Popat Sanjay, Januszewski Adam, O'Brien Mary, Ahmad Tanya, Lewanski Conrad, Dernedde Ulrike, Jankowska Petra, Mulatero Clive, Shah Riyaz, Hicks Jonathan, Geldart Tom, Cominos Mathilda, Gray Gill, Spicer James, Bell Karen, Roitt Simon, Morris Clive, Ngai Yenting, Hughes Laura, Hackshaw Allan, Wilson William
The Royal Marsden NHS Foundation Trust, London, UK.
Imperial College London and St Bartholomew's Hospital NHS Trust, London, UK.
Br J Cancer. 2025 Feb;132(3):245-252. doi: 10.1038/s41416-024-02901-6. Epub 2024 Dec 5.
Here we present long-term outcomes of first line afatinib in comorbid patients with suspected or confirmed EGFR mutant NSCLC otherwise considered unsuitable for chemotherapy, and the clinical utility of serial ctDNA monitoring.
TIMELY (NCT01415011) was a multicentre, single arm, phase II trial conducted in the UK. Patients aged ≥18 were treated with daily oral afatinib (40 mg) until disease progression or unacceptable toxicity. Blood samples for ctDNA analysis were obtained at baseline and 12-weekly until treatment discontinuation. The primary endpoint was PFS.
Thirty-nine patients were enrolled between March 2013 and August 2015. Median follow-up was 98 months (range 69-101). Median PFS was 7.9 months (95% CI 4.6-10.5). Seven patients (18%) continued afatinib beyond 18 months, 3 beyond 36 months and 2 were still on treatment at last follow-up 101 months post-treatment initiation. Analysis of baseline ctDNA samples identified 8 EGFR mutant cases that were not identified by tissue genotyping and ctDNA clearance was associated with improved PFS and OS.
Afatinib is a viable treatment option for tissue or ctDNA-detected EGFR mutant NSCLC comorbid patients, with a proportion achieving long-term clinical benefit. Plasma ctDNA testing improved EGFR mutant identification and its clearance predicted improved PFS and OS.
在此，我们展示了一线阿法替尼治疗合并其他疾病、疑似或确诊为表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者（这些患者被认为不适合化疗）的长期疗效，以及连续循环肿瘤DNA（ctDNA）监测的临床应用价值。
“及时治疗”（TIMELY，NCT01415011）是在英国进行的一项多中心、单臂、II期试验。年龄≥18岁的患者每日口服阿法替尼（40毫克），直至疾病进展或出现不可接受的毒性反应。在基线时以及每12周采集一次血样用于ctDNA分析，直至治疗中断。主要终点是无进展生存期（PFS）。
2013年3月至2015年8月期间共纳入39例患者。中位随访时间为98个月（范围69 - 101个月）。中位PFS为7.9个月（95%置信区间4.6 - 10.5）。7例患者（18%）使用阿法替尼超过18个月，3例超过36个月，2例在治疗开始后101个月的最后一次随访时仍在接受治疗。对基线ctDNA样本的分析发现了8例通过组织基因分型未检测到的EGFR突变病例，ctDNA清除与PFS和总生存期（OS）的改善相关。
对于组织或ctDNA检测到的EGFR突变的NSCLC合并患者，阿法替尼是一种可行的治疗选择，部分患者可实现长期临床获益。血浆ctDNA检测改善了EGFR突变的识别，其清除预示着PFS和OS的改善。
