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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

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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.

In: EUR J CANCER, Vol. 188, 07.2023, p. 140-151.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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, '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', EUR J CANCER, vol. 188, pp. 140-151. https://doi.org/10.1016/j.ejca.2023.04.008

APA

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., ... 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. EUR J CANCER, 188, 140-151. https://doi.org/10.1016/j.ejca.2023.04.008

Vancouver

Zaremba A, Mohr P, Gutzmer R, Meier F, Pföhler C, Weichenthal M 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. EUR J CANCER. 2023 Jul;188:140-151. https://doi.org/10.1016/j.ejca.2023.04.008

Bibtex

@article{a829742293c446358b8385763ea37c32,
title = "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",
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.",
keywords = "Humans, Immune Checkpoint Inhibitors/therapeutic use, Proto-Oncogene Proteins B-raf/genetics, B7-H1 Antigen, Prospective Studies, Melanoma/drug therapy, Skin Neoplasms/drug therapy, Retrospective Studies, Registries, Membrane Proteins/genetics, GTP Phosphohydrolases/genetics",
author = "Anne Zaremba and Peter Mohr and Ralf Gutzmer and Friedegund Meier and Claudia Pf{\"o}hler and Michael Weichenthal and Patrick Terheyden and Andrea Forschner and Ulrike Leiter and Jens Ulrich and Jochen Utikal and Julia Welzel and Martin Kaatz and Christoffer Gebhardt and Rudolf Herbst and Anca Sindrilaru and Edgar Dippel and Michael Sachse and Frank Meiss and Lucie Heinzerling and Sebastian Haferkamp and Carsten Weishaupt and Harald L{\"o}ffler and Sophia Kreft and Klaus Griewank and Elisabeth Livingstone and Dirk Schadendorf and Selma Ugurel and Lisa Zimmer",
note = "Copyright {\textcopyright} 2023 Elsevier Ltd. All rights reserved.",
year = "2023",
month = jul,
doi = "10.1016/j.ejca.2023.04.008",
language = "English",
volume = "188",
pages = "140--151",
journal = "EUR J CANCER",
issn = "0959-8049",
publisher = "Elsevier Limited",

}

RIS

TY - JOUR

T1 - 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

AU - Zaremba, Anne

AU - Mohr, Peter

AU - Gutzmer, Ralf

AU - Meier, Friedegund

AU - Pföhler, Claudia

AU - Weichenthal, Michael

AU - Terheyden, Patrick

AU - Forschner, Andrea

AU - Leiter, Ulrike

AU - Ulrich, Jens

AU - Utikal, Jochen

AU - Welzel, Julia

AU - Kaatz, Martin

AU - Gebhardt, Christoffer

AU - Herbst, Rudolf

AU - Sindrilaru, Anca

AU - Dippel, Edgar

AU - Sachse, Michael

AU - Meiss, Frank

AU - Heinzerling, Lucie

AU - Haferkamp, Sebastian

AU - Weishaupt, Carsten

AU - Löffler, Harald

AU - Kreft, Sophia

AU - Griewank, Klaus

AU - Livingstone, Elisabeth

AU - Schadendorf, Dirk

AU - Ugurel, Selma

AU - Zimmer, Lisa

N1 - Copyright © 2023 Elsevier Ltd. All rights reserved.

PY - 2023/7

Y1 - 2023/7

N2 - 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.

AB - 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.

KW - Humans

KW - Immune Checkpoint Inhibitors/therapeutic use

KW - Proto-Oncogene Proteins B-raf/genetics

KW - B7-H1 Antigen

KW - Prospective Studies

KW - Melanoma/drug therapy

KW - Skin Neoplasms/drug therapy

KW - Retrospective Studies

KW - Registries

KW - Membrane Proteins/genetics

KW - GTP Phosphohydrolases/genetics

U2 - 10.1016/j.ejca.2023.04.008

DO - 10.1016/j.ejca.2023.04.008

M3 - SCORING: Journal article

C2 - 37245442

VL - 188

SP - 140

EP - 151

JO - EUR J CANCER

JF - EUR J CANCER

SN - 0959-8049

ER -