Pfizer Oncology, San Diego, California, USA.
Georgia Cancer Center, Augusta, Georgia, USA.
Cancer Med. 2023 Sep;12(17):17981-17992. doi: 10.1002/cam4.6439. Epub 2023 Aug 8.
The BELA and BFORE trials compared bosutinib starting doses of 500 mg once daily (QD) and 400 mg QD, respectively, with imatinib in adults with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML). The B1871048 trial evaluated bosutinib 400 mg QD in Japanese patients with newly diagnosed CP-CML.
This analysis assessed the impact of a lower bosutinib starting dose on key efficacy and safety outcomes.
MATERIALS & METHODS: A pharmacokinetic model was used to estimate metrics of bosutinib exposure, and logistic regression was used to investigate relationships with efficacy (cumulative major molecular response [MMR] and cumulative complete cytogenetic response [CCyR]) and safety outcomes (eight prespecified adverse events).
Totals of 573 and 574 patients were included in the efficacy and safety endpoint analyses, respectively. Cumulative MMR and CCyR were similar across studies. Log(C ) and log(C ) were significant predictors of MMR and CCyR, and the probability of achieving MMR or CCyR increased 1.3-fold or 2.7-fold for every 1 unit increase in log(C ) or log(C ), respectively. An exposure-response relationship was identified between time-to-event and risk of diarrhea, nausea, and vomiting. Significant relationships were also observed between time-to-event and log(C ), C , and C with diarrhea, nausea, and vomiting, respectively.
A bosutinib exposure-response relationship with safety and efficacy was observed.
Compared with 500 mg QD, a bosutinib starting dose of 400 mg QD improved tolerability in some patients with newly diagnosed CP-CML without compromising efficacy.
gov identifiers: NCT00574873; NCT02130557; NCT03128411.
BELA 和 BFORE 试验分别比较了起始剂量为 500mg 每日一次（QD）和 400mg QD 的博舒替尼与伊马替尼在新诊断的慢性期慢性髓性白血病（CP-CML）成人中的疗效。B1871048 试验评估了新诊断的 CP-CML 日本患者中博舒替尼 400mg QD 的疗效。
本分析评估了较低的博舒替尼起始剂量对关键疗效和安全性结局的影响。
采用药代动力学模型估算博舒替尼暴露度指标，并采用逻辑回归分析其与疗效（累积主要分子反应[MMR]和累积完全细胞遗传学反应[CCyR]）和安全性结局（8 项预设不良事件）的关系。
疗效和安全性终点分析分别纳入了 573 例和 574 例患者。各项研究中的累积 MMR 和 CCyR 相似。log(C )和 log(C )是 MMR 和 CCyR 的显著预测指标，log(C )或 log(C )每增加 1 个单位，MMR 或 CCyR 的概率分别增加 1.3 倍或 2.7 倍。还观察到时间-事件与腹泻、恶心和呕吐风险之间存在暴露-反应关系。腹泻、恶心和呕吐与时间-事件之间也存在显著的关系，分别与 log(C )、C 、C 相关。
观察到博舒替尼安全性和疗效与暴露量之间存在相关性。
与 500mg QD 相比，新诊断的 CP-CML 患者起始剂量为 400mg QD 可改善部分患者的耐受性，而不影响疗效。
gov 标识符：NCT00574873；NCT02130557；NCT03128411。
