Acral Lentiginous Melanoma Harboring a ROS1 Gene Fusion With Clinical Response to Entrectinib
Kasey L Couts1, Caroline E McCoach1, Danielle Murphy1
1Kasey L. Couts, Caroline E. McCoach, Jacqueline Turner, Karl D. Lewis, William A. Robinson, and Robert C. Doebele, University of Colorado Denver, Aurora, CO; and Danielle Murphy and Jason Christiansen, Ignyta, San Diego, CA.
Purpose:
ROS1 gene fusions demonstrate oncogenic activity, and patients with non-small-cell lung cancer (NSCLC) harboring a ROS1 fusion benefit from the use of a ROS1 inhibitor; however, clinical response to ROS1 inhibitors remains largely uncharacterized outside of NSCLC. ROS1 fusions have been identified in multiple tumor types but have not been reported in cutaneous melanoma.
Patients And Methods:
Tumors from 22 patients with acral lentiginous melanoma (ALM) were analyzed with targeted RNA sequencing to detect fusions in ROS1, NTRK1, NTRK2, NTRK3, and ALK genes. A patient harboring a ROS1 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.
Results:
Targeted sequencing identified a GOPC-ROS1 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 ROS1 fusions were identified by immunohistochemistry, resulting in a frequency of 3.0% in ALM and 1.3% in all melanomas.
Conclusion:
ROS1 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.
Insights
ROS1 gene fusions, previously uncharacterized in melanoma, were identified in acral lentiginous melanoma (ALM). A patient with ALM harboring a ROS1 fusion showed a significant response to entrectinib, indicating a new therapeutic option for this cancer subset.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- ROS1 gene fusions drive oncogenic activity and are targetable in non-small-cell lung cancer (NSCLC).
- Clinical response to ROS1 inhibitors is largely uncharacterized in tumor types outside of NSCLC.
- ROS1 fusions have not been previously reported in cutaneous melanoma.
Purpose of the Study:
- To investigate the presence and clinical significance of ROS1 gene fusions in cutaneous melanoma.
- To evaluate the response of melanoma patients with ROS1 fusions to ROS1/TRK/ALK inhibitors.
Main Methods:
- Targeted RNA sequencing of 22 acral lentiginous melanoma (ALM) tumors to detect fusions in ROS1, NTRK1, NTRK2, NTRK3, and ALK.
- Enrollment of a patient with a GOPC-ROS1 fusion in a phase I basket trial of entrectinib (a ROS1/TRK/ALK inhibitor).
- ROS1 immunohistochemistry screening of an additional 78 melanoma tumors across different subtypes.
Main Results:
- A GOPC-ROS1 fusion was identified in one patient with ALM via targeted sequencing.
- The patient with ALM and a GOPC-ROS1 fusion experienced a dramatic and durable partial response to entrectinib (-55% at 11 months).
- ROS1 fusions were detected in 3.0% of ALM and 1.3% of all melanomas analyzed; no additional fusions were found by immunohistochemistry.
Conclusions:
- ROS1 fusions can occur in cutaneous melanoma, particularly in the ALM subtype, and are responsive to targeted therapy.
- This study expands the understanding of ROS1 inhibitor efficacy beyond NSCLC.
- The identification of ROS1 fusions offers potential new therapeutic avenues for a subset of patients with ALM.
