剂量调整对阿法替尼治疗表皮生长因子受体突变阳性肺腺癌的安全性和疗效的影响：随机 LUX-Lung 3 和 6 试验的事后分析。
Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials.
机构信息
National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan.
Massachusetts General Hospital and Harvard Medical School, Boston, USA.
出版信息
Ann Oncol. 2016 Nov;27(11):2103-2110. doi: 10.1093/annonc/mdw322. Epub 2016 Sep 6.
BACKGROUND
Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials.
PATIENTS AND METHODS
Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not.
RESULTS
Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}.
CONCLUSIONS
Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy.
CLINICAL TRIAL REGISTRATION
Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.
背景
阿法替尼 40mg/天适用于 EGFR 突变阳性的非小细胞肺癌（NSCLC）的一线治疗。对于药物相关的 3 级或特定的延长 2 级不良事件（AE），剂量可以减少 10mg 至最低 20mg。在这里，我们评估了在 III 期 LUX-Lung 3 和 6（LL3/6）试验中阿法替尼剂量减少对 AE、药代动力学和无进展生存期（PFS）的影响。
方法
在 LL3（全球）和 LL6（中国、泰国、韩国）中，未经治疗的晚期 EGFR 突变阳性 NSCLC 患者被随机分配接受阿法替尼或化疗。所有接受阿法替尼治疗的患者（LL3，n=229；LL6，n=239）均纳入事后分析。评估阿法替尼剂量减少前后常见 AE 的发生率和严重程度。比较剂量减少至 30mg 与维持 40mg 的患者的阿法替尼血浆浓度。比较治疗前 6 个月内剂量减少与未剂量减少的患者的 PFS。
结果
LL3 和 LL6 中分别有 53.3%（122/229）和 28.0%（67/239）的患者发生剂量减少；大多数（86.1%和 82.1%）发生在治疗的前 6 个月内。剂量减少导致药物相关 AE 的发生率降低，并且在阿法替尼血浆浓度较高的患者中更可能发生。在第 43 天，剂量减少至 30mg 的患者（n=59）的阿法替尼血浆浓度几何均数为 23.3ng/ml，而维持 40mg 的患者（n=284）为 22.8ng/ml。在治疗前 6 个月内剂量减少的患者与未剂量减少的患者相比，中位 PFS 相似[LL3：11.3 与 11.0 个月[风险比（HR）1.25]；LL6：12.3 与 11.0 个月（HR 1.00）]。
结论
基于耐受性的剂量调整是一种减少阿法替尼相关 AE 的有效措施，而不会影响治疗效果。
临床试验注册
Clinicaltrials.gov 标识符：NCT00949650 和 NCT0112393。
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