MD Anderson Cancer Center, Houston, TX, USA.
Breast Cancer Res Treat. 2013 Jan;137(2):471-82. doi: 10.1007/s10549-012-2369-x. Epub 2012 Dec 13.
This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib-pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.
这项多中心 II 期研究评估了拉帕替尼、帕唑帕尼和联合用药在复发的 HER2+炎性乳腺癌患者中的疗效。在队列 1 中，76 名患者按 1:1 随机分为两组，分别接受拉帕替尼 1500mg+安慰剂或拉帕替尼 1500mg+帕唑帕尼 800mg（双盲），每天一次，直到疾病进展、无法耐受的毒性或死亡。由于在另一项研究（VEG20007）中观察到这种剂量联合用药出现 3 级以上腹泻，因此队列 1 关闭。方案进行了修订，另外 88 名患者（队列 2）按 5:5:2 的比例随机分配，分别接受每日单药拉帕替尼 1500mg、拉帕替尼 1000mg+帕唑帕尼 400mg 或单药帕唑帕尼 800mg 治疗。主要终点是总缓解率（ORR）。次要终点包括缓解持续时间、无进展生存期（PFS）、总生存期和安全性。在队列 1 中，拉帕替尼（n=38）和联合用药（n=38）组的 ORR 分别为 29%和 45%；中位 PFS 分别为 16.1 和 14.3 周。联合用药组（71%）比拉帕替尼组（24%）更常见≥3 级不良事件（AE）。联合用药组因 AE 导致的剂量减少和中断也比拉帕替尼单药组更常见（分别为 45%和 53%，0%和 11%）。在队列 2 中，接受拉帕替尼（n=36）、拉帕替尼+帕唑帕尼（n=38）和帕唑帕尼（n=13）治疗的患者的 ORR 分别为 47%、58%和 31%；中位 PFS 分别为 16.0、16.0 和 11.4 周。拉帕替尼、联合用药和帕唑帕尼治疗组中，分别有 17%、50%和 46%的患者发生≥3 级 AE，因 AE 而停药的发生率分别为 0%、24%和 23%。与拉帕替尼单药治疗相比，拉帕替尼-帕唑帕尼联合用药的 ORR 更高，但 PFS 无改善。联合用药还导致毒性增加，需要更多的剂量减少、调整和治疗延迟。在这一人群中，单药拉帕替尼的活性得到了证实。
