Abstract 1066P
Background
RAS pathway alterations in NSCLC have been linked to worse prognosis and remain a challenging therapeutic target. HRAS, a RAS family members, is under-investigated and its activation depends on farnesylation, making it an appealing target for farnesyltransferase inhibitors. Although KRAS has been associated with immune modulation in NSCLC, the role of HRAS remains unclear. We aimed to investigate the relationship of HRAS gene mutations and the TME.
Methods
Molecular profiling of 29,767 NSCLC tumor samples was performed at Caris Life Sciences to obtain whole exom sequencing, whole transcriptome sequencing and immunohistochemistry. MAPK signaling activity (MPAS) and immune cell fraction were assessed by mRNA analysis. Wilcoxon, Fisher’s exact were used for statistical significance. Overall survival was calculated using the Kaplan-Meier method. Comparisons were conducted between HRAS mutated (mt) tumors and the entire NSCLC general cohort (GC).
Results
HRAS mt were detected in 0.4% of NSCLC tumors (n=128), with a majority among smokers. HRAS mt displayed less B cell, macrophage M2, NK cell, CD4+ and CD8+ T cells infiltrates compared to GC (q<0.05 ). In addition, HRAS Q61 was found to be correlated with worse prognosis in pts treated with pembro (HR = 2.779, 95% CI [1.04-7.423], p =0.03) but not G12 or G13, and displayed the highest MPAS score (p = 0.05), which had previously been demonstrated to indicate immune evasion. The median difference for survival curves was -246 days between HRAS mt squamous cell carcinomas (SCC, all smokers) and GC SCC in pts treated with pembro (HR 1.72, 95% CI 0.85-3.64, p =0.126). HRAS mt SCC showed less infiltration with M1, B cells, myeloid dendritic cells (mDC) and also displayed a significantly higher MPAS score and LAG3 expression as compared to GC (0.53 vs -0.31, p = 0.03; 2.10 vs 1.03 TPM, p = 0.04). No similar trends were observed in adenocarcinoma histology.
Conclusions
HRAS mt NSCLC displayed a relatively immune-cold pattern with less CD4+ and CD8+ T cells infiltrates compared to GC. HRAS mt SCC also showed an immune-cold TME associated with high MAPK pathway activation and high LAG3 expression. This warrants further investigation, in particular in HRAS Q61 or HRAS mt SCC, with combination therapies targeting MAPK pathway or LAG3 protein.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
J. Yin: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. H. Borghaei: Financial Interests, Personal, Advisory Board: BMS, Lilly, Genentech, Celgene, Pfizer, Takeda. C. Nabhan: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. M. Nagasaka: Financial Interests, Personal, Invited Speaker, honoraria: AstraZeneca. All other authors have declared no conflicts of interest.