Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer
Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer
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DOI：
10.1007/s00280-020-04066-4
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发表时间：
2020-05-01
影响因子：
3
通讯作者：
Schellens, Jan H. M.
中科院分区：
文献类型：
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作者：
Huijberts, Sanne C. F. A.;van Geel, Robin M. J. M.;Schellens, Jan H. M.
目的 KRAS 癌基因突变通过 MAPK 途径引起持续信号传导。同时抑制 MEK、EGFR 和 HER2 可在体外和体内完全抑制 KRAS 突变体 (KRASm) 和 PIK3CA 野生型肿瘤的肿瘤生长。在这项 I 期研究中，患有晚期 KRASm 和 PIK3CA 野生型结直肠癌 (CRC)、非小细胞肺癌 (NSCLC) 和胰腺癌的患者接受拉帕替尼和曲美替尼联合治疗，以评估推荐的 2 期治疗方案 (RP2R)。方法 患者接受递增剂量的连续或间歇性每日一次 (QD) 口服拉帕替尼和曲美替尼，分别从连续 750 mg 和 1 mg 开始。结果 34 名患者（16 名 CRC、15 名非小细胞肺癌、3 名胰腺癌）纳入了 6 个剂量水平，其中 8 名患者经历了剂量限制性毒性，包括 3 级腹泻 (n = 2)、皮疹 (n = 2)、恶心 (n = 1)、多种 2 级毒性 (n = 1) 和天冬氨酸转氨酶升高 (n = 1)，导致无法接受计划剂量的 75% (n = 2) 或治疗延迟 (n = 2)。连续给药的 RP2R 为 750 mg 拉帕替尼 QD 加 1 mg 曲美替尼 QD，间歇给药为 750 mg 拉帕替尼 QD 和曲美替尼 1.5 mg QD，连续 5 天/停药 2 天。在 24 名可评估疗效的患者中，有 6 名患者出现了目标病灶的消退，其中 1 名患者确诊为 NSCLC 部分缓解。药代动力学结果符合预期。结论 对于毒性可控的患者，拉帕替尼和曲美替尼可以联合使用间歇给药方案。已观察到 NSCLC 抗肿瘤活性的初步迹象，并证明了药效学靶点参与。
Purpose KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Methods Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Results Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Conclusion Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.