Michael Constantin Kirchberger1, Selma Ugurel2, Johanna Mangana3, Markus Valentin Heppt4, Thomas Kurt Eigentler5, Carola Berking6, Dirk Schadendorf7, Gerold Schuler8, Reinhard Dummer9, Lucie Heinzerling10. 1. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054 Erlangen, Germany. Electronic address: Michael.Kirchberger@uk-erlangen.de. 2. Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany. Electronic address: Selma.Ugurel@uk-essen.de. 3. Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland. Electronic address: Johanna.Mangana@usz.ch. 4. Department of Dermatology and Allergy, Munich University Hospital (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany. Electronic address: Markus.Heppt@med.uni-muenchen.de. 5. Department of Dermatology, Center for Dermatooncology, University Hospital Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany. Electronic address: Thomas.Eigentler@med.uni-tuebingen.de. 6. Department of Dermatology and Allergy, Munich University Hospital (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany. Electronic address: Carola.Berking@med.uni-muenchen.de. 7. Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. 8. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054 Erlangen, Germany. Electronic address: Gerold.Schuler@uk-erlangen.de. 9. Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland. Electronic address: Reinhard.Dummer@usz.ch. 10. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054 Erlangen, Germany. Electronic address: Lucie.Heinzerling@uk-erlangen.de.
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.
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 melanomapatients (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.
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