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

Zaremba A, Mohr P, Gutzmer R, Meier F, Pföhler C, Weichenthal M, Terheyden P, Forschner A, Leiter U, Ulrich J, Utikal J, Welzel J, Kaatz M, Gebhardt C, Herbst R, Sindrilaru A, Dippel E, Sachse M, Meiss F, Heinzerling L, Haferkamp S, Weishaupt C, Löffler H, Kreft S, Griewank K, Livingstone E, Schadendorf D, Ugurel S, Zimmer L (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 188

Pages Range: 140-151

DOI: 10.1016/j.ejca.2023.04.008

Abstract

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.

Involved external institutions

Universitätsklinikum Essen Germany (DE) Elbe Kliniken Stade-Buxtehude Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Universität des Saarlandes (UdS) Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Universität zu Lübeck Germany (DE) Universitätsklinikum Tübingen Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Universitätsklinikum Augsburg Germany (DE) SRH Wald-Klinikum Gera Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) HELIOS Kliniken Germany (DE) Universitätsklinikum Ulm Germany (DE) Klinikum der Stadt Ludwigshafen am Rhein gGmbH Germany (DE) Klinikum Bremerhaven-Reinkenheide Germany (DE) Universitätsklinikum Freiburg Germany (DE) Klinikum der Universität München Germany (DE) Universitätsklinikum Regensburg Germany (DE) Universitätsklinikum Münster Germany (DE) SLK-Kliniken Heilbronn GmbH Germany (DE)

How to cite

APA:

Zaremba, A., Mohr, P., Gutzmer, R., Meier, F., Pföhler, C., Weichenthal, M.,... Zimmer, L. (2023). 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. European Journal of Cancer, 188, 140-151. https://doi.org/10.1016/j.ejca.2023.04.008

MLA:

Zaremba, Anne, et al. "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." European Journal of Cancer 188 (2023): 140-151.

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