Dataset Information

Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer.

ABSTRACT: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-positive metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclinical modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concentration profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems.

SUBMITTER: Chudasama VL

PROVIDER: S-EPMC3745717 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer.

Chudasama V L VL Schaedeli Stark F F Harrold J M JM Tibbitts J J Girish S R SR Gupta M M Frey N N Mager D E DE

Clinical pharmacology and therapeutics 20120912 4

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-positive metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclinical modeling ...[more]

PMID: 22968044

Similar Datasets

Project description:Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker.We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted.Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine.T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).

Project description:ImportanceERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life.ObjectiveTo determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2).Design, setting, and participantsThe MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease.InterventionsPatients in the phase 1 mBC cohort received capecitabine (750 mg/m2, 700 mg/m2, or 650 mg/m2 twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone.Main outcomes and measuresThe phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR).ResultsIn phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m2 in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, -4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported.Conclusions and relevanceAdding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects.Trial registrationClinicalTrials.gov Identifier: NCT01702558.

Project description:PURPOSE:This article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent. BACKGROUND:The development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody-drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, trastuzumab. RESULTS:Preclinical and phase 1-3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac toxicity has not been demonstrated. Both in vitro cell line-based studies as well as exploratory analyses of archived tumor samples from the clinical trials are seeking to understand potential mechanisms of resistance to T-DM1. Ongoing studies are also evaluating the use of T-DM1 in the first-line metastatic, neoadjuvant, and adjuvant settings, as well as in combination with other targeted therapies. CONCLUSION:T-DM1 represents the first successfully developed antibody drug conjugate for the treatment of HER2-positive advanced breast cancer.

Dataset Information

Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer.

Publications

Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure