Impact of STK11 / KEAP1 / SMARCA4 co-mutations in RAS-activated KRAS wild-type metastatic NSCLC treated with immune checkpoint inhibitors.

作者：Cassio Murilo Hidalgo-Filho, Eleonora Gariazzo, Valentina Santo, Leonardo Brunetti, Xinan Wang, Federica Pecci, Biagio Ricciuti · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.16_suppl.8565 · 研究领域：Chromatin Remodeling and Cancer、Melanoma and MAPK Pathways、Cancer Mechanisms and Therapy

8565 Background: RAS-activated KRAS wild-type (RASa/KRASwt) non-small cell lung cancer (NSCLC) shares key biological features with KRAS-mutant (KRASm) tumors, including MAPK pathway activation. In KRASm NSCLC, co-mutations in STK11 , KEAP1 and SMARCA4 are associated with poor outcomes to immune checkpoint inhibitors (ICI). Whether these alterations similarly impact outcomes in RASa/KRASwt tumors is unknown. Methods: We analyzed patients with metastatic NSCLC treated with ICI at Dana-Farber Cancer Institute. RASa/KRASwt tumors were defined by pathogenic alterations in RAS–MAPK pathway genes ( NF1 , NF2 , BRAF , RAF1 , MAP2K1/2 , MAP3K1 , MAPK1 , PTPN11 , SOS1 , HRAS , NRAS , RIT1 , RASA1 , GNAS ). Co-mutations in STK11 , KEAP1 and SMARCA4 were evaluated using targeted exome sequencing. Survival analyses were performed using log-rank test and survival risks estimated with Cox regression models. Results: Among 1,215 patients included, 492 (40%) had KRASm tumors and 264 (22%) were RASa/KRASwt. Compared with RASa/KRASwt tumors, KRASm tumors were more frequent in female patients (65% vs 50%, p<0.001), ever-smokers (93% vs 86%, p=0.004) and non-squamous histology (98% vs 88%, p<0.001). The frequency of KEAP1 (21% vs 22%), STK11 (26% vs 20%) and SMARCA4 (10% vs 12%) mutations was similar between the groups. High tumor mutation burden (≥10 mut/Mb) was more frequent in RASa/KRASwt tumors (60% vs 46%, p<0.001), while PD-L1 expression, age and performance status were comparable....