Abstract 1130P
Background
Inherited pathogenic variants (PV) in the CDKN2A tumour suppressor gene are among the strongest known risk factors for cutaneous melanoma. CDKN2A encodes for the cell cycle inhibitors p16ink4 and p14ARF, and dysregulation of the p16/RB1 pathway is a well-known mechanism of resistance to MAPK-directed targeted therapy due to the interplay between the two pathways. For this reason, we wondered whether patients with germline CDKN2A PVs may achieve suboptimal results with BRAF and MEK inhibitors.
Methods
We identified twenty CDKN2A PVs carriers who received first-line treatment with BRAF and MEK inhibitors for BRAF-mutant advanced melanoma by reviewing medical records of carriers enrolled in follow-up studies for familial melanoma. By a binomial test, we evaluated if there was a statistically significant difference in the response rate observed in the carriers compared with an expected rate calculated from phase III clinical trials and “real-world” studies.
Results
The baseline prognostic features of the 20 identified patients were poorer than those reported in phase III clinical trials, with 12 patients (60%) having stage M1c disease and 5 patients (25%) brain metastases at baseline. Seventeen patients (85%) achieved a partial response; no complete responses were observed. The overall response rate was numerically higher than that expected from phase III trials (66%), although not statistically significant (p-value=0.097; 95% CI: 0.62-0.97); the difference was statistically significant (p-value=0.012; 95% CI: 0.62-0.97) when the comparison was performed with real-world studies.
Conclusions
The clinical activity of BRAF and MEK inhibitors in patients with BRAF-mutant advanced melanoma and germline CDKN2A PVs was not inferior to that observed in clinical trials and real-world studies, which we believe is helpful information for clinicians who manage patients with melanoma.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
F. Spagnolo: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self): Roche; Honoraria (self): BMS; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self): Merck; Honoraria (self), Advisory/Consultancy: Sunpharma; Honoraria (self): Sanofi. P. Queirolo: Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Sunpharma; Honoraria (self), Advisory/Consultancy: Pierre Fabre. All other authors have declared no conflicts of interest.