Immune checkpoint inhibition in patients with NRAS mutated and NRAS wild type melanoma: a multicenter Dermatologic Cooperative Oncology Group study on 637 patients from the prospective skin cancer registry ADOREG

Anne Zaremba*, Peter Mohr, Ralf Gutzmer, Friedegund Meier, Claudia Pföhler, Michael Weichenthal, Patrick Terheyden, Andrea Forschner, Ulrike Leiter, Jens Ulrich, Jochen Utikal, Julia Welzel, Martin Kaatz, Christoffer Gebhardt, Rudolf Herbst, Anca Sindrilaru, Edgar Dippel, Michael Sachse, Frank Meiss, Lucie HeinzerlingSebastian Haferkamp, Carsten Weishaupt, Harald Löffler, Sophia Kreft, Klaus Griewank, Elisabeth Livingstone, Dirk Schadendorf, Selma Ugurel, Lisa Zimmer

*Korrespondierende/r Autor/-in für diese Arbeit
1 Zitat (Scopus)


Background: Melanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown. Patients and methods: Advanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan–Meier approach. Results: Among 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS-mutated (NRASmut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33–47] in NRASmut patients and 41% [95% CI, 35–48] in NRAS-wild type (NRASwt) patients; 2-year OS was 54% [95% CI, 48–61] in NRASmut patients and 57% [95% CI, 50–64] in NRASwt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44–66] in NRASmut patients and 53% [95% CI, 41–67] in NRASwt patients; 2-year OS was 58% [95% CI, 49–70] in NRASmut patients and 62% [95% CI, 51–75] in NRASwt patients). The ORR to anti-PD1 was 35% for NRASwt patients and 26% for NRASmut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (> 5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients. Conclusions: The PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRASwt and NRASmut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status.

ZeitschriftEuropean Journal of Cancer
Seiten (von - bis)140-151
PublikationsstatusVeröffentlicht - 07.2023

Strategische Forschungsbereiche und Zentren

  • Profilbereich: Lübeck Integrated Oncology Network (LION)
  • Zentren: Universitäres Cancer Center Schleswig-Holstein (UCCSH)


  • 205-19 Dermatologie
  • 205-14 Hämatologie, Onkologie