Regimens combining BRAF and MEK inhibitors have revolutionized the treatment of patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant cutaneous melanoma. As only dabrafenib (D) was available in France, the objective of this study was to provide access to T and to assess, in the French population, the benefits of the combination of T (D+T) previously reported.
This single arm, open label, multicenter, non-randomized study included patients with histologically confirmed stage III unresectable or IV BRAF V600-mutant melanoma, with or without brain metastases (BM). Patients received D (150 mg twice/day) combined with T (2 mg once/day). Outcomes were overall response rate (ORR), progression-free survival (PFS), and frequencies of adverse events (AEs). Median PFS was estimated using the Kaplan-Meier method.
Between March 2015 and November 2016, 914 patients were screened in 40 French centers and 856 received at least one dose of D+T. The table presents baseline characteristics. Median followup was 5.63 months. ORR was 50.2% in the overall population and 41.5% in patients with BM. Median PFS was 8.02 months (95% CI, [7.33-8.77]) in the overall population and 5.68 months (95% CI, [5.29-6.87]) in patients with BM. The safety profile was consistent with previous reports. Among AEs of special interest, pyrexia/hyperthermia was the most frequent: 38.2% (327/856) all grades; grade (G) 1 29.0%, G2 14.8%, G3 4.0% and G4 0.5%.Table: 1260P
Baseline demographic and disease characteristics
|Parameter||Statistics||Total (N = 856)|
|Age at screening (years)||Mean (SD)||58.5 (14.8)|
|Male||n (%)||474 (55.4)|
|Female||n (%)||382 (44.6)|
|ECOG PS scale at screening|
|0||n (%)||531 (62.0)|
|1||n (%)||242 (28.3)|
|2||n (%)||69 (8.1)|
|3||n (%)||13 (1.5)|
|4||n (%)||1 (0.1)|
|Stage at screening|
|II||n (%)||1 (0.1)|
|III unresectable||n (%)||67 (7.8)|
|IV||n (%)||788 (92.1)|
|TNM staging at screening (M) a|
|M0||n (%)||68 (8.0)|
|M1a||n (%)||81 (9.5)|
|M1b||n (%)||88 (10.3)|
|M1c||n (%)||617 (72.2)|
|If M1c, brain metastasis b|
|No||n (%)||342 (55.4)|
|Yes||n (%)||275 (44.6)|
|Type of BRAF mutation|
|E||n (%)||727 (84.9)|
|K||n (%)||93 (10.9)|
|Other||n (%)||36 (4.2)|
|LDH (IU/L) c||Mean (SD)||377.2 (464.8)|
|LDH (IU/L) in classes c|
|≤ 400||n (%)||483 (76.9)|
|]400 ; 800]||n (%)||100 (15.9)|
|>800||n (%)||45 (7.2)|
|Sequence of dabrafenib and trametinib|
|1st sequence: patient with no prior systemic anti-cancer treatment||n (%)||449 (52.5)|
|2nd sequence: patient with one prior systemic anti-cancer treatment||n (%)||260 (30.4)|
|3rd sequence: patient with two prior systemic anti-cancer treatments||n (%)||88 (10.3)|
|>3rd sequence: patient with three or more prior systemic anti-cancer treatments||n (%)||59 (6.9)|
Abbreviations: ECOG= Eastern Cooperative Oncology Group; PS= Performance Status; LDH= Lactate Dehydrogenase; SD= Standard Deviation. Footnotes: a Data was missing for 2 patients b Percentage based on subjects with M1c stage at screening (N = 617) c Based on patients with known LDH at baseline (N = 628)
This is, to date, the largest prospective study worldwide in BRAF V600-mutant cutaneous melanoma patients treated with the D+T combination. It confirms the efficacy and tolerability of D+T in this population, including pts with BM.
Clinical trial identification
Legal entity responsible for the study
Novartis Pharma S.A.S. (France) Novartis Pharma S.A.S. (France).
Novartis Pharma S.A.S. (France).
Editorial assistance in the writting of the abstract was provided by Jone Iriondo-Alberdi (PhD) of ITEC Services.
P. Saiag: Advisory board: BMS, MSD, Novartis, GSK, Merck Serono, Roche, Novartis, Pierre Fabre, Amgen. C. Robert: Honoraria, Consulting, Advisory board: Amgen, BMS, Merck, Novartis, Roche, GSK. J.J. Grob: Honoraria: BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer, Incyte; Consulting or advisory role: BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer, Incyte; Research funding (self and institution), Travel, accomodation, expenses: BMS, Roche, MSD. L. Mortier: Honoraria: BMS, MSD, Roche, Novartis, Amgen, Merck, Incyte; Consulting or advisory role: BMS, MSD, Roche, Novartis, Amgen, Merck, Incyte; Travel, accomodations, expenses: BMS, Roche, MSD. C. Lebbe: Honoraria: BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer, Incyte; Consulting or advisory role: BMS; Research funding (self and institution), Travel, accommodation, expenses: BMS, MSD. S. Mansard: Advisory board, Travel expenses: Novartis, BMS, MSD, Roche. E-M. Neidhardt: Advisory board: Novartis, BMS. T. Lesimple: Advisory board: Roche, Novartis, MSD, Incyte. C. Bedane: Advisory board: Novartis; Investigator: Combi I study. A. Szenik, A. Denden: Employee: Novartis. C. Dutriaux: Advisory boards, Investigator: Roche, Amgen, BMS, MSD, Merk Serono, Novartis. All other authors have declared no conflicts of interest.