Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA.
Aichi Cancer Center, Nagoya, Japan.
Clin Pharmacol Ther. 2021 Oct;110(4):986-996. doi: 10.1002/cpt.2291. Epub 2021 Jun 10.
Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer and for HER2-positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here, we present dose justification for the approved 5.4 mg/kg every-3-weeks (Q3W) dose based on exposure-efficacy evaluated in patients with HER2-positive breast cancer (N = 337) from these 2 trials. Exposure-safety was assessed in patients with all tumor types (N = 639, n = 512 with breast cancer) across 5 trials, including J101 and DESTINY-Breast01. T-DXd doses ranged from 0.8-8.0 mg/kg Q3W; most patients received 5.4 (n = 312) or 6.4 mg/kg (n = 291). For each end point, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T-DXd and released drug. A statistically significant association was observed between intact T-DXd area under the concentration-time curve (AUC) and confirmed objective response rate (ORR; P = 0.028). No significant exposure-response relationships were observed between intact T-DXd or released drug and duration of response or progression-free survival; however, follow-up was limited. All evaluated safety end points demonstrated a significant (P < 0.05) relationship with either intact T-DXd or released drug, with higher adverse event (AE) rates projected at higher exposures. Dose-response projections suggested an increase in ORR (67.5% vs. 62.9%) and toxicity (e.g., grade ≥ 3 all-cause treatment-emergent AEs: 61% vs. 54%) with T-DXd 6.4 vs. 5.4 mg/kg. Results demonstrate the benefit-risk profile at different doses and guide clinicians in the use of the 5.4-mg/kg Q3W dose in patients with HER2-positive metastatic breast cancer.
曲妥珠单抗德拉斯替康（T-DXd）是一种 HER2 靶向抗体药物偶联物，由新型酶切连接子和膜通透性拓扑异构酶 I 抑制剂有效载荷组成。T-DXd 已获批用于治疗 HER2 阳性转移性乳腺癌和 HER2 阳性转移性胃癌。在乳腺癌中的批准基于 DESTINY-Breast01（U201；NCT03248492）和 J101（NCT02564900）试验的结果。在这里，我们根据这两项试验中 HER2 阳性乳腺癌患者（N=337）的暴露-疗效评估，为批准的 5.4mg/kg，每 3 周（Q3W）剂量提供剂量合理性依据。在包括 J101 和 DESTINY-Breast01 在内的 5 项试验中，对所有肿瘤类型（N=639，n=512 例乳腺癌）的患者进行了暴露安全性评估。T-DXd 剂量范围为 0.8-8.0mg/kg，Q3W；大多数患者接受 5.4（n=312）或 6.4mg/kg（n=291）。对于每个终点，使用 T-DXd 和释放药物的各种暴露指标进行多变量逻辑或 Cox 回归分析。在完整 T-DXd 浓度-时间曲线下面积（AUC）和确认的客观缓解率（ORR；P=0.028）之间观察到统计学显著关联。在完整 T-DXd 或释放药物与反应持续时间或无进展生存期之间未观察到显著的暴露-反应关系；然而，随访是有限的。所有评估的安全性终点均与完整 T-DXd 或释放药物显著相关（P<0.05），较高的暴露水平预测较高的不良事件（AE）发生率。剂量反应预测显示，与 5.4mg/kg 相比，T-DXd 6.4mg/kg 可提高 ORR（67.5% vs. 62.9%）和毒性（例如，所有原因导致的≥3 级治疗突发不良事件：61% vs. 54%）。结果表明不同剂量的获益-风险特征，并指导临床医生在 HER2 阳性转移性乳腺癌患者中使用 5.4mg/kg，每 3 周一次的剂量。
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