Memorial Sloan Kettering Cancer Center, New York, NY, USA; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Chinese Thoracic Oncology Group, Guangzhou, China.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Eur J Cancer. 2024 Oct;210:114257. doi: 10.1016/j.ejca.2024.114257. Epub 2024 Aug 14.
No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment.
We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS).
Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019).
Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.
目前对于 HER2 突变型 NSCLC 的一线治疗方法尚无明确答案。快速进行组织测序是精准药物开发在一线治疗中面临的主要障碍。ctDNA 分析具有克服这些障碍并指导治疗的潜力。
我们回顾性分析了 2016 年 1 月至 2022 年 9 月期间在 Memorial Sloan Kettering Cancer Center（MSK）接受前瞻性临床 ctDNA 测序并接受系统治疗的转移性 HER2 突变型 NSCLC 患者。HER2 突变通过 MSK-IMPACT、MSK-ACCESS 或 Resolution ctDx LungTM 检测进行下一代测序鉴定。主要终点为下一次治疗的时间（TTNT）和总生存期（OS）。
63 例患者纳入主要分析。化疗免疫治疗（33/63，52.4%）是主要的一线治疗方法，TTNT 中位数为 5.1 个月（95%CI 4.1-6.1），而接受二线 T-DXd 治疗的 55.0%（22/40）患者的 TTNT 中位数为 9.2 个月（95%CI，0-22.2）。40 例患者在一线治疗前进行了血浆 ctDNA 检测，中位 OS 为 28.0 个月（95%CI 21-34），其中 31 例（78.0%）患者可检测到 ctDNA。ctDNA 检测到 HER2 突变的中位周转时间为 13 天，偶尔与 EGFR 和 MET 改变同时发生，并进行了纵向跟踪，与治疗反应相关。基线时可检测到 ctDNA 的患者 OS 明显缩短（风险比（HR），5.25；95%CI，1.2-23.9；p=0.019）。
化疗免疫治疗仍然是转移性 HER2 突变型 NSCLC 的主要治疗选择。ctDNA 可以快速检测 HER2 和共突变，具有指导和监测一线治疗的潜力。作为一种负预后生物标志物，基线时可检测到 ctDNA 需要在未来的研究中考虑用于患者选择。
