Alexander Strasak

Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2–Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.

Analysis of safety data in clinical trials using a recurrent event approach.

As an important aspect of the clinical evaluation of an investigational therapy, safety data are routinely collected in clinical trials. To date, the analysis of safety data has largely been limited to descriptive summaries of incidence rates or contingency tables aiming to compare simple rates between treatment arms. Many have argued that this traditional approach failed to take into account important information including severity, onset time, and multiple occurrences of a safety event. In addition, premature treatment discontinuation due to excessive toxicity causes informative censoring and may lead to potential bias in the interpretation of safety events. In this article, we propose a framework to summarize safety data with mean frequency function and compare safety events of interest between treatments with a generalized log-rank test, taking into account the aforementioned characteristics ignored in traditional analysis approaches. In addition, a multivariate generalized log-rank test to compare the overall safety profile of different treatments is proposed. In the proposed method, safety events are considered to follow a recurrent event process with a terminal event for each patient. The terminal event is modeled by a process of two types of competing risks: safety events of interest and other terminal events. Statistical properties of the proposed method are investigated via simulations. An application is presented with data from a phase II oncology trial.

Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens

AIMS We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physicians Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physicians choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer. METHODS We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 maximum concentration (Cmax ), cycle 1 minimum concentration (Cmin ) and area under the concentration-time curve at steady state (AUCss ). Kaplan-Meier analyses [overall survival (OS), progression-free survival (PFS)] and logistic regression [overall response rate (ORR), safety] were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 Cmin were compared with matched TPC-treated patients. RESULTS T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 Cmin and AUCss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 Cmax . No relationship between exposure and safety was identified. HRs for the comparison of T-DM1-treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 [95% confidence interval (CI) 0.63, 1.47] for OS and 0.92 (95% CI 0.64, 1.32) for PFS. CONCLUSIONS Exposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC-treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure.

Abstract P4-15-09: Phase 1 study of trastuzumab emtansine in HER2-positive metastatic breast cancer patients with normal or reduced hepatic function

Introduction Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab, a stable linker, and the microtubule inhibitor DM1. In phase 3 studies of HER2-positive metastatic breast cancer (MBC), T-DM1 significantly increased progression-free survival (EMILIA and TH3RESA) and overall survival (EMILIA) vs. control regimens. Few patients (2–4%) treated with T-DM1 experience grade ≥3 increases in transaminases. Currently, there are no data on the pharmacokinetics (PK) of T-DM1 in patients with hepatic impairment. This international, multicenter, open-label, parallel group, phase 1 PK study (BO25499/NCT01513083) is designed to assess the PK of T-DM1 and relevant analytes in MBC patients with normal hepatic function and mild or moderate hepatic impairment; safety and efficacy will also be evaluated. Methods To obtain 8 evaluable patients, up to 10 patients each with HER2-positive MBC and ECOG performance status of 0–2 were enrolled in 1 of 3 independent cohorts based on hepatic function per Child-Pugh criteria: normal hepatic function, mild hepatic impairment (Child-Pugh A), and moderate hepatic impairment (Child-Pugh B). Patients with severe hepatic impairment (Child Pugh C) were ineligible. Patients received 3 cycles of T-DM1 3.6 mg/kg every 3 weeks. After 3 cycles, patients could continue to receive T-DM1 until disease progression, unmanageable toxicity, or study termination in the present study, or enroll in an extension study (BO25430/TDM4529g). PK samples were collected during cycle 1 (days 1 [predose, 30 m and 4 h postinfusion], 2, 3, 4, 8, 11, 15, and 18); cycle 2 (day 1 [predose, 30 m postinfusion]); and cycle 3 (days 1 [predose, 30 m postinfusion], 8, 15, and 22). T-DM1, total trastuzumab, DM1, MCC-DM1, and Lys-MCC-DM1 were measured using validated assays. Adverse events were graded per NCI CTCAE, v4.03. All analyses are descriptive. The clinical cutoff date for this interim analysis was January 30, 2014. Results PK data were fully evaluable for 10 out of 10 patients each in the normal and mild cohorts and for 6 out of 7 patients in the moderate cohort. Compared with the normal cohort, T-DM1 clearance at cycle 1 was ∼1.9- and 3.3-fold faster in the mild and moderate cohorts, respectively. The trend of faster clearance was less apparent for cycle 3 after repeated dosing, with similar T-DM1 exposures across the 3 cohorts. Plasma concentrations of DM1 and DM1-containing catabolites were largely comparable across the 3 cohorts. No new safety signals were seen relative to the known safety profile of T-DM1. Updated safety data will be presented. Conclusions There is a trend for faster clearance of T-DM1 at cycle 1 in patients with mild and moderate hepatic impairment vs. those with normal hepatic function, which can be partly explained by demographic and pathophysiological covariates such as tumor burden, albumin, and body weight. The study’s small sample size could also partly explain the variability. Work to better understand the mechanisms for the observed differences in clearance is ongoing. No increase in the systemic concentration of DM1 was observed in patients with mild or moderate hepatic impairment vs. those with normal hepatic function. No additional safety concerns were observed. Citation Format: Chunze Li, Priya Agarwal, Susan Dent, Anthony Goncalves, Joo-Hee Yi, Alexander Strasak, Marjorie Green, Sandhya Girish, Pat LoRusso. Phase 1 study of trastuzumab emtansine in HER2-positive metastatic breast cancer patients with normal or reduced hepatic function [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-09.