Mutation in Non-Tyrosine Kinase Domain of as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma.

PURPOSE

Despite the success of targeted therapy in c-ros oncogene 1 ()-rearranged cancers, especially non-small cell lung cancer (NSCLC), the clinical significance of mutation has not yet been understood. We sought to elucidate the predictive effect of mutation for immune checkpoint inhibitor (ICI) therapy in melanoma.

METHODS

The Cancer Genome Atlas [TCGA ( = 10967)] and Memorial Sloan Kettering Cancer Center [MSK ( = 10,945)] datasets, as well as two clinical cohorts of melanoma received ICI [CA209-038 ( = 73) and MEL-IPI ( = 110)], were included to explore the prevalence, prognostic effect, and immunotherapeutic predictive effect of mutation in melanoma. Overall survival (OS) was defined as the primary outcome.

RESULTS

Overall, melanoma accounted for the highest proportion of mutation (20%) which made up the majority (95%) of the -alterated cases. Remarkably, 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 mutated patients, providing an explanation for the favorable responses to ICI therapy. Precisely, mutation in non-protein tyrosine kinase (PTK) domain but not PTK mutation was responsible for the immunotherapy-specific responses of the mutated patients in melanoma.

CONCLUSIONS

Collectively, mutation, specifically the non-PTK mutation, is a potential predictor of ICI therapy in melanoma, which is distinct from the well-established role of rearrangement for targeted therapy in NSCLC.