Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants

Cancers

卷:13

Remco van Doorn¹  Ellen Kapiteijn²  Hildur Helgadottir³  Bruna Dalmasso⁴  Paola Ghiorzo⁴  Francesco Spagnolo⁵  Enrica Tanda⁵  Miriam Potrony⁶  Susana Puig⁶  Paola Queirolo⁷ 

[1] Department of Dermatology, Leiden University Medical Center, 2333 Leiden, The Netherlands;

[2] Department of Medical Oncology, Leiden University Medical Center, 2333 Leiden, The Netherlands;

[3] Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital Solna, 171 64 Stockholm, Sweden;

[4] IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy;

[5] Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;

[6] Melanoma Unit, Dermatology Department, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08007 Barcelona, Spain;

[7] Melanoma, Sarcoma & Rare Tumors Division, European Institute of Oncology (IEO), 20141 Milan, Italy;

关键词: melanoma;    CDKN2A;    targeted therapy;    BRAF inhibitors;    MEK inhibitors;    genetic counseling;   

DOI  :  10.3390/cancers13102440

来源: DOAJ

【 摘 要 】

Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/−MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/−MEKi with an expected rate derived from phase III trials and “real-world” studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (p-value = 0.143; 95% CI = 0.60–0.97); the difference was statistically significant (p-value = 0.019; 95% CI = 0.62–0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/−MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.

【 授权许可】

Unknown