A phase I dose-escalation study of a biosimilar trastuzumab in Chinese metastasis breast cancer patients

Zhou, Xinna; Yu, Jing; Wang, Wenmiao; Song, Gonghua; Wang, Xiaoli; Ren, Jun; Di, Lijun; Wang, Xinghe

doi:10.1186/s40064-015-1603-5

Cited by 21 publications

(10 citation statements)

References 21 publications

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“…DRL_TZ and RMP administered as a single 6 mg/kg intravenous dose were comparably well tolerated in the study population. The profile of drug-related events was similar to that observed in other TZ trials with frequently reported drug-related AEs being pyrexia, headache, chills and fatigue 16 27 29 . No new or unexpected safety events were observed.…”

Section: Discussionsupporting

confidence: 75%

A randomized, double-blind, parallel-group, single-dose comparative pharmacokinetic study of DRL_TZ, a candidate biosimilar of trastuzumab, with Herceptin® (EU) in healthy adult males

Lickliter

Dadhania

Trivedi

et al. 2021

Indian Journal of Medical Research

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Background & objectives : Trastuzumab (TZ) is a recombinant DNA-derived humanized monoclonal antibody approved for human epidermal growth factor receptor 2 positive early breast cancer, metastatic breast and gastric cancers. For the development of TZ biosimilars, establishing pharmacokinetic equivalence is required. The primary objective of this study was to compare the pharmacokinetics (PK) of Dr Reddy’s Laboratories TZ (DRL_TZ) with that of EU-approved Reference Medicinal Product (RMP), Herceptin ® in healthy adult male subjects. Methods : In this double-blind, parallel-group, phase I study (TZ-01-003), healthy male subjects aged 18-55 yr were randomized 1:1 to receive a single intravenous infusion of 6 mg/kg of TZ as DRL_TZ or RMP. Similarity for primary PK parameters was defined as the 90 per cent confidence intervals (CIs) for the geometric mean ratios (GMRs) falling within 75-133 per cent limits. Primary endpoints included area under the concentration–time curve - from time zero (pre-dose) to the last quantifiable concentration [AUC (0–t) ] and from time zero (pre-dose) extrapolated to infinity [AUC (0–∞) ], and maximum observed serum concentration (C max ). Secondary objectives were to compare the safety and immunogenicity of DRL_TZ with that of the RMP. Results : Thirty two subjects were dosed (DRL_TZ, 16; RMP, 16). Primary PK parameters were found to be comparable with their 90 per cent CIs for the GMR falling within the usual more stringent limits of 80-125 per cent. The number of subjects reporting at least one TEAE in both the arms was similar. No serious adverse events were reported. Fifteen subjects, eight in DRL_TZ arm and seven in Herceptin ® arm, tested positive for anti-drug antibodies (ADAs), none of the ADAs were neutralizing in nature. Interpretation & conclusions : In this study, DRL_TZ demonstrated PK equivalence with the RMP and had comparable safety and immunogenicity profiles in healthy adult male subjects.

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Section: Discussionsupporting

confidence: 75%

A randomized, double-blind, parallel-group, single-dose comparative pharmacokinetic study of DRL_TZ, a candidate biosimilar of trastuzumab, with Herceptin® (EU) in healthy adult males

Lickliter

Dadhania

Trivedi

et al. 2021

Indian Journal of Medical Research

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“…Only one developed arrhythmia among the seven patients showing isotope uptake in myocardium on image [ 27 ]. In one small cohort including 27 metastatic BC patients, trastuzumab was believed to cause arrhythmias in 6 patients, one of which developed sinus bradycardia and others were unspecified [ 28 ]. In a larger study including 68,113 BC patients, the chemotherapy group was shown to have higher Af incidence, while in the subgroup analysis, there were no significant differences regarding trastuzumab use [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

The association of trastuzumab with atrial fibrillation and heart failure in breast cancer patients in routine clinical practice: a population-based propensity score matching and competing risk model analysis

Huang

Tsai

et al. 2022

Breast Cancer Res Treat

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Purpose Trastuzumab, a potent anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, is conditionally reimbursed by the Taiwan National Health Insurance (NHI) for HER2-positive breast cancer (BC). Trastuzumab-induced cardiotoxicity studies have well characterized heart failure (HF) but fewer addressed arrhythmia, particularly the association of potential life threatening atrial fibrillation (Af) is poorly characterized. We aimed to study the trastuzumab-related risk of Af and HF using the claimed data of Taiwan NHI. Methods A nationwide retrospective cohort of patients with BC from the Taiwan NHI reimbursement database from January 2007 to December 2016 was analyzed. Propensity score matching and competing risk model analysis were used for adjusting confounding concurrent medication or comorbidities and competing events. The HF study was used to validate the method used. Results For Af, 12,472 trastuzumab users were matched with 12,472 non-trastuzumab users. For HF, 12,241 trastuzumab users and 12,241 non-users were enrolled. We found that trastuzumab users had significantly worse HF-free survival but not Af-free survival than non-trastuzumab users. In the competing risk analysis, the use of trastuzumab did not increase the risk of Af (hazard ratio [HR] 0.76, P = 0.0006) but was associated with HF (HR 1.19, P = 0.0052). The risk trends among stratifications by comorbidities and concurrent medication remained in similar directions for both Af and HF. Conclusion Trastuzumab in real-world practice was associated with an increased risk of HF, but was not associated with an increased risk of Af in BC patients. Trastuzumab-induced arrhythmogenic effects may be masked by concurrent heart-protecting measures, more prominent roles of comorbidities or concurrent medications under real-world settings. Further studies are required.

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“…If the study did not provide the maximum and minimum concentration, the median or mean +/− standard deviation, maximum or minimum is reported. The final set of reported studies are included in Table S1 (34, 71–94).…”

Section: Methodsmentioning

confidence: 99%

Anthracycline-induced cardiotoxicity associates with a shared gene expression response signature to TOP2-inhibiting breast cancer drugs in cardiomyocytes

Matthews,

Johnson,

Horn

et al. 2023

Preprint

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TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified eight genes in loci associated with AC toxicity by GWAS or TWAS. All eight genes, includingRARGandSLC28A3,respond to at least two ACs, and their expression correlates with the release of cardiotoxicity markers. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.Author summaryAnthracycline drugs such as Doxorubicin are effective treatments for breast cancer; however, they can cause cardiotoxicity in some women. It is unclear whether women would experience the same toxicity for all drugs in this class, or whether specific drugs would be better tolerated in specific individuals. We used anin vitrosystem of induced pluripotent stem cell-derived cardiomyocytes from six healthy females to test the effects of five breast cancer drugs on cell heath and global gene expression. We identified a strong shared cellular and gene expression response to drugs from the same class. However, there is more variation in gene expression levels between individuals following treatment with each anthracycline compared to untreated cells. We found that genes in regions previously associated with Doxorubicin-induced cardiotoxicity in cancer patients, respond to at least two drugs in the class. This suggests that drugs in the same class induce similar effects on an individual’s heart. This work contributes to our understanding of how drug response, in the context of off-target effects, varies across individuals.

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A phase I dose-escalation study of a biosimilar trastuzumab in Chinese metastasis breast cancer patients

Cited by 21 publications

References 21 publications

A randomized, double-blind, parallel-group, single-dose comparative pharmacokinetic study of DRL_TZ, a candidate biosimilar of trastuzumab, with Herceptin® (EU) in healthy adult males

A randomized, double-blind, parallel-group, single-dose comparative pharmacokinetic study of DRL_TZ, a candidate biosimilar of trastuzumab, with Herceptin® (EU) in healthy adult males

The association of trastuzumab with atrial fibrillation and heart failure in breast cancer patients in routine clinical practice: a population-based propensity score matching and competing risk model analysis

Anthracycline-induced cardiotoxicity associates with a shared gene expression response signature to TOP2-inhibiting breast cancer drugs in cardiomyocytes

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