A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.
A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.
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DOI：
10.1007/s00280-017-3283-z
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发表时间：
2017-05
影响因子：
3
通讯作者：
Lara PN Jr
中科院分区：
文献类型：
--
作者：
Wakelee HA;Gettinger S;Engelman J;Jänne PA;West H;Subramaniam DS;Leach J;Wax M;Yaron Y;Miles DR;Lara PN Jr
卡博替尼是一种多激酶抑制剂，针对 MET、AXL 和 VEGFR2，可能与 NSCLC 中的 EGFR 抑制协同作用。在既往接受过厄洛替尼治疗的进展性 NSCLC 和 EGFR 突变患者中单独或与厄洛替尼联合评估卡博替尼。这是一项 Ib/II 期研究 (NCT00596648)。 I 期的主要目标是评估安全性、药代动力学和药效学，并确定先前厄洛替尼治疗失败的患者中卡博替尼加厄洛替尼的最大耐受剂量 (MTD)。在 II 期中，先前对厄洛替尼有反应或病情稳定但出现进展的患者被随机分配至卡博替尼 100 mg 每日一次单药组与卡博替尼 100 mg 每日一次和厄洛替尼 50 mg 每日一次（I 期 MTD），主要目标是估计客观缓解率 (ORR)。 64 名患者在 I 期接受治疗。确定 100 mg 卡博替尼加 50 mg 厄洛替尼或 40 mg 卡博替尼加 150 mg 厄洛替尼的剂量为 MTD。腹泻是最常见的剂量限制性毒性和最常见的 AE（87.5% 的患者）。 I 期的 ORR 为 8.2% (90% CI 3.3–16.5)。在 II 期中，卡博替尼组的一名患者 (N = 15) 出现部分缓解，ORR 为 6.7% (90% CI 0.3–27.9)，而卡博替尼加厄洛替尼没有缓解 (N = 13)。没有证据表明卡博替尼的共同给药会显着改变厄洛替尼的药代动力学，反之亦然。尽管卡博替尼/厄洛替尼在 I 期试验中有反应，但在 II 期联合用药组中，对厄洛替尼获得性耐药的患者没有出现反应。卡博替尼似乎没有使这些患者对厄洛替尼重新敏感。本文的在线版本 (doi:10.1007/s00280-017-3283-z) 包含补充材料，可供授权用户使用。
Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib. This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR). Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3–16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3–27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa. Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib. The online version of this article (doi:10.1007/s00280-017-3283-z) contains supplementary material, which is available to authorized users.