DM1; this was not unexpected because patients had received prior trastuzumab treatment; these baseline values had no impact on T-DM1 exposure. Seven of 108 evaluable patients developed anti–T-DM1 antibodies, with no obvious impact on pharmacokinetics (Table A2).
Pharmacokinetics of trastuzumab-DM1 (T-DM1), total trastuzumab, and plasma DM1. Mean concentration-time profiles for serum T-DM1, serum total trastuzumab, and plasma DM1 are shown for all pharmacokinetically evaluable patients over four cycles.
DISCUSSION
The treatment of HER2-positive MBC after initial HER2-directed therapy continues to be a significant medical need. ADCs represent a novel approach for tumor-targeted therapies. By combining the targeted specificity and effector functions of trastuzumab with DM1, T-DM1 specifically delivers the cytotoxic agent into HER2-positive tumors at much higher concentrations than achievable using free drug. Clinical development of the DM1 parent compound, maytansine, was stopped because of its narrow therapeutic window as a free agent.9,10,18–20 The stability of T-DM1's MCC linker, evidenced by the approximately 60-fold molar difference between levels of circulating DM1 and T-DM1, minimizes systemic exposure to DM1, contributing to the favorable toxicity profile of T-DM1.
In this single-arm study for heavily pretreated patients with HER2-positive MBC, many of whom had previously received two HER2-directed therapies, T-DM1 administration resulted in objective responses by IRF and investigator assessment. In a post hoc exploratory analysis, ORR in patients who received both prior lapatinib and trastuzumab was not significantly different from overall ORR, suggesting that T-DM1 is active after progression on prior HER2-directed inhibitors.
The ORR in this study compares favorably with ORRs associated with other therapies in development for treatment of HER2-positive breast cancer. Treatment with neratinib (HKI-272), an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor, resulted in a 24% ORR among patients previously treated with trastuzumab.21 However, grade 3 or 4 diarrhea was observed in 30% of patients, and 29% of patients required dose reduction because of this AE. Pertuzumab is an HER2-directed monoclonal antibody that blocks heterodimerization and ligand-dependent signaling of HER1/HER2 and HER2/HER3 heterodimers.22 Pertuzumab in combination with trastuzumab demonstrated clinical activity (ORR, 24.2%) in patients with HER2-positive MBC previously treated with trastuzumab.23 Other targeted agents are being assessed in combination with trastuzumab for treatment of HER2-positive MBC. Treatment with the mammalian target of rapamycin inhibitor everolimus, combined with paclitaxel and trastuzumab, resulted in an ORR of 20% among HER2-positive patients previously treated with paclitaxel and trastuzumab alone.24 Treatment with the heat shock protein 90 inhibitor tanespimycin, in combination with trastuzumab, resulted in a response rate of 24% in patients with HER2-positive MBC who had experienced progression after prior trastuzumab treatment.25
The development of targeted therapies such as trastuzumab and T-DM1 underscores the necessity to optimize assays that reliably and accurately measure target expression. Despite the availability of US Food and Drug Administration–approved diagnostic kits to assess HER2 status by IHC and FISH, standardization of diagnostic procedures and reagents is lacking, contributing to a documented 20% discordance between HER2 status assessed locally and by high-volume central laboratories.26 In this study, 22% of patients were retrospectively shown to have HER2-normal expression, consistent with published reports of false-positive rates for HER2 expression. HER2-positive status based on central retrospective assessment was associated with higher ORR and longer PFS compared with HER2-normal status. Additionally, exploratory data suggest that median PFS and, to some extent, ORR, may be influenced by levels of HER2 expression as assessed by quantitative RT-PCR. These results further support the specificity of T-DM1 against HER2-positive tumors, suggesting a possible correlation between increased HER2 expression and T-DM1 activity. These data also support the relevance of HER2 assessments in archival primary tissue, even in trastuzumab-experienced patients. It is currently unclear whether similar associations exist for centrally assessed HER2 status of metastatic lesions at the time of disease occurrence or progression after initial therapy. Prospective studies will be required to validate these findings and confirm whether HER2 expression is a predictive marker for T-DM1 response and to further define RT-PCR–based cutoff values for HER2 expression that would reliably predict responsiveness to T-DM1.
T-DM1 was well tolerated. Dose-intensity (dose delivered/expected dose) was high (median, 99.7%). thrombocytopenia, the phase I dose-limiting toxicity, was among the most common grade 3 or 4 AEs. However, grade 3 or 4 hemorrhage was uncommon and was rarely associated temporally with thrombocytopenia; platelet transfusions were uncommon. No cardiac events resulted in dose modifications; the patient population in this study was prescreened for normal cardiac function, and cardiotoxic potential seems to be low. However, the cardiotoxic potential of T-DM1 in trastuzumab-naive patients after anthracycline treatment remains to be studied. There was no overt evidence of T-DM1 cumulative toxicity. In this study, dose modifications and study discontinuations as a result of AEs were infrequent. Patients continued to receive T-DM1 for more than 1 year, indicating that long-term administration of T-DM1 was tolerable.
As in the phase I study,8 T-DM1 had a predictable pharmacokinetic profile characterized by relatively low clearance, a volume of distribution limited to plasma volume, and a half-life of approximately 4 days. Systemic plasma DM1 concentrations were consistently low, with no evidence of DM1 accumulation after repeated T-DM1 dosing. These observations further support the principle that an ADC maximizes delivery of cytotoxic therapy to tumors while minimizing exposure to normal tissue. Absence of DM1 accumulation also contributes to continued tolerability after repeated T-DM1 administration. Finally, the frequency of antitherapeutic antibodies to T-DM1 was low and did not impact the pharmacokinetic profile of T-DM1.
In summary, these data demonstrate the efficacy and safety of the novel ADC T-DM1 in patients with HER2-positive MBC who were heavily pretreated with multiple agents, including one or more HER2-directed agents, and who therefore had limited therapeutic alternatives. An analogous single-agent study (TDM4374g) of T-DM1 (3.6 mg/kg every 3 weeks) in a more homogenous patient population (all patients received prior trastuzumab, lapatinib, a taxane, an anthracycline, and capecitabine) showed similar activity.27 An ongoing randomized phase III trial (EMILIA, study TDM4370g) is comparing efficacy and toxicity of single-agent T-DM1 treatment (3.6 mg/kg every 3 weeks) against combined capecitabine and lapatinib treatment in patients with HER2-positive MBC who have received prior trastuzumab-based therapy. T-DM1 is also being studied in combination with conventional chemotherapy and other targeted therapies.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Sandhya Girish, Genentech (C); Lukas Amler, Genentech (C); Maoxia Zheng, Genentech (C); Yu-Waye Chu, Genentech (C); Barbara Klencke, Genentech (C) Consultant or Advisory Role: Charles L. Vogel, Genentech (C); Ian E. Krop, Genentech (U); Joyce A. O'Shaughnessy, Genentech (C) Stock Ownership: Sandhya Girish, Roche; Lukas Amler, Roche; Maoxia Zheng, Roche; Yu-Waye Chu, Roche; Barbara Klencke, Roche Honoraria: Charles L. Vogel, Genentech; Steven Limentani, Genentech; Joyce A. O'Shaughnessy, Genentech Research Funding: Hope S. Rugo, Genentech, Roche; Charles L. Vogel, Genentech; Steven Limentani, Genentech; Elizabeth Tan-Chiu, Genentech; Ian E. Krop, Genentech Expert Testimony: None Other Remuneration: Charles L. Vogel, Genentech
AUTHOR CONTRIBUTIONS
Conception and design: Howard A. Burris III, Hope S. Rugo, Svetislava J. Vukelja, Charles L. Vogel, Rachel A. Borson, Steven Limentani, Elizabeth Tan-Chiu, Ian E. Krop, Richard A. Michaelson, Yu-Waye Chu, Barbara Klencke, Joyce A. O'Shaughnessy
Provision of study materials or patients: Howard A. Burris III, Hope S. Rugo, Svetislava J. Vukelja, Charles L. Vogel, Rachel A. Borson, Steven Limentani, Elizabeth Tan-Chiu, Ian E. Krop, Richard A. Michaelson, Joyce A. O'Shaughnessy
Collection and assembly of data: Howard A. Burris III, Hope S. Rugo, Elizabeth Tan-Chiu, Sandhya Girish, Lukas Amler, Maoxia Zheng, Yu-Waye Chu, Barbara Klencke, Joyce A. O'Shaughnessy
Data analysis and interpretation: Howard A. Burris III, Hope S. Rugo, Svetislava J. Vukelja, Charles L. Vogel, Rachel A. Borson, Steven Limentani, Ian E. Krop, Richard A. Michaelson, Sandhya Girish, Lukas Amler, Maoxia Zheng, Yu-Waye Chu, Barbara Klencke, Joyce A. O'Shaughnessy
Manuscript writing: Howard A. Burris III, Hope S. Rugo, Svetislava J. Vukelja, Charles L. Vogel, Rachel A. Borson, Steven Limentani, Elizabeth Tan-Chiu, Ian E. Krop, Richard A. Michaelson, Sandhya Girish, Lukas Amler, Maoxia Zheng, Yu-Waye Chu, Barbara Klencke, Joyce A. O'Shaughnessy
Final approval of manuscript: Howard A. Burris III, Hope S. Rugo, Svetislava J. Vukelja, Charles L. Vogel, Rachel A. Borson, Steven Limentani, Elizabeth Tan-Chiu, Ian E. Krop, Richard A. Michaelson, Sandhya Girish, Lukas Amler, Maoxia Zheng, Yu-Waye Chu, Barbara Klencke, Joyce A. O'Shaughnessy
Acknowledgment
We are grateful to all the patients, investigators, and health practitioners who participated in this study. At Genentech, we thank Bei Wang, Joo-Hee Yi, and Dr Ola Saad for pharmacokinetic and bioanalytical support; Dr Barbara Tong for biostatistical support and critical reading of the manuscript; and Dr Abie Craiu for assistance with preparation of the manuscript.
Appendix
Pharmacokinetic Parameter Estimates After Administration of T-DM1 3.6 mg/kg Every 3 Weeks
Impact of ATA on T-DM1 Pharmacokinetics
Footnotes
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See accompanying editorial on page 351
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Clinical trial information can be found for the following: NCT00509769.
- Received March 30, 2010.
- Accepted September 30, 2010.
