Effect of Trastuzumab Deruxtecan on QT/QTc Interval and Pharmacokinetics in HER2‐Positive or HER2‐Low Metastatic/Unresectable Breast Cancer

Abstract

HER2-targeted anticancer therapies may be associated with cardiovascular adverse events. This study evaluated effects of the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd, DS-8201a) on QT/QTc interval and its pharmacokinetics. Patients with heavily pretreated, metastatic HER2-expressing breast cancer were enrolled at seven study sites in Japan. T-DXd was administered intravenously at 6.4 mg/kg on day 1 of each 21day cycle. Primary end points were baseline-adjusted QTcF interval and pharmacokinetics parameters. Key secondary end points included safety events, serum concentration of T-DXd and DXd at the time of electrocardiographic measurements, and antitumor activity parameters. Among 51 total patients, 47 (92.2%) had HER2-low breast cancer (immunohistochemistry 1+ or 2+ and in situ hybridization-negative/equivocal/missing). Pharmacokinetic parameters after a single dose of T-DXd were consistent with previous studies. After multiple doses, T-DXd showed moderate accumulation (accumulation ratio (cycle 3/cycle 1), 1.35), but DXd showed minimal accumulation (1.09). The upper bound of the 90% confidence interval for mean ΔQTcF interval was < 10 ms at all timepoints, and at mean maximum serum concentration was also < 10 ms. Based on concentration-QT analysis, ΔQTcF increased with increasing concentrations of T-DXd and DXd. No clinically meaningful QTcF prolongation was observed. T-DXd had a manageable safety profile and showed antitumor activity in HER2-low breast cancer. In this study, a T-DXd dose of 6.4 mg/kg, higher than the 5.4-mg/kg dose currently approved for breast cancer, was not associated with clinically relevant QTcF prolongation in heavily pretreated patients with HER2-expressing metastatic breast cancer. This study adds to our understanding of T-DXd for treatment of HER2-low breast cancer.

Incidence of HER2-targeted antibody-drug conjugates-related cardiac events: a meta-analysis

“…Prolongation of corrected QT interval is known to be associated with fatal torsade de pointes arrhythmias. However, studies have revealed that both T-DM1 42 and T-DXd 57 did not have a clinically significant impact for the prolonged QTc interval remained below the safety threshold of 10 milliseconds. Our research revealed that ejection fraction decrease and congestive cardiac failure were the highest proportion of all-grade and serious CEs, respectively.…”

Revolutionizing Breast Cancer Treatment: Unveiling the Effectiveness and Safety of Trastuzumab Deruxtecan through a Comprehensive Meta-Analysis

“…Through manual retrieval, a total of 1437 articles were obtained, 523 articles were obtained after removing duplicates, 28 articles were obtained by checking the titles and abstracts of the articles, 12 articles [16][17][18][19][20][21][22][23][24][25][26][27] were finally included in the analysis by reading the full text. See Figure 1.…”

“…8 studies [16][17][18][20][21][22][23]25] involving 642 people mentioned ORR, (I2=63.1%, p=0.008) indicating significant heterogeneity between studies. Figure 5 shows ORR in BC patients treated with T-DXd inhibitors [ES=0.57, 95% CI(0.50,0.64); P=0.000].…”

“…The sensitivity analysis showed that the results of the analysis were within the 95% CI interval (Supplementary S3), and P=0.798 ＞ 0.05 for Egger's publication bias assessment, implying a small potential for publication bias (Supplementary S4). DCR 7 studies [16][17][18]20,22,23,25] involving 627 people mentioned DCR, (I2= 56.6%, p = 0.032) also indicating a substantial level of heterogeneity across the studies. Figure 6 shows DCR in BC patients treated with T-DXd inhibitors [ES= 0.94, 95% CI(0.91, 0.97); P=0.000].…”

“…A total of 9 single-arm clinical studies [16][17][18][19][20][21][22][23]25] were included, and none of them achieved OS. For PFS, only 2 studies [17,20] had statistics, which was not statistically significant. Therefore, OS and PFS of single-arm studies are not counted in this article.…”