Lessons learned: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape.
Background: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC.
Methods: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed.
Results: No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9-54.3), and progression-free survival was 5.6 months (95% CI, 3.5-not reached).
Conclusion: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.
经验总结
• 阿西替尼联合克唑替尼具有可控的安全性和耐受性特性，与单一疗法用药时的个体药物特征相一致。
• 鉴于当前的治疗环境，本文中所报告的阿西替尼/克唑替尼联合疗法的抗肿瘤活性不支持将此联合疗法用于转移性肾细胞癌的进一步研究。
摘要
背景。血管内皮生长因子 (VEGF) 抑制剂已成功用于治疗转移性肾细胞癌 (mRCC)；然而，大多数情况下最终会产生耐药性。在抑制VEGF后，酪氨酸蛋白激酶 Met (MET) 的表达增加，且两者的抑制作用在控制肿瘤生长和转移方面显现出附加效应。因此，我们对阿西替尼联合克唑替尼治疗晚期实体瘤和转移性肾细胞癌的效果进行了研究。
方法。此项 IB 期研究包括剂量递增阶段(起始剂量:阿西替尼 3 mg，加上克唑替尼 200 mg)，以评估实体瘤患者的最大耐受剂量 (MTD)；剂量扩展阶段，以检验对mRCC治疗无效患者的初步疗效。此外，还对安全性、药代动力学和生物标志物进行了评估。
结果。在剂量递增阶段(n=22)，无患者出现剂量限制性毒性；预估的MTD为:阿西替尼 5 mg，加上克唑替尼 250 mg。最常见的≥ 3 级不良事件为高血压 (18.2%) 和疲劳 (9.1%)。在剂量扩展阶段，总体反应率为 30% [95% 置信区间 (CI)，11.9‐54.3]，无进展生存期为 5.6 个月(95% CI，3.5‐ 未达到)。
结论。在达到预估的MTD时，阿西替尼联合克唑替尼疗法具有可管理的安全特性，且有证据表明，对治疗mRCC显示出适度的抗肿瘤活性。
Trial registration: ClinicalTrials.gov NCT01999972.
© AlphaMed Press; the data published online to support this summary are the property of the authors.