City of Hope, Duarte, California.
Cancer. 2014 Apr 15;120(8):1145-54. doi: 10.1002/cncr.28561. Epub 2014 Feb 5.
This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health-related quality of life of dacomitinib (PF-00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild-type non-small cell lung cancer (NSCLC).
Patients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild-type or known EGFR-sensitizing mutant tumor, and Eastern Cooperative Oncology Group performance status of 0 to 2 received 45 mg of dacomitinib once daily continuously in 21-day cycles.
A total of 66 patients enrolled (adenocarcinoma, n = 50; those without adenocarcinoma [nonadenocarcinoma], n = 16). The objective response rate (ORR) for patients with adenocarcinoma (primary endpoint) was 5% (2 partial responses; 1-sided P = .372 for null hypothesis [H0 ]: ORR ≤ 5%) and 6% (1 partial response) for patients with nonadenocarcinoma. Responders included: 2 of 25 EGFR mutation-positive tumors; 1 of 3 EGFR wild-type with HER2 amplification. Median progression-free survival was 12 weeks overall (n = 66) and 18 weeks (n = 26) for patients with EGFR mutation-positive tumors. Common treatment-related adverse events were of grade 1 or 2 severity, manageable with standard supportive care, and included diarrhea (grade 3 [G3], 12%), acneiform dermatitis (G3, 6%), exfoliative rash (G3, 3%), dry skin (G3, 0%), fatigue (G3, 3%), and stomatitis (G3, 2%). Six patients (9%) discontinued due to treatment-related adverse events. By patient report, NSCLC symptoms of dyspnea, cough, and pain (chest, arm/shoulder) showed improvement first observed after 3 weeks on therapy.
Dacomitinib demonstrated preliminary activity and acceptable tolerability in heavily pretreated patients, and may offer benefit in molecularly defined patient subsets.
这项 2 期临床试验（ClinicalTrials.gov 标识符 NCT00548093）评估了达克替尼（PF-00299804）的疗效、安全性和对健康相关生活质量的影响，达克替尼是一种不可逆的表皮生长因子受体（EGFR）/HER1、HER2 和 HER4 酪氨酸激酶抑制剂（TKI），用于治疗 KRAS 野生型非小细胞肺癌（NSCLC）患者。
晚期 NSCLC 患者、1 或 2 种化疗方案和厄洛替尼治疗进展、KRAS 野生型或已知 EGFR 敏感突变肿瘤、东部合作肿瘤组（ECOG）表现状态为 0 至 2 分，接受每日一次达克替尼 45mg 连续治疗 21 天周期。
共纳入 66 例患者（腺癌 50 例；非腺癌[非腺癌]16 例）。腺癌患者的客观缓解率（ORR）为 5%（2 例部分缓解；1 侧 P =.372 为零假设[H0]：ORR ≤ 5%），非腺癌患者为 6%（1 例部分缓解）。缓解者包括：25 例 EGFR 突变阳性肿瘤中有 2 例；3 例 EGFR 野生型伴 HER2 扩增中有 1 例。总体而言，66 例患者的中位无进展生存期为 12 周，26 例 EGFR 突变阳性肿瘤患者的中位无进展生存期为 18 周。常见的治疗相关不良事件为 1 级或 2 级严重程度，可通过标准支持性治疗管理，包括腹泻（3 级[G3]，12%）、痤疮样皮炎（G3，6%）、剥脱性皮疹（G3，3%）、皮肤干燥（G3，0%）、疲劳（G3，3%）和口腔炎（G3，2%）。6 例（9%）患者因治疗相关不良事件而停止治疗。根据患者报告，非小细胞肺癌症状呼吸困难、咳嗽和疼痛（胸部、手臂/肩部）在开始治疗 3 周后首次观察到改善。
达克替尼在既往治疗较多的患者中表现出初步疗效和可接受的耐受性，并且可能在分子定义的患者亚群中提供获益。
