Evaluation of biosimilar trastuzumab MYL-1401O in HER2-positive early-stage and metastatic breast cancer in real-life data

Background The trastuzumab biosimilar MYL-1401O has demonstrated equivalent efficacy and comparable safety to reference trastuzumab (RTZ) in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) as non-dual HER2 therapy. Here, we present the first real-world comparison of MYL-1401O versus RTZ with single/dual HER2-targeted therapy for the neoadjuvant, adjuvan and palliative first-/second-line treatment with HER2-positive early breast cancer (EBC) and metastatic breast cancer (MBC) patients in two tertiary hospitals in Turkey. Methods We retrospectively investigated medical records in the Severance Breast Cancer Registry in Turkey. We identified patients with HER2-positive EBC (n=159) who had received neoadjuvant chemotherapy (n= 92) with RTZ or MYL-1401O±pertuzumab and adjuvant chemotherapy (n=67) with RTZ or MYL-1401O plus taxan between january 2018 and jun 2021. Stage IV MBC (n=53) who had received palliative first-line treatment with RTZ or MYL-1401O, and docetaxel±pertuzumab (THP) or second-line treatment with RTZ or MYL-1401O, and taxan between january 2018 and jun 2021. Primary endpoints were pathological complete response in neoadjuvant grup (pCR) and progression-free survival (PFS) in adjuvant and metastatic grup. Secondary endpoints in the metastatic patient group (MBC) was overall response rate (ORR), disease control rate (DCR) and cardiac safety. Results The rate of achieving pCR in the group receiving neoadjuvant chemotherapy was similar between MYL and RTZ (62.7% [37/59] and 55.9% [19/34] p=0.509). Median PFS similar in EBC-adjuvant group, 12-24-36 months PFS respectively 96.3%, 84.7%, 71.5% in patients with MYL and 100%, 88.5%, 64.8% in patients with RTZ (95% CI p=0.577). Median PFS similar in metastatic group, 23.0 (9.8-16.1) months in patients with MYL-1401O and 23 (19.9-26.0) months in patients with RTZ (95% CI p=0.270). The ORR, DCR, and cardiac safety profiles did not also show significant difference efficacy outcomes between two groups. Conclusion These real-world data suggest that biosimilar trastuzumab MYL-1401O has similar effectiveness and cardiac safety to RTZ in HER2-positive EBC and MBC patients when administered as part of single/dual HER2-targeted therapy with chemotherapy in the neoadjuvant, adjuvant or palliative setting.

Trabectedin-Related Heart Failure: Case Report and a Systematic Review of the Literature

New drugs come not only with benefits but also with unexpected toxicities which need to be promptly recognized and managed. Starting from a scholar case of acute heart failure with preserved ejection fraction following the administration of trabectedin (ET-743, Yondelis®) in a patient with a metastatic solitary fibrous tumor, we performed a systematic review of the literature encompassing the results of previous cardiac safety analysis published ten years ago, a review of clinical trials published during the last 10 years as well as single-case descriptions related to trabectedin cardiotoxicity. The estimated incidence of cardiac toxicity was 3,4% among patients receiving trabectedin, with recent data suggesting a higher rate of heart failure than previously recognized. Previous or concomitant anthracyclines exposure may represent a risk factor. Assaying for NT-pro-BNP may be useful for the early detection of individuals with trabectedin-induced heart failure.

Thorough QT Study to Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for Gonorrhea, on Cardiac Repolarization in Healthy Adults

Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae . To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin 2 g (therapeutic), zoliflodacin 4 g (supratherapeutic), placebo, and moxifloxacin 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia’s formula (QTcF). At each time point up to 24 hours after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the pre-dose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1-4 hours after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, ECG morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well-tolerated. These findings suggest zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin.

Cardiac Safety of Clonidine and Quetiapine in Post-Cardiac Surgery Intensive Care Unit Patients

Background: Clonidine and quetiapine are frequently used medications in the cardiac surgery intensive care unit (ICU). Objective: The purpose of this study is to assess the impact of clonidine compared to quetiapine on cardiac safety outcomes in adult cardiac surgery ICU patients. Methods: This was a single-center, retrospective observational analysis at a tertiary care, academic medical center. Results: One hundred and sixty-one cardiac surgery patients who were administered clonidine or quetiapine during their ICU stay were included between June 2015 and May 2017. The major endpoint of this study was a cardiac safety composite of bradycardia, hypotension, and QTc prolongation. Minor endpoints included ICU and hospital length of stay, and in-hospital mortality. There were 115 patients included in the clonidine arm and 46 patients in the quetiapine arm. There was no difference between groups with regard to the major endpoint (30.43% vs 33.15%; P < .8). There was a shorter ICU and hospital length of stay in the clonidine arm compared to quetiapine P < .0001. All other endpoints were not statistically significant. Conclusion: Patients who received clonidine tended to have undergone less complex procedures, be younger, and have a lower APACHE II score than patients who received quetiapine. The incidence of composite cardiac safety outcomes was not different in clonidine compared to quetiapine in cardiac surgery ICU patients.