Abstract 5251: GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma

Abstract Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) including atezolizumab, pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that Tumor Mutation Burden (TMB) was significantly (p < 0.001) associated with mutations in genes like GRIN2A in Non-Small Cell Lung Cancer (NSCLC), which means that the mutation of GRIN2A gene may be related to the efficacy of immunotherapy in patients with NSCLC, but the association between GRIN2A mutation and TMB or survival in melanoma is unknown. Methods: The association between GRIN2A mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Miao2018.Pancancer.249.WES, which worked as training cohort while the validation cohort was retrieved from Melanoma.Allen2015.WES.110. Wilcoxon test was used for the comparison of TMB and Tumor Neoantigen Burden (TNB). Progress Free Survival (PFS):Overall survival (OS) analyses were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. Statistical significance was set at p=0.05. Results: In the training cohort, 33.8% (51/151) melanoma patients harbored GRIN2A mutation. GRIN2A mutation is associated with higher TMB (p<0.001) and higher TNB (p<0.001). Survival analysis demonstrated that GRIN2A mutation resulted in significantly longer PFS (5.6 vs 3.3months; HR, 0.58; p=0.027) and longer OS (22.5 vs 12.8 months; HR, 0.61; p=0.039) in melanoma patients treated with ICIs. While validation cohort1 showed that 22.7% (25/110) melanoma patients harbored GRIN2A mutation and GRIN2A mutation resulted in an increasing trend on TMB with strongly significant difference (p<0.001) and significantly longer OS (22.5 vs 8.3months; HR, 0.53; p=0.025). Conclusions: This study shows that GRIN2A mutation is correlated with higher TMB and TNB in melanoma and serve as a predictive biomarker of ICI benefit in melanoma. Citation Format: Ling Ye, Dandan Fan, Yaoxu Chen, Mengli Huang. GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5251.