Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado, Aurora, CO.
Department of Thoracic Oncology, Massachusetts General Hospital Cancer Center, Boston, MA.
Clin Lung Cancer. 2018 Sep;19(5):e655-e665. doi: 10.1016/j.cllc.2018.04.015. Epub 2018 May 5.
The present phase Ib study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of high-dose intermittent (HDI) afatinib monotherapy for patients with advanced solid tumors. The planned focus was patients with epidermal growth factor receptor (EGFR) T790M non-small-cell lung cancer (NSCLC).
Eligible patients had histologically confirmed advanced solid tumors that were unsuitable for, or unresponsive to, standard therapy. The study used a 3+3 design with a starting dose of 90 mg/d for 3 days every 14 days (28-day cycles) and incremental dose escalations to 200 mg/d.
Thirty-five patients (18 with NSCLC) were treated (6 at 90 mg; 3 at 120 mg; 9 at 150 mg; 11 at 160 mg; and 6 at 200 mg). One patient in the 90-mg cohort (grade 3 rash) and 2 patients in the 200-mg cohort (grade 3 diarrhea; grade 3 mucositis) experienced a dose-limiting toxicity. The MTD was 160 mg. The most common treatment-related adverse events were diarrhea (total, 88.6%; grade 3, 14.3%), rash/acne (total, 62.9%; grade 3, 2.9%), and fatigue (total, 40.0; grade 3, 0%). The maximum afatinib plasma concentration at the MTD was 313 ng/mL, exceeding the in vitro IC (inhibitor concentration decreased by one half) range for T790M inhibition. The trough levels suggested no systematic change in afatinib plasma concentrations during long-term treatment at this dosing schedule. Of the 13 T790M NSCLC patients, 1 achieved an objective response (7.7%).
HDI afatinib was feasible and tolerable and could potentially be further explored for NSCLC indications, including patients with central nervous system disease, rare EGFR mutations, or T790M NSCLC intolerant of third-generation EGFR tyrosine kinase inhibitors.
本Ib 期研究评估了高剂量间歇（HDI）阿法替尼单药治疗晚期实体瘤患者的最大耐受剂量（MTD）、安全性、药代动力学和抗肿瘤活性。计划重点是表皮生长因子受体（EGFR）T790M 非小细胞肺癌（NSCLC）患者。
符合条件的患者有组织学证实的晚期实体瘤，不适合或对标准治疗无反应。该研究采用 3+3 设计，起始剂量为 90 mg/d，每 14 天使用 3 天（28 天周期），并进行递增剂量爬坡至 200 mg/d。
35 名患者（18 名 NSCLC 患者）接受了治疗（6 名 90 mg 组；3 名 120 mg 组；9 名 150 mg 组；11 名 160 mg 组；6 名 200 mg 组）。90 mg 队列的 1 名患者（3 级皮疹）和 200 mg 队列的 2 名患者（3 级腹泻；3 级黏膜炎）出现剂量限制性毒性。MTD 为 160 mg。最常见的治疗相关不良事件是腹泻（总发生率为 88.6%；3 级发生率为 14.3%）、皮疹/痤疮（总发生率为 62.9%；3 级发生率为 2.9%）和疲劳（总发生率为 40.0%；3 级发生率为 0%）。在 MTD 时，阿法替尼的最大血浆浓度为 313ng/mL，超过了体外 T790M 抑制的 IC（抑制剂浓度降低一半）范围。在这种给药方案下，长期治疗时阿法替尼血浆浓度的谷值提示无系统变化。在 13 名 T790M NSCLC 患者中，1 名患者获得客观缓解（7.7%）。
HDI 阿法替尼是可行且可耐受的，对于 NSCLC 适应证，包括中枢神经系统疾病、罕见 EGFR 突变或不耐受第三代 EGFR 酪氨酸激酶抑制剂的 T790M NSCLC 患者，可能需要进一步探索。
