Non-V600E/K BRAF Mutations in Metastatic Melanoma: Molecular Description, Frequency, and Effectiveness of Targeted Therapy in a Large National Cohort

Author:

Girod Manon1,Dalle Stéphane2,Mortier Laurent3,Dalac Sophie4,Leccia Marie-Thèrèse5,Dutriaux Caroline6,Montaudié Henri7ORCID,de Quatrebarbes Julie8,Lesimple Thierry9ORCID,Brunet-Possenti Florence10ORCID,Saiag Philippe11,Maubec Eve12ORCID,Legoupil Delphine13,Stoebner Pierre-Emmanuel14,Arnault Jean Philippe15ORCID,Lefevre Wendy16,Lebbe Celeste17ORCID,Dereure Olivier118ORCID

Affiliation:

1. Department of Dermatology, University of Montpellier, Montpellier, France

2. Department of Dermatology, Service de dermatologie, Hôpital Lyon Sud, Centre de recherche en cancérologie de Lyon, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, Lyon, France

3. Department of Dermatology, Hôpital Huriez, Lille, France

4. Department of Dermatology, Hôpital du bocage, Dijon, France

5. Department of Dermatology, Hôpital La Tronche, Grenoble, France

6. Department of Dermatology, Centre Hospitalier Universitaire, Bordeaux, France

7. Department of Dermatology, University Hospital of Nice, Université Côte d'Azur and INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, Nice, France

8. Department of Dermatology, Centre Hospitalier Annecy, Annecy, France

9. Department of Medical Oncology, Centre Régional de Lutte contre le Cancer Eugène Marquis, Rennes, France

10. Department of Dermatology, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France

11. Department of General and Oncologic Dermatology, Ambroise-Paré Hospital, APHP & EA3440 "Biomarkers in Cancerology and Hemato-Oncology”, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France

12. Department of Dermatology, Hôpital Avicenne, Bobigny, France

13. Department of Dermatology, Centre Hospitalier Universitaire, Brest, France

14. Department of Dermatology, Hôpital Carremeau, Nimes, France

15. Department of Dermatology, Centre Hospitalier Universitaire, Amiens, France

16. Department of Dermatology, MelBase, Hôpital Saint-Louis, Paris, France

17. Department of Dermatology, DMU ICARE, AP-HP Hôpital Saint Louis and INSERM U976, Université de Paris, Paris, France

18. INSERM U1058 Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, Montpellier, France

Abstract

PURPOSE Mitogen-activating protein kinase inhibitors (MAPKis) are largely used in V600E/K BRAF–mutated metastatic melanomas, but data regarding effectiveness of targeted therapy in patients with rare BRAF mutations and molecular description of these infrequent mutations are scarce. PATIENTS AND METHODS A multicenter study was conducted on patients with metastatic melanoma harboring a well-identified mutation of BRAF and enrolled from March 2013 to June 2021 in the French nationwide prospective cohort MelBase. The molecular BRAF mutation pattern, response to MAPKis when applicable, and survival data were analyzed. RESULTS Of 856 selected patients, 51 (6%) harbored a non-V600E/K BRAF mutation involving codons V600 (24 of 51, 47%; V600G 27.4%, V600R 15.6%), K601 (6 of 51, 11.7%), and L597 (4 of 51, 7.8%). An objective response to MAPKis either BRAF inhibitor (BRAFi) alone or combined with MEK inhibitor was achieved in 56% (353 of 631) of V600E/K, 58% (11 of 19) of non-E/K V600, and 22% (2 of 9) of non-V600 BRAF-mutated patients, with a median progression-free survival of 7.7, 7.8, and 2.8 months, respectively. Overall, objective response rate was higher with BRAFi + MEK inhibitor combination than with BRAFi in monotherapy for each subset. CONCLUSION Rare BRAF mutations are not anecdotal in the metastatic melanoma population. Although data interpretation must remain careful owing to the limited size of some subsets of patients, non-E/K V600 BRAF mutations seem to confer a high sensitivity to targeted therapy, whereas MAPKis seem less effective in patients with non-V600 BRAF mutations. However, this strategy may be used as an alternative option in the case of immunotherapy failure in the latter population.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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