AUTHOR=Ma Si-Cong , Zhu Hong-Bo , Wang Jian , Zhang Yan-Pei , Guo Xue-Jun , Long Li-Li , Guo Ze-Qin , Wu De-Hua , Dong Zhong-Yi , Bai Xue 

TITLE=De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.666145

DOI=10.3389/fonc.2021.666145

ISSN=2234-943X

ABSTRACT=<sec><title>Purpose</title><p>Despite the success of targeted therapy in c-ros oncogene 1 (<italic>ROS1</italic>)-rearranged cancers, especially non-small cell lung cancer (NSCLC), the clinical significance of <italic>ROS1 de novo</italic> mutation has not yet been understood. We sought to elucidate the predictive effect of <italic>ROS1</italic> mutation for immune checkpoint inhibitor (ICI) therapy in melanoma.</p></sec><sec><title>Methods</title><p>The Cancer Genome Atlas [TCGA (<italic>n</italic> = 10967)] and Memorial Sloan Kettering Cancer Center [MSK (<italic>n</italic> = 10,945)] datasets, as well as two clinical cohorts of melanoma received ICI [CA209-038 (<italic>n</italic> = 73) and MEL-IPI (<italic>n</italic> = 110)], were included to explore the prevalence, prognostic effect, and immunotherapeutic predictive effect of <italic>ROS1</italic> mutation in melanoma. Overall survival (OS) was defined as the primary outcome.</p></sec><sec><title>Results</title><p>Overall, melanoma accounted for the highest proportion of <italic>ROS1</italic> mutation (~20%) which made up the majority (~95%) of the <italic>ROS1</italic>-alterated cases. Remarkably, <italic>ROS1</italic> mutation yielded longer OS from ICI than the wild-type counterpart in the MSK melanoma population [hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.30–0.74], and two external melanoma cohorts (CA209-038: HR 0.42, 95% CI 0.20–0.89; MEL-IPI: HR 0.55, 95% CI 0.34–0.91), without affecting the prognosis of patients. Elevated tumor mutational burden and enrichment of DNA damage repair was observed in <italic>ROS1</italic> mutated patients, providing an explanation for the favorable responses to ICI therapy. Precisely, <italic>ROS1</italic> mutation in non-protein tyrosine kinase (PTK) domain but not PTK mutation was responsible for the immunotherapy-specific responses of the <italic>ROS1</italic> mutated patients in melanoma.</p></sec><sec><title>Conclusions</title><p>Collectively, <italic>ROS1</italic> mutation, specifically the non-PTK mutation, is a potential predictor of ICI therapy in melanoma, which is distinct from the well-established role of <italic>ROS1</italic> rearrangement for targeted therapy in NSCLC.</p></sec>