Who's Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma.

Mucosal melanoma can be driven by various driver mutations in genes such as , , or . However, some cases present with only weak drivers, or lacking known oncogenic drivers, suggesting immunotherapy over targeted therapy. While resistance mechanisms to immunotherapy in cutaneous melanoma have been uncovered, including alterations in /, or , a switch of oncogenic drivers under immunotherapy has not yet been observed. We report three cases of metastatic sinonasal melanoma that switched oncogenic drivers from , or no driver to during or after immunotherapy, thereby showing progressive disease. One of the cases presented with three spatially separate driver mutations in the primary tumor, whereas the clone persisted under immunotherapy. In comparison, three different control cases receiving radiotherapy only did not show a change of the detectable molecular drivers in their respective recurrences or metastases. In summary, these data provide an important rationale for longitudinal molecular testing, based on evidence for an unforeseen recurrent event of molecular driver switch to in progressing sinonasal melanoma. These findings provide the basis for further studies on a potential causal relation of emerging mutant clones and immunotherapy.