Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.
Burning Rock Biotech, Guangdong, Guangzhou 510300, People's Republic of China.
Neoplasia. 2024 Dec;58:101073. doi: 10.1016/j.neo.2024.101073. Epub 2024 Oct 19.
In-depth insight into the genomic features of the uncommon EGFR p.L861Q mutant NSCLC is scarcely performed, and no consensus on the preferred treatment strategy has been established. Moreover, the therapeutic implications of EGFR-TKI stratified by clinical and molecular features remained largely unknown.
A multi-center NGS database comprising 44,993 NSCLC samples was utilized for the genomic landscape profiling of EGFR p.L861Q mutation. Furthermore, a real-world cohort of 207 patients harboring EGFR p.L861Q mutation with complete treatment history was curated for comprehensive clinical analysis.
L861Q is prevalent in approximately 2.1% of EGFR-mutated NSCLC and is typically co-mutated with EGFR p.G719X on the same allele (20%) and exhibits co-occurrent EGFR copy number amplification in approximately 17% of cases. In the first-line setting, afatinib and third-generation EGFR-TKI have been shown to yield notably superior treatment outcomes compared to first-generation EGFR-TKI (1 vs.2 vs.3 generations, ORR: 15.8% vs.56.5% vs.46.7%, P=0.01; median PFS: 6.4 vs.13.5 vs.15.1 months, P=0.002). This finding consistently held for patients without CNS metastases (1 vs.2 vs.3 generations, median PFS:6.0 vs.18.2 vs.14.1 months, P=0.003). In contrast, third-generation EGFR-TKI demonstrated superior efficacy compared to afatinib or first-generation TKI among the subgroup of brain metastasis (Pooled 1/2-generation vs.3-generation TKI, brain ORR:0.00% vs.33.33%; median PFS:7.9 vs.19.3 months, P=0.021). Additional concurrent EGFR mutations or EGFR amplification did not yield a discernible impact on the efficacy of EGFR-TKI.
The present study comprehensively elucidates the molecular features of EGFR p.L861Q mutation and underscores the optimal therapeutic choice of first-line EGFR-TKI based on brain metastatic status.
深入了解罕见的 EGFR p.L861Q 突变 NSCLC 的基因组特征的研究很少，也尚未达成一致的首选治疗策略。此外，基于临床和分子特征对 EGFR-TKI 进行分层的治疗意义在很大程度上仍是未知的。
利用包含 44993 例 NSCLC 样本的多中心 NGS 数据库，对 EGFR p.L861Q 突变进行基因组特征分析。此外，对 207 例携带 EGFR p.L861Q 突变且具有完整治疗史的真实世界队列进行了全面的临床分析。
L861Q 突变在 EGFR 突变的 NSCLC 中约占 2.1%，通常与 EGFR p.G719X 突变共同发生在同一等位基因上（20%），并且在约 17%的病例中存在 EGFR 拷贝数扩增。在一线治疗中，阿法替尼和第三代 EGFR-TKI 与第一代 EGFR-TKI 相比，疗效显著更优（1 代 vs.2 代 vs.3 代，ORR：15.8% vs.56.5% vs.46.7%，P=0.01；中位 PFS：6.4 个月 vs.13.5 个月 vs.15.1 个月，P=0.002）。对于无脑转移的患者，这一发现也是一致的（1 代 vs.2 代 vs.3 代，中位 PFS：6.0 个月 vs.18.2 个月 vs.14.1 个月，P=0.003）。相比之下，在脑转移亚组中，第三代 EGFR-TKI 与阿法替尼或第一代 TKI 相比，疗效更优（阿法替尼/1/2 代联合 vs.3 代 TKI，脑 ORR：0.00% vs.33.33%；中位 PFS：7.9 个月 vs.19.3 个月，P=0.021）。此外，同时存在其他 EGFR 突变或 EGFR 扩增并未对 EGFR-TKI 的疗效产生明显影响。
本研究全面阐明了 EGFR p.L861Q 突变的分子特征，并强调了根据脑转移状态选择一线 EGFR-TKI 的最佳治疗选择。
