Pooled analysis of cardiac safety of T-DM1 in HER2-positive metastatic breast cancer patients

Proposal
1702

Title of Proposed Research

Lead Researcher

Evandro de Azambuja

Affiliation

Institut Jules BordetBrEAST Data Center, Brussels Belgium

Funding Source

This work will be self funded

Potential Conflicts of Interest

Received Honoraria and Travel Grants from Roche. Is PI in Academic studies funded by research grants from Roche to Institut Jules Bordet. Received Travel Grants from Roche. Received Honoraria from Roche. The institut she heads has received multiple grants from Roche to develop academic research.

Data Sharing Agreement Date

24 July 2017

Lay Summary

Breast Cancer is one of the most important disease for women worldwide, both because it is very frequent and because it leads to a high number of deaths. Most women who die after the diagnosis of breast cancer do so because of metastatic disease. Therefore research has in the last decades focused very frequently on understanding better the agressive types of breast cancer in order to develop better treatments for them. 30 years ago a specific type of breast cancer - called HER2-positive, was discovered. This type of breast cancer exploits a normal mechanism of growth in breast cells, the HER2 receptor to overgrow and spread to other parts of the body. This discovery kicked-off an era of incredible evolution in the treatment of this type of breast cancer as drugs that target the HER2 receptor were developed. Trastuzumab-emtansine (T-DM1), is one such drug, recently come into use after proving to be beneficial in patients with metastatic breast cancer. Classically, drugs that target HER2 have caused significant side effects connected to heart function. Individual studies performed with T-DM1 showed few cases of heart toxicity, and therefore understanding the specific clinical course of this toxicity has not yet been possible. Therefore the goal of this study is to gather the results of all the major studies testing T-DM1 (totaling over 2000 patients) in order to provide the best and most complete picture of this important complication. We will study the incidence and seriousness of heart toxicity in patients using T-DM1. We will also investigate if there are risk factors (characteristics that make more likely) for development of heart toxicity. Finally we will study how fast patients recover from this complication. Once the analysis of the data is completed, the results will be presented to the wider community of medical oncology in both clinical symposia and as a publication in scientific journals. This information will be used in deciding which patient can and cannot receive T-DM1, and how to manage patients receiving T-DM1 and develop this toxicity.

Study Data Provided

[{ "PostingID": 1364, "Title": "ROCHE-TDM4374g", "Description": "A Phase II, single-arm, open-label study, of Trastuzumab-MCC-DM1 adminstered intravenously to patients with HER2-positive metastatic breast cancer" },{ "PostingID": 1365, "Title": "ROCHE-TDM4258g", "Description": "A phase II, single-arm, open-label study of Trastuzumab-MCC-DM1 administered intravenously to patients with HER2-positive metastatic breast cancer who have progressed while receiving HER2-directed therapy" },{ "PostingID": 1366, "Title": "ROCHE-TDM4688g", "Description": "A phase II, open-label study to evaluate corrected QT interval effects of Trastuzumab-MCC-DM1 (T-DM1) in patients with HER2-positive recurrent locally advanced or metastatic breast cancer and to evaluate the safety and tolerability of combined T-DM1 and Pertuzumab in patients with early disease progression while receiving T-DM1 alone." },{ "PostingID": 2573, "Title": "ROCHE-BO21976", "Description": "A randomized, multicenter phase II study of the efficacy and safety of Trastuzumab-MCC-DM1 vs. Trastuzumab (Herceptin) and Docetaxel (Taxotere) in patients with metastatic HER2-positive breast cancer who have not received prior therapy for metastatic disease." },{ "PostingID": 2574, "Title": "ROCHE-BO21977", "Description": "A randomized, Multicenter, Phase III Open-Label study of the efficacy and safety of Trastuzumab-MCC-DM1 vs. Capecitabine + Lapatinib in patients with HER2-Positive locally advanced or metastic breast cancer who have received prior Trastuzumab-based therapy." },{ "PostingID": 4550, "Title": "ROCHE-BO22589", "Description": "A Study of Trastuzumab-DM1 Plus Pertuzumab Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer" },{ "PostingID": 4551, "Title": "ROCHE-BO25734", "Description": "A Phase III Randomized, Multicenter, Two Arm, Open-label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared With Treatment of Physician's Choice in Patients With HER2-positive Metastatic Breast Cancer Who Have Received at Least Two Prior Regimens of HER2 Directed Therapy" }]

Statistical Analysis Plan

The incidence of cardiac events will be calculated separately for each cardiac endpoint as the ratio of patients with each specific cardiac event to the total number of patients exposed to T- DM1 provided that the exposure duration will be comparable in all the trials. If not, groups of trials might be considered for stratifying the analysis. In addition, cumulative incidence functions will be estimated in the framework of competing risks.To elucidate the potential confounding effects of prior anticancer agents on cardiac function, cardiac events will be analyzed according to prior exposure to chemotherapy (anthracycline and/or taxanes) and/or anti-HER2 agents (trastuzumab, pertuzumab and/or lapatinib).To elucidate the potential confounding effects of concurrent administration of potentially cardiotoxic anticancer agents, cardiac events will be analyzed in the following cohorts:o Single agent T-DM1o T-DM1 in combination with pertuzumab.Differences between cohorts will be tested using the Kruskal-Wallis test. The incidence of any cardiac endpoint will be estimated using the cardiac risk factors for T-DM1-associated cardiac endpoints identified in the individual trials. Logistic regression modelling stratified by study will be used to assess the association between potential risk factors and the incidence of cardiac endpoints. As these analyses are exploratory, p-values will be used as descriptive measures rather than inferential.As secondary objective, the time to cardiac event will be calculated as the time from first dose of T-DM1 to the diagnosis of a cardiac event. This secondary analysis will be especially important if there is evidence that treatment duration differ between the different trials. The duration will be calculated as the time from diagnosis of a cardiac event until time of resolution (if applicable). A Cox's proportional hazards model will be used to assess the time to cardiac event.If a considerable number of cardiac events are encountered, we will try to identify a predictive model of T-DM1-induced cardiac toxicity.All statistical analyses will be performed by senior statisticians (L. Ameye / M. Paesmans) at the Institut Jules Bordet, Brussels, Belgium.Data to be collected are reported in Appendix I.This statistical analysis plan is subject to revision once we will have the opportunity to examine data availability from each trial as well as to look at the homogeneity of assessments and of definitions.

Publication Citation

Arlindo R. Ferreira, Sofia Ferreira, Matteo Lambertini, Christian Maurer, Samuel Martel, Luis Costa, Noam Ponde, Evandro de Azambuja,
Association between pertuzumab-associated diarrhoea and rash and survival outcomes in patients with HER2-positive metastatic breast cancer: Exploratory analysis from the CLEOPATRA trial, European Journal of Cancer, Volume 144, 2021, Pages 351-359, ISSN 0959-8049,
https://doi.org/10.1016/j.ejca.2020.11.023.