Relevance of detection of RAF fusion in pan-negative melanoma in routine practice.

Abstract

e21500 Background: Pan-negative melanomas (i.e. without MAPK kinase pathway alteration and C-kit wild type) account for 30% of melanomas (according to the AACR GENIE database). In case of immunotherapy failure, therapeutic options are limited. Oncogene fusions represent a target of interest in many solid cancers (NSCLC, Cholangiocarcinoma, Glioma, GIST, pancreatic acinar carcinoma, thyroid, and prostate cancers). In melanoma, the frequency of oncogene fusion is not well documented and not routinely investigated. Methods: We conducted a single-center retrospective study. The objective was to determine the frequency of oncogene fusion detected by RNA sequencing (Archer Fusion pLex) performed in routine practice, in patients with advanced or metastatic pan negative melanoma. Data on clinical, pathological, and molecular characteristics and patient outcomes were collected. Analysis was carried out on the genetic material available for the diagnosis of the disease except for 1 patient who benefited from a new anatomopathological sample during an unfavorable evolution. In parallel, an extended molecular alteration search was performed using extended targeted NGS (OncoMine Comprehensive Assay panel). Results: We identified 48 patients with an advanced pan negative melanoma between January 2021 and January 2022 with a median age at diagnosis of 63 years. It was a cutaneous melanoma in 72,9 % (35/48) of the cases, a mucous melanoma in 14,5% (7/48) of the cases and a melanoma of unknown primary site in 12,5% (6/48) of the cases. The detection of fusion transcript was made in 89,5 % (43/48) of the cases. We identified 6 patients with a RAF fusion, including 4 BRAF gene fusion (MKLN1-BRAF, AGK-BRAF, SNX29-BRAF, PTPRJ-BRAF) and 2 RAF1 fusion (MAP4-RAF1, EFCC1-RAF1). Of the other molecular alterations, NF1 mutation was the most frequent molecular alteration identified (25 % (12/48) of patients). At lower frequencies, 6,8 % (3/48) of patients had a PI3K mutation, and 8,3 % (4/48) of patients had NOTCH, PTCH1, GNAQ mutations. Among the 6 patients with RAF fusions, all the patients initially received treatment with anti-PD1+/- anti-CTLA4 immunotherapy. After immunotherapy failure, 4 patients benefited from second-line targeted therapy (2 with BRAF and MEK inhibitors combination, 2 MEK inhibitors alone). One patient presented an objective imaging response, the other three patients have not yet benefited from reassessment imaging. Conclusions: In a population of pan negative melanoma, we detected 12,5 % (6/48) of RAF fusion. Fusion detection allowed the introduction of a second line of targeted therapy, in the absence of a validated therapeutic option in 66,6 % (4/6) of cases This study suggests the relevance of detecting RAF fusion in a selected population.