No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study.

Michele Guida ,Marcella Occelli ,Pietro Quaglino ,Lucia Stigliano ,Nicola Bartolomeo ,Sabino Strippoli ,Paolo A Ascierto ,Laura Ridolfi ,Ivana De Risi ,Vanna Chiarion-Sileni ,Alessandro Marco Minisini ,Elisabetta Gambale ,Gabriele Madonna ,Anna Di Giacomo ,Francesco Spagnolo ,Paola Queirolo ,Davide Quaresmini ,Marco Tucci ,Jacopo Pigozzo

doi:10.3390/cancers13030475

Abstract

Simple SummaryNeuroblastoma RAS Viral Oncogen Homolog (NRAS) mutant melanoma is usually considered more aggressive and more responsive to checkpoint inhibitor immunotherapy (CII) than NRAS wildtype. We retrospectively recruited 331 metastatic melanoma patients treated with CII as first line: 162 NRAS-mutant/BRAF wild-type and 169 wt/wt. No substantial differences were observed among the two cohorts regarding the melanoma onset and disease-free interval. Also, overall response to CII, progression-free survival and overall survival were similar in the two groups. Therefore, our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant melanoma. The controversy in the published data could be due to different patient characteristics and treatment heterogeneity. We believe our data adds evidence to clear up these controversial issues.Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7–18) versus 9 months (95% CI, 6–16) and 32 (95% CI, 23–49) versus 27 months (95% CI, 16–35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM.

Highlights

The medical treatment of metastatic melanoma (MM) has recently been significantly improved by the identification of specific genetic alterations, such as BRAF, NRAS and cKIT mutations
We found very similar patient characteristics between the two groups at study accrual and a good balance of prognostic factors
We found no differences in age, lactate dehydrogenase (LDH) levels, number of metastatic sites, or Eastern Cooperative Oncology Group (ECOG) PS

Summary

Introduction

The medical treatment of metastatic melanoma (MM) has recently been significantly improved by the identification of specific genetic alterations, such as BRAF, NRAS and cKIT mutations. In the last few years, immunotherapy has played a primary role in the treatment of MM due to the availability of new drugs, such as monoclonal antibodies directed toward the checkpoint molecules CTLA-4 (cytotoxic T lymphocyte antigen-4) and PD-1 (programmed death antigen 1) or its ligand. This approach is able to reverse the immunosuppressive status and restart a potent antitumoural immune response. The anti-CTLA-4 antibody ipilimumab is able to induce a response rate of approximately 15% with approximately 20%

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