MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients
Kirchberger MC, Ugurel S, Mangana J, Heppt MV, Eigentler TK, Berking C, Schadendorf D, Schuler G, Dummer R, Heinzerling L (2018)
Publication Type: Journal article
Publication year: 2018
Journal
Book Volume: 98
Pages Range: 10-16
DOI: 10.1016/j.ejca.2018.04.010
Abstract
BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though BRAF mutations can be effectively targeted with specific inhibitors, this approach has proven more challenging in cases of NRAS mutations. Previous reports suggested that immunotherapy might be more successful in NRAS-mutated compared to BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study, overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients. Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which Q61 mutations were predominant (95%). RESULTS: Patients with NRAS mutant melanoma showed similar response rates to checkpoint inhibitor therapy compared to NRAS wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13% for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median overall survival of patients with NRAS mutant melanoma was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma patients (P = 0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma. CONCLUSIONS: Immune checkpoint inhibition shows comparable response rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less favourable in case of NRAS mutation. Additional MEK inhibition might improve clinical benefit.
Authors with CRIS profile
Gerold Schuler
Lehrstuhl für Haut- und Geschlechtskrankheiten
Lucie Heinzerling
Department of Dermatology
Involved external institutions
Universitätsklinikum Essen
Germany (DE)
Universitätsspital Zürich (USZ)
Switzerland (CH)
Klinikum der Universität München
Germany (DE)
Universitätsklinikum Tübingen
Germany (DE)
Germany (DE)
Universitätsspital Zürich (USZ)
Switzerland (CH)
Klinikum der Universität München
Germany (DE)
Universitätsklinikum Tübingen
Germany (DE)
How to cite
APA:
Kirchberger, M.C., Ugurel, S., Mangana, J., Heppt, M.V., Eigentler, T.K., Berking, C.,... Heinzerling, L. (2018). MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients. European Journal of Cancer, 98, 10-16. https://dx.doi.org/10.1016/j.ejca.2018.04.010
MLA:
Kirchberger, Michael Constantin, et al. "MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients." European Journal of Cancer 98 (2018): 10-16.
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