BRAF and NRAS Mutation Status and Response to Checkpoint Inhibition in Advanced Melanoma

Olivier J van Not; Willeke A M Blokx; Alfons J M van den Eertwegh; Melissa M de Meza; John B Haanen; Christian U Blank; Maureen J B Aarts; Franchette W P J van den Berkmortel; Jan Willem B de Groot; Geke A P Hospers; Ellen Kapiteijn; Djura Piersma; Rozemarijn S van Rijn; Marion Stevense-den Boer; Astrid A M van der Veldt; Marye J Boers-Sonderen; Anne M L Jansen; Michel W J M Wouters; Karijn P M Suijkerbuijk

doi:10.1200/PO.22.00018

BRAF and NRAS Mutation Status and Response to Checkpoint Inhibition in Advanced Melanoma

Olivier J van Not
, Willeke A M Blokx
, Alfons J M van den Eertwegh
, Melissa M de Meza
, John B Haanen
, Christian U Blank
, Maureen J B Aarts
, Franchette W P J van den Berkmortel
, Jan Willem B de Groot
, Geke A P Hospers
, Ellen Kapiteijn
, Djura Piersma
, Rozemarijn S van Rijn
, Marion Stevense-den Boer
, Astrid A M van der Veldt
, Marye J Boers-Sonderen
, Anne M L Jansen
, Michel W J M Wouters
, Karijn P M Suijkerbuijk

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

PURPOSE: Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma.

MATERIALS AND METHODS: All patients with advanced melanoma treated with first-line anti-PD-1 or ipilimumab-nivolumab between 2012 and 2021 in the nationwide Dutch Melanoma Treatment Registry were included in this cohort study. Objective response rate, progression-free survival (PFS), and overall survival (OS) were analyzed according to BRAF and NRAS status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS.

RESULTS: In total, 1764 patients received anti-PD-1 and 759 received ipilimumab-nivolumab. No significant differences in PFS were found in the anti-PD-1 cohort. In the ipilimumab-nivolumab cohort, median PFS was significantly higher for BRAF-mutant melanoma (9.9 months; 95% CI, 6.8 to 17.2) compared with NRAS-mutant (4.8 months; 95% CI, 3.0 to 7.5) and double wild-type (5.3 months; 95% CI, 3.6 to 7.1). In multivariable analysis, BRAF-mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for BRAF-mutant melanoma compared with NRAS-mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens.

CONCLUSION: Ipilimumab-nivolumab-treated patients with BRAF-mutant melanoma display improved PFS and OS compared with patients with NRAS-mutant and double wild-type melanoma. BRAF mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma.

Original language	English
Article number	e2200018
Journal	JCO Precision Oncology
Volume	6
DOIs	https://doi.org/10.1200/PO.22.00018
Publication status	Published - Sept 2022

Keywords

Cohort Studies
GTP Phosphohydrolases/genetics
Humans
Immune Checkpoint Inhibitors/pharmacology
Ipilimumab/therapeutic use
Melanoma/drug therapy
Membrane Proteins/genetics
Mutation
Nivolumab/therapeutic use
Proto-Oncogene Proteins B-raf/genetics

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10.1200/PO.22.00018

po.22.00018Final published version, 433 KBLicence: Taverne

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van Not, O. J., Blokx, W. A. M., van den Eertwegh, A. J. M., de Meza, M. M., Haanen, J. B., Blank, C. U., Aarts, M. J. B., van den Berkmortel, F. W. P. J., de Groot, J. W. B., Hospers, G. A. P., Kapiteijn, E., Piersma, D., van Rijn, R. S., Stevense-den Boer, M., van der Veldt, A. A. M., Boers-Sonderen, M. J., Jansen, A. M. L., Wouters, M. W. J. M., & Suijkerbuijk, K. P. M. (2022). BRAF and NRAS Mutation Status and Response to Checkpoint Inhibition in Advanced Melanoma. JCO Precision Oncology, 6, Article e2200018. https://doi.org/10.1200/PO.22.00018

@article{6823bc1a15b143c5a93109db546befd9,

title = "BRAF and NRAS Mutation Status and Response to Checkpoint Inhibition in Advanced Melanoma",

abstract = "PURPOSE: Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma.MATERIALS AND METHODS: All patients with advanced melanoma treated with first-line anti-PD-1 or ipilimumab-nivolumab between 2012 and 2021 in the nationwide Dutch Melanoma Treatment Registry were included in this cohort study. Objective response rate, progression-free survival (PFS), and overall survival (OS) were analyzed according to BRAF and NRAS status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS. RESULTS: In total, 1764 patients received anti-PD-1 and 759 received ipilimumab-nivolumab. No significant differences in PFS were found in the anti-PD-1 cohort. In the ipilimumab-nivolumab cohort, median PFS was significantly higher for BRAF-mutant melanoma (9.9 months; 95\% CI, 6.8 to 17.2) compared with NRAS-mutant (4.8 months; 95\% CI, 3.0 to 7.5) and double wild-type (5.3 months; 95\% CI, 3.6 to 7.1). In multivariable analysis, BRAF-mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for BRAF-mutant melanoma compared with NRAS-mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens. CONCLUSION: Ipilimumab-nivolumab-treated patients with BRAF-mutant melanoma display improved PFS and OS compared with patients with NRAS-mutant and double wild-type melanoma. BRAF mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma. ",

keywords = "Cohort Studies, GTP Phosphohydrolases/genetics, Humans, Immune Checkpoint Inhibitors/pharmacology, Ipilimumab/therapeutic use, Melanoma/drug therapy, Membrane Proteins/genetics, Mutation, Nivolumab/therapeutic use, Proto-Oncogene Proteins B-raf/genetics",

author = "\{van Not\}, \{Olivier J\} and Blokx, \{Willeke A M\} and \{van den Eertwegh\}, \{Alfons J M\} and \{de Meza\}, \{Melissa M\} and Haanen, \{John B\} and Blank, \{Christian U\} and Aarts, \{Maureen J B\} and \{van den Berkmortel\}, \{Franchette W P J\} and \{de Groot\}, \{Jan Willem B\} and Hospers, \{Geke A P\} and Ellen Kapiteijn and Djura Piersma and \{van Rijn\}, \{Rozemarijn S\} and \{Stevense-den Boer\}, Marion and \{van der Veldt\}, \{Astrid A M\} and Boers-Sonderen, \{Marye J\} and Jansen, \{Anne M L\} and Wouters, \{Michel W J M\} and Suijkerbuijk, \{Karijn P M\}",

year = "2022",

month = sep,

doi = "10.1200/PO.22.00018",

language = "English",

volume = "6",

journal = "JCO Precision Oncology",

publisher = "Lippincott Williams \& Wilkins",

}

van Not, OJ, Blokx, WAM, van den Eertwegh, AJM, de Meza, MM, Haanen, JB, Blank, CU, Aarts, MJB, van den Berkmortel, FWPJ, de Groot, JWB, Hospers, GAP, Kapiteijn, E, Piersma, D, van Rijn, RS, Stevense-den Boer, M, van der Veldt, AAM, Boers-Sonderen, MJ, Jansen, AML, Wouters, MWJM & Suijkerbuijk, KPM 2022, 'BRAF and NRAS Mutation Status and Response to Checkpoint Inhibition in Advanced Melanoma', JCO Precision Oncology, vol. 6, e2200018. https://doi.org/10.1200/PO.22.00018

TY - JOUR

T1 - BRAF and NRAS Mutation Status and Response to Checkpoint Inhibition in Advanced Melanoma

AU - van Not, Olivier J

AU - Blokx, Willeke A M

AU - van den Eertwegh, Alfons J M

AU - de Meza, Melissa M

AU - Haanen, John B

AU - Blank, Christian U

AU - Aarts, Maureen J B

AU - van den Berkmortel, Franchette W P J

AU - de Groot, Jan Willem B

AU - Hospers, Geke A P

AU - Kapiteijn, Ellen

AU - Piersma, Djura

AU - van Rijn, Rozemarijn S

AU - Stevense-den Boer, Marion

AU - van der Veldt, Astrid A M

AU - Boers-Sonderen, Marye J

AU - Jansen, Anne M L

AU - Wouters, Michel W J M

AU - Suijkerbuijk, Karijn P M

PY - 2022/9

Y1 - 2022/9

N2 - PURPOSE: Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma.MATERIALS AND METHODS: All patients with advanced melanoma treated with first-line anti-PD-1 or ipilimumab-nivolumab between 2012 and 2021 in the nationwide Dutch Melanoma Treatment Registry were included in this cohort study. Objective response rate, progression-free survival (PFS), and overall survival (OS) were analyzed according to BRAF and NRAS status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS. RESULTS: In total, 1764 patients received anti-PD-1 and 759 received ipilimumab-nivolumab. No significant differences in PFS were found in the anti-PD-1 cohort. In the ipilimumab-nivolumab cohort, median PFS was significantly higher for BRAF-mutant melanoma (9.9 months; 95% CI, 6.8 to 17.2) compared with NRAS-mutant (4.8 months; 95% CI, 3.0 to 7.5) and double wild-type (5.3 months; 95% CI, 3.6 to 7.1). In multivariable analysis, BRAF-mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for BRAF-mutant melanoma compared with NRAS-mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens. CONCLUSION: Ipilimumab-nivolumab-treated patients with BRAF-mutant melanoma display improved PFS and OS compared with patients with NRAS-mutant and double wild-type melanoma. BRAF mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma.

AB - PURPOSE: Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma.MATERIALS AND METHODS: All patients with advanced melanoma treated with first-line anti-PD-1 or ipilimumab-nivolumab between 2012 and 2021 in the nationwide Dutch Melanoma Treatment Registry were included in this cohort study. Objective response rate, progression-free survival (PFS), and overall survival (OS) were analyzed according to BRAF and NRAS status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS. RESULTS: In total, 1764 patients received anti-PD-1 and 759 received ipilimumab-nivolumab. No significant differences in PFS were found in the anti-PD-1 cohort. In the ipilimumab-nivolumab cohort, median PFS was significantly higher for BRAF-mutant melanoma (9.9 months; 95% CI, 6.8 to 17.2) compared with NRAS-mutant (4.8 months; 95% CI, 3.0 to 7.5) and double wild-type (5.3 months; 95% CI, 3.6 to 7.1). In multivariable analysis, BRAF-mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for BRAF-mutant melanoma compared with NRAS-mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens. CONCLUSION: Ipilimumab-nivolumab-treated patients with BRAF-mutant melanoma display improved PFS and OS compared with patients with NRAS-mutant and double wild-type melanoma. BRAF mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma.

KW - Cohort Studies

KW - GTP Phosphohydrolases/genetics

KW - Humans

KW - Immune Checkpoint Inhibitors/pharmacology

KW - Ipilimumab/therapeutic use

KW - Melanoma/drug therapy

KW - Membrane Proteins/genetics

KW - Mutation

KW - Nivolumab/therapeutic use

KW - Proto-Oncogene Proteins B-raf/genetics

U2 - 10.1200/PO.22.00018

DO - 10.1200/PO.22.00018

M3 - Article

C2 - 36130145

VL - 6

JO - JCO Precision Oncology

JF - JCO Precision Oncology

M1 - e2200018

ER -

BRAF and NRAS Mutation Status and Response to Checkpoint Inhibition in Advanced Melanoma

Abstract

Keywords

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