Efficacy Of T-DM1 Research Articles

The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer: latest evidence and ongoing studies.

The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 (HER2) has been drastically improved by the development of HER2-targeted therapies including trastuzumab and lapatinib. While outcomes for patients diagnosed with HER2-positive breast cancer have been greatly impacted by these therapies, treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge. Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate that consists of the HER2-targeted monoclonal antibody, trastuzumab, joined via a stable linker to a derivative of maytansine, a highly potent cytotoxic chemotherapy. While other antibody drug conjugates have been developed clinically, this is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I studies have shown T-DM1 is safe, tolerable and has activity in trastuzumab- and lapatinib-pretreated breast cancer. Moreover, phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings. Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the HER2-positive metastatic breast cancer setting. This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy and safety of T-DM1 for the treatment of HER2-positive breast cancer.

Potentiation of trastuzumab emtansine (T-DM1)-driven antitumor activity by pertuzumab in a HER2-positive gastric cancer model.

e13502 Background: The efficacy and safety of T-DM1 combined with pertuzumab in HER2-positive breast cancer is currently being investigated in a phase III clinical trial (MARIANNE). Anti-HER2 therapy with T-DM1 combined with pertuzumab in HER2-positive gastric cancer is of great interest. In a previous study in a HER2-positive gastric cancer xenograft model, T-DM1 in combination with pertuzumab demonstrated enhanced antitumor activity compared with each agent alone, and potentiated ADCC and apoptosis activity (AACR, 2011). In this study, we investigated the mechanisms underlying the enhanced activity observed with these two drugs. Methods: The binding of T-DM1 to cell surface HER2 was measured in a HER2-positive human gastric cancer cell line (NCI-N87) by flow cytometry using Alexa Fluor 647-labeled T-DM1. The phosphorylation status of HER signaling molecules was assessed by Western blot, and cellular localization of T-DM1 was determined by fluorescence microscopy using labeled T-DM1 in the presence/absence of pertuzumab. Results: Binding of T-DM1 to cell surface HER2 was significantly increased in the presence of pertuzumab. Concomitant treatment with T-DM1 and pertuzumab led to a reduction of phosphorylated (p)EGFR or pHER3 in EGF or heregulin-stimulated cells, respectively, resulting in suppression of downstream pERK or pAkt pathways. Fluorescence microscopy revealed that pertuzumab facilitated the internalization of HER2-bound T-DM1 from the cell surface into the cytoplasm. Conclusions: Results suggest that the enhanced antitumor activity observed with the combination of T-DM1 and pertuzumab may be attributed to 1) increased binding of T-DM1 to HER2, which could potentially augment ADCC and diminish downstream HER2-signaling, and 2) increased T-DM1 internalization into the cytoplasm, which may potentiate tumor cell death caused by DM1. These results suggest that T-DM1 in combination with pertuzumab may provide clinical benefit for patients with HER2-positive gastric cancer.

Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer

PurposeTrastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate.MethodsMultiple analytes—T-DM1, total trastuzumab (TT), DM1, and key metabolites—were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays.ResultsPK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w.ConclusionsThe PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.

P1-12-13: Comparative Pharmacokinetics (PK) of Trastuzumab Emtansine (T-DM1) in Patients Who Have or Who Have Not Received Prior Treatment for Human Epidermal Growth Factor 2 (HER2)-Positive Metastatic Breast Cancer (MBC).

Abstract Background: T-DM1, an antibody-drug conjugate composed of trastuzumab, a stable linker, and the cytotoxic agent DM1, is in development for the treatment of HER2−positive cancers. Single-agent T-DM1 3.6 mg/kg every 3 weeks (q3w) has demonstrated clinical activity in 2 phase II studies (TDM4258g and TDM4374g) in patients with pretreated HER2−positive MBC. The efficacy and safety of T-DM1 vs trastuzumab + docetaxel was investigated in patients with no prior MBC treatment in the randomized phase II study TDM4450g/BO21976. Here we report the PK of T-DM1 from that study and compare these data with those from studies that enrolled pretreated patients. Methods: In all 3 studies, PK parameters, including maximum concentration (Cmax), area under the concentration-time curve (AUC), terminal half-life (t½), steady-state volume of distribution (Vss), and clearance (CL) were estimated by noncompartmental analysis (NCA) for serum T-DM1, serum total trastuzumab (conjugated and unconjugated), and plasma DM1. The effects of baseline trastuzumab and HER2 extracellular domain (ECD) concentration on T-DM1 exposure were explored and the relationship between T-DM1 exposure and clinical response (objective response rate [ORR] and progression-free survival [PFS]) was modeled. Results: T-DM1 PK from evaluable patients enrolled in 3 studies are shown in Table 1. No significant correlations were observed between efficacy (as measured by ORR) and T-DM1 exposure (AUC, Cmax) after administration of T-DM1 to pretreated patients; efficacy-exposure analyses (ORR and PFS) for previously untreated patients will be presented. Patients with measurable concentrations of trastuzumab at baseline had a greater AUC during cycle 1; however, this did not impact ORR. Baseline circulating HER2 ECD concentrations also had no effect on ORR for pretreated patients. The impact of baseline trastuzumab and HER2 ECD concentrations on ORR and PFS in previously untreated patients will be presented. Conclusions: Single-agent T-DM1 has similar PK in patients who have received prior therapy for MBC and in those who have not. The PK of T-DM1 was not affected by prior trastuzumab treatment or by circulating HER2 ECD, and no significant correlations were observed between efficacy (ORR) and T-DM1 exposure (AUC, Cmax) or HER2 ECD for pretreated patients. The relationships between efficacy and T-DM1 exposure and HER2 ECD concentrations will be presented for patients without prior MBC treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-13.

P1-12-02: Patient-Reported Outcomes (PROs) from a Randomized Phase II Study (TDM4450g/BO21976) of Trastuzumab Emtansine (T-DM1) vs Trastuzumab Plus Docetaxel (HT) in Previously Untreated HER2−Positive Metastatic Breast Cancer (MBC).

Abstract Background: T-DM1 is an antibody-drug conjugate in development for HER2−positive cancer. As a single-agent, it has demonstrated promising efficacy and safety when administered after multiple lines of HER2−directed therapy. In the current study, we compared the safety and efficacy of T-DM1 to standard first-line treatment for HER2−positive MBC. This abstract highlights the PRO results in the context of efficacy and safety. Methods: Patients with HER2−positive MBC and no prior MBC therapy were randomized 1:1 to T-DM1 3.6 mg/kg IV q3w or H 6 mg/kg IV (8 mg/kg in cycle 1) + T 75 or 100 mg/m2 IV q3w. Primary objectives were investigator-assessed progression free survival (PFS) and safety. Key secondary end points included objective response rate and the FACT-B Trial Outcome Index (TOI). Patients completed the FACT-B on day 1 of each treatment cycle. The FACT-B TOI, the primary PRO end point, comprises a subset of the FACT-B and provides a summary measure of physical and functional well being and breast cancer specific symptoms. Time to FACT-B TOI worsening (ie, ≥5 point decrease in TOI) was assessed with Kaplan-Meier methods and a Cox model. A repeated measures mixed effects (RMME) model was used to evaluate potential treatment effects on TOI across cycles. Preliminary PRO results based on a data cutoff of November 15, 2010, are included here; final data will be presented. Results: A total of 137 patients were randomized (67 T-DM1, 70 HT). Baseline patient and disease characteristics were similar in each arm. Patients treated with T-DM1 had longer PFS (14.2 vs 9.2 months, HR=0.59, P= 0.035) with less toxicity (eg, 46.4% grade 3/4 adverse events with T-DM1 vs 89.4% with HT) than those treated with HT. ORR was similar in both arms (64.2% T-DM1, 58.0% HT). A total of 132 patients (65 T-DM1, 67 HT) were evaluable for PRO analyses with a high compliance rate. In a preliminary analysis, FACT-B TOI worsening was significantly delayed in the T-DM1 arm compared with the control arm (7.5 vs 3.5 months, HR=0.58, P=0.022). The RMME model showed a mean difference of 3.65 in FACT-B TOI scores (P=0.023), mainly driven by physical well being (PWB) scores (mean difference 2.28, P=0.002), favoring T-DM1. In addition, 5 of 7 PWB items showed significantly better mean scores in the T-DM1 arm: “lack of energy” (P=0.011), “trouble meeting needs of family” (P=0.025), “bothered by side effects” (P<0.001), “feeling ill” (P=0.016) and “forced to spend time in bed” (P=0.015); the 2 remaining items, “nausea” and “pain,” showed numerically better mean scores with T-DM1. Conclusions: Compared to HT, T-DM1 as first-line treatment of HER2−positive MBC conferred longer PFS and a more favorable toxicity profile. The PRO data suggest that T-DM1 is also associated with meaningfully improved tolerability relative to HT, contributing to an overall clinical benefit and better health-related quality of life. Thus, T-DM1 may improve the standard of care for patients with previously untreated HER2−positive MBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-02.

Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer

Introduction: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that combines intracellular delivery of the potent cytotoxic agent, DM1 (a derivative of maytansine) with the antitumor activity of trastuzumab. While there are several ADCs in Phase III development, T-DM1 is the only one in which the targeting antibody has antitumor properties. T-DM1 is also the only ADC that is directed toward the human EGFR 2 (HER2). Effective therapies are limited in HER2-positive advanced or metastatic breast cancer (MBC), particularly following progression on available HER2-targeted therapies.Areas covered: The mechanisms of action, preclinical efficacy and clinical profile of T-DM1 are reported. The latest preclinical and clinical data for T-DM1 are examined.Expert opinion: T-DM1 has significant antitumor potency in vitro and in vivo, which is maintained in tumors resistant to trastuzumab or lapatinib. In Phase I and II trials, T-DM1 provided objective tumor responses and was well tolerated across various lines of therapy in patients with HER2-positive MBC. In addition, it showed similar efficacy to trastuzumab plus docetaxel in first-line MBC. Ongoing trials (including two Phase III studies) are investigating T-DM1 as single-agent therapy or combined with other chemotherapeutic or biologic agents, and the results should help to define the place of T-DM1 within current treatment algorithms for HER2-positive disease.

Abstract S3-6: Combination Therapy of the Novel PI3K Inhibitor GDC-0941 and Dual PI3K/mTOR Inhibitor GDC-0980 with Trastuzumab-DM1 Antibody Drug Conjugate Enhances Anti-Tumor Activity in Preclinical Breast Cancer Models In Vitro and In Vivo

Abstract The receptor tyrosine kinase, HER2/ErbB2, is a validated clinical target for HER2-amplified breast cancer, as evidenced by the U.S.F.D.A. approval of the humanized HER2 antibody, trastuzumab (Herceptin®), and the dual HER2/EGFR small molecule tyrosine kinase inhibitor lapatinib (Tykerb®). An alternative approach for targeting HER2 is the direct covalent coupling of a cytotoxic drug to trastuzumab. We have previously reported the potent in vitro and in vivo efficacy of T-DM1, trastuzumab (T) linked to the microtubule polymerization inhibitory drug maytansinoid (DM1), in trastuzumab-sensitive and-refractory breast tumor models (1). Inhibition of signaling through PI3K, which is hyperactivated in HER2-amplified breast cancer due to constitutive activity of overexpressed HER2 and/or through mutation of the p110-α subunit of PI3K, also offers an additional therapeutic approach. Therefore the specific aims of our study were to determine if the combination of a novel pan-PI3K inhibitor (GDC-0941) or a dual PI3K/mTOR inhibitor (GDC-0980) enhanced the anti-tumor activity of T-DM1 in HER2-amplified breast cancer lines in vitro and as xenografts in vivo. The breast cancer cell lines tested, MCF7 neo/HER2 and KPL4, harbor the E545K and H1047R PIK3CA mutations, respectively. Combination treatment of T-DM1 with either GDC-0941 or GDC-0980 in vitro resulted in a synergistic inhibition of cellular viability. Biochemical biomarker analyses revealed inhibition of phospho-Akt and phospho-ERK by both T-DM1 and GDC-0941, decreased phosphorylation of Rb and PRAS40 by GDC-0941, and increased levels of the mitotic markers phospho-histone H3 and cyclin B1 after treatment with T-DM1. In addition, T-DM1 treatment resulted in apoptosis as determined by appearance of the 23 kDa PARP-cleavage fragment, decreased levels of Bcl-XL, as well as activation of caspases 3 and 7. Addition of GDC-0941 to T-DM1 further enhanced apoptosis induction. In vivo, increased and sustained tumor regressions were observed when GDC-0941 was combined with T-DM1 as compared to single-agent activity in the MCF7 neo/HER2 and KPL4 sub-cutaneous xenograft models in a dose-dependent fashion. Moreover, an increased number of sustained complete regressions (CRs) were observed when GDC-0980 was combined with T-DM1 in the KPL4 xenograft model when compared to the combination treatment with GDC-0941 (% CRs = 88% for GDC-0980 + T-DM1 vs. 50% for GDC-0941 + T-DM1). The results of our pre-clinical studies provides evidence for the use of rational drug combinations of PI3K inhibitors such as GDC-0941 and GDC-0980 with T-DM1 in HER2-amplified breast cancer that harbor PIK3CA mutations and may offer additional treatment options for patients whose disease progresses on trastuzumab or lapatinib-based therapy. 1. Lewis Phillips, G. et al. Cancer Res 2008; 68: (22). Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-6.

Abstract 5607: Dual targeting of HER2: Enhanced antitumor efficacy of trastuzumab-DM1 combined with pertuzumab

Abstract The EGFR family of transmembrane receptors consists of HER1 (ErbB1/EGFR), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). These receptors are often dysregulated in human solid tumors. For example, amplification and overexpression of HER2 occur in approximately 20 percent of human breast cancers and are predictive of poor clinical outcome. A principal means by which these receptors exert their growth-stimulatory effect is through homo- and hetero-dimerization which can occur in either a ligand-dependent or -independent manner and subsequently promotes receptor tyrosine kinase activity, leading to autophosphorylation and activation of downstream signal transduction pathways. The humanized HER2 antibody, trastuzumab (Herceptin®), is approved for use in adjuvant and metastatic HER2-positive breast cancer and has shown significant clinical benefit. Trastuzumab-DM1 (T-DM1, TMAb-mcc-DM1, trastuzumab emtansine) is an antibody-cytotoxic drug conjugate composed of the maytansine derivative DM1 directly coupled, through a thioether SMCC linker, to trastuzumab. We previously reported the potent in vitro and in vivo efficacy of T-DM1 in trastuzumab-sensitive and -refractory breast tumor models. Both trastuzumab and T-DM1 bind domain IV of the HER2 extracellular domain (ECD) and inhibit HER2 function in a ligand-independent manner. T-DM1 provides additional efficacy through selective delivery of the cytotoxic agent DM1 to HER2-overexpressing cancer cells. Pertuzumab is a humanized HER2 antibody that binds domain II of the HER2 ECD and thereby inhibits ligand-induced activation of HER2 by blocking dimerization of HER2 with other HER family members. Pertuzumab in combination with trastuzumab has shown impressive preclinical as well as clinical activity in HER2-positive breast cancer. The purpose of our studies was to evaluate the in vitro and in vivo efficacy of T-DM1 combined with pertuzumab. Our in vitro results show that combination treatment resulted in synergistic inhibition of cell proliferation in human breast and lung cancer cells that over-express HER2. Drug combination effects were analyzed by the Chou and Talalay method for determining combination index values. Similarly, we observed enhanced in vivo efficacy when administering T-DM1 in combination with pertuzumab, as compared with either agent alone, in breast and lung cancer xenograft models. Treatment of cells with T-DM1 combined with pertuzumab also resulted in a synergistic increase in apoptosis as measured by increased activity of the apoptotic enzymes, caspases 3 and 7, and increased levels of the apoptotic population in cell cycle experiments. Together, these studies support the hypothesis that T-DM1 in combination with pertuzumab for HER2-amplified cancer may offer an additional therapeutic approach for patients whose disease progresses on trastuzumab and lapatinib-based therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5607.