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. ROS1 mutation rate is high in melanoma. Studies have shown that ROS1 substitutions/indels correlated with higher TMB (Tumor Mutation Burden) and PD-L1+/TMB-H proportions than wild-type genotypes in NSCLC, which means that the mutation of ROS1 gene may be related to the efficacy of immunotherapy in patients with NSCLC, but the association between ROS1 mutation and TMB or survival in melanoma is unknown.
The association between ROS1 mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Melanoma.Allen2015.WES.110, which worked as training cohort while the validation cohort1 was retrieved from Pancancer.Samstein2018.NGS.1661 and validation cohort2 was from Melanoma.Hugo2016.WES.38. Wilcoxon test was used for the comparison of TMB. 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.
In the training cohort, 18.2% (20/110) melanoma patients harbored ROS1 mutation. ROS1 mutation is associated with higher TMB (p=0.00002). Survival analysis demonstrates that ROS1 mutation results in significantly longer OS (21.75 vs 7.65 months; HR, 0.55; p=0.046) in melanoma patients treated with ICIs. While the validation cohort1 shows that 20.1% (63/313) melanoma patients harbored ROS1 mutation,which results in an increasing trend on TMB with strongly significant difference (p=1.32*e-17)and significantly longer OS (19 vs 18 months; HR, 0.58; p=0.041). Besides, validation cohort2 also shows that ROS1 mutation results in an higher TMB with significant difference (p=0.017) and significantly longer OS (26.6 vs 14.4 months; HR, 0.25; p=0.045).
This study shows that ROS1 mutation is correlated with higher TMB in melanoma and serves as a predictive biomarker of ICI benefit in melanoma.
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D. Fan: Financial Interests, Personal and Institutional, Member: 3DMed. Inc.. Y. Chen: Financial Interests, Personal and Institutional, Member: 3DMed. Inc.. M. Huang: Financial Interests, Personal and Institutional, Member: 3DMed. Inc.. All other authors have declared no conflicts of interest.