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, Anne ; Mohr, Peter ; Gutzmer, Ralf ; Meier, Friedegund

; Pföhler, Claudia ; Weichenthal, Michael ; Terheyden, Patrick ; Forschner, Andrea ; Leiter, Ulrike ; Ulrich, Jens ; Utikal, Jochen ; Welzel, Julia ; Kaatz, Martin ; Gebhardt, Christoffer

; Herbst, Rudolf ; Sindrilaru, Anca ; Dippel, Edgar ; Sachse, Michael ; Meiss, Frank

; Heinzerling, Lucie ; Haferkamp, Sebastian ; Weishaupt, Carsten ; Löffler, Harald ; Kreft, Sophia ; Griewank, Klaus ; Livingstone, Elisabeth ; Schadendorf, Dirk ; Ugurel, Selma ; Zimmer, Lisa

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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 muta-tional status and programmed cell death ligand-1 (PD-L1) expression in melanoma is un-known.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 pa-tients 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 & GE; 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. & COPY; 2023 Elsevier Ltd. All rights reserved.

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