Yoshihara Kazutaka, Kobayashi Yoshimasa, Endo Seiko, Fukae Masato, Hennig Stefanie, Kastrissios Helen, Kamiyama Emi, Garimella Tushar, Abutarif Malaz
Quantitative Clinical Pharmacology, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Certara Inc., Melbourne, Australia.
J Clin Pharmacol. 2023 Nov;63(11):1232-1243. doi: 10.1002/jcph.2295. Epub 2023 Jul 12.
This study evaluated the benefit/risk of trastuzumab deruxtecan (T-DXd) 6.4 mg/kg in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer using pharmacometrics. A population pharmacokinetic (PopPK) model was developed using data from patients with gastric cancer, breast cancer, or other tumors in T-DXd clinical trials, primarily conducted in Asia. Post hoc model-estimated pharmacokinetic metrics were used in exposure-efficacy (objective response rates, ORRs) and exposure-safety analyses. The PopPK analysis included 808 patients (217 with gastric cancer, 512 with breast cancer, and 79 with other cancers). In gastric cancer, the T-DXd 6.4 mg/kg steady-state exposure metrics were lower compared with 6.4 mg/kg in breast cancer, but were similar to 5.4 mg/kg in breast cancer. Tumor type was selected as a significant covariate on T-DXd clearance. In exposure-efficacy analysis among 160 patients with gastric cancer, the T-DXd steady-state minimum concentration was associated with a confirmed ORR in univariate logistic regression analysis (P = .023). The model-predicted confirmed ORRs in gastric cancer were 36.0% (90%CI 29.3% to 43.7%) with 5.4 mg/kg and 40.0% (90%CI 33.1% to 47.6%) with 6.4 mg/kg. Among 808 patients in the exposure-safety analyses, the model-predicted estimates for the rates of any-grade interstitial lung disease (ILD) over a period of 180 days were 10.2% (90%CI 8.7% to 12.8%) with 6.4 mg/kg in gastric cancer and 9.7% (90%CI 8.2% to 11.8%) with 5.4 mg/kg in breast cancer. In gastric cancer, the efficacy of T-DXd was higher at 6.4 mg/kg than at 5.4 mg/kg. Exposure and ILD rates were comparable between 6.4 mg/kg in gastric cancer and 5.4 mg/kg in breast cancer. This study identified T-DXd 6.4 mg/kg as the recommended dose in HER2-positive gastric cancer.
本研究采用药代动力学方法评估了曲妥珠单抗德曲妥珠单抗（T-DXd）6.4mg/kg用于治疗人表皮生长因子受体2（HER2）阳性胃癌患者的获益/风险。利用T-DXd临床试验中主要来自亚洲的胃癌、乳腺癌或其他肿瘤患者的数据建立了群体药代动力学（PopPK）模型。事后模型估计的药代动力学指标用于暴露-疗效（客观缓解率，ORR）和暴露-安全性分析。PopPK分析纳入了808例患者（217例胃癌患者、512例乳腺癌患者和79例其他癌症患者）。在胃癌患者中，T-DXd 6.4mg/kg的稳态暴露指标低于乳腺癌患者中的6.4mg/kg，但与乳腺癌患者中的5.4mg/kg相似。肿瘤类型被选为T-DXd清除率的显著协变量。在160例胃癌患者的暴露-疗效分析中，在单因素逻辑回归分析中，T-DXd稳态最低浓度与确认的ORR相关（P = 0.023）。模型预测的胃癌患者确认ORR在5.4mg/kg时为36.0%（90%CI 29.3%至43.7%），在6.4mg/kg时为40.0%（90%CI 33.1%至47.6%）。在暴露-安全性分析的808例患者中，模型预测的180天内任何级别的间质性肺疾病（ILD）发生率在胃癌患者6.4mg/kg时为10.2%（90%CI 8.7%至12.8%），在乳腺癌患者5.4mg/kg时为9.7%（90%CI 8.2%至11.8%）。在胃癌中，T-DXd 6.4mg/kg的疗效高于5.4mg/kg。胃癌患者6.4mg/kg时的暴露和ILD发生率与乳腺癌患者5.4mg/kg时相当。本研究确定T-DXd 6.4mg/kg为HER2阳性胃癌的推荐剂量。
