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

Abstract

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&lt;0.001), ever-smokers (93% vs 86%, p=0.004) and non-squamous histology (98% vs 88%, p&lt;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&lt;0.001), while PD-L1 expression, age and performance status were comparable. Within the RASa/KRASwt cohort, 103 patients (39%) had co-mutations in STK11 /KEAP1/ SMARCA4 and were more frequently ever-smokers compared with non co-mutated RASa/KRASwt (95% vs 80%, p&lt;0.001), with otherwise similar clinical characteristics. As expected, co-mutations were associated with shorter median progression free survival (mPFS) and median overall survival (OS) in KRASm group (mPFS: 4.4 vs 6.2 mo., HR:1.33 (1.1-1.62), p=0.004; mOS: 11.4 vs 21.7 months(mo), HR:1.43 (1.16-1.78), p&lt;0.001). However, among RASa/KRASwt tumors, concurrent mutations in STK11/KEAP1/SMARCA4 had no impact on survival outcomes (mPFS: 5.9 vs 4.1 mo., HR:0.79 (0.6-1.02), p=0.07; mOS: 15.8 vs 14.8 mo, HR: 1.02 (0.77-1.35), p=0.89). This differential effect was confirmed by a significant interaction between RAS status and co-mutational status (aHR 1.71, p=0.004). For OS, interaction analysis did not show a differential effect of co-mutations according to RAS status (aHR 1.43; p=0.073). Conclusions: Known co-mutations that confer worse outcomes to ICI in KRASm NSCLC do not appear to have the same impact in KRASwt tumors with other RAS activating mutations. RASa/KRASwt tumors with co-mutations behave more similarly to KRAS wild-type NSCLCs, highlighting biological heterogeneity within RAS-driven tumors and potential implications for patient selection for treatment intensification or de-escalation strategies.