Acral Lentiginous Melanoma Harboring a <i>ROS1</i> Gene Fusion With Clinical Response to Entrectinib.

Abstract

<i>ROS1</i> gene fusions demonstrate oncogenic activity, and patients with non-small-cell lung cancer (NSCLC) harboring a <i>ROS1</i> fusion benefit from the use of a ROS1 inhibitor; however, clinical response to ROS1 inhibitors remains largely uncharacterized outside of NSCLC. <i>ROS1</i> fusions have been identified in multiple tumor types but have not been reported in cutaneous melanoma. Tumors from 22 patients with acral lentiginous melanoma (ALM) were analyzed with targeted RNA sequencing to detect fusions in <i>ROS1</i>, <i>NTRK1</i>, <i>NTRK2</i>, <i>NTRK3</i>, and <i>ALK</i> genes. A patient harboring a <i>ROS1</i> fusion was enrolled in a phase I basket trial of a ROS1/TRK/ALK inhibitor (entrectinib). An additional 78 tumors with different subtypes of melanoma were screened by ROS1 immunohistochemistry. Targeted sequencing identified a <i>GOPC</i>-<i>ROS1</i> fusion in a patient with ALM. The patient underwent a dramatic and durable response to entrectinib, with a RECIST (version 1.1) partial response of -38% at 3 months and -55% at 11 months. The response is ongoing, and the patient has not developed any new lesions. No additional <i>ROS1</i> fusions were identified by immunohistochemistry, resulting in a frequency of 3.0% in ALM and 1.3% in all melanomas. <i>ROS1</i> fusions occur and can respond to targeted therapy in cutaneous melanoma; however, they may be specific to ALM subtype. This report expands knowledge of ROS1 inhibitor response outside of NSCLC and identifies new therapeutic options for a subset of patients with ALM.