Factors associated with disease progression in patients treated with trametinib in combination with dabrafenib for unresectable advanced BRAFV600-mutant melanoma: An open label, non randomized study

Background BRAF and MEK inhibitors dabrafenib (D) and trametinib (T) have transformed BRAFV600-mutant melanoma patients’ (pts) treatment. In a large prospective trial of pts treated with combination D+T, which also included pts with brain metastasis (BM), we assessed factors associated with progression and stratified the population into risk groups using regression tree analysis (RTA). Methods This phase IIIb single arm, open label, multicenter, French study included in 40 centers pts with histologically confirmed unresectable stage IIIc or IV BRAFV600-mutant melanoma. Selection criteria allowed presence of BM, ECOG ≤2, previous advanced melanoma treatments (except BRAFi+MEKi combination). Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modeled with multivariate Cox regression model. Risk subgroups were identified using an exponential RTA. Significance was set at p Results Between March 2015 and November 2016, 914 pts were screened and 856 received at least 1 dose of D+T. Overall, 92% of pts had AJCC stage IV melanoma, 38% ECOG ≥1 and 32% BM. Among the 587 pts with known LDH at baseline, 38% had >ULN. Median PFS was 8.02 months (95%CI, 7.33-8.77). Significant independent factors associated with lower PFS were ECOG ≥1, elevated serum LDH, ≥3 metastatic sites, and presence of BM (Table). Pts with Table . 1338P Multivariate Cox proportional hazards analysis of PFS by prognostic factors - All Subjects Treated Population (N = 856) N (%) HR 95% CI p value LDH at baseline * 366 (42.8) 1 (=reference) - - [1 - 2[ ULN 160 (18.7) 1.64 [1.26 - 2.14] 0.0003 ≥2 ULN 61 (7.1) 2.45 [1.70 - 3.53] Missing 269 (31.4) 1.34 [1.05 - 1.71] 0.0167 ECOG * 0 531 (62.0) 1 (=reference) - - 1 242 (28.3) 1.49 [1.19 - 1.87] 0.0005 ≥2 83 (9.7) 2.32 [1.69 - 3.19] Metastatic sites * 344 (40.2) 1 (=reference) - - ≥3 445 (52.0) 1.61 [1.28 - 2.02] Missing 67 (7.8) 1.05 [0.63 - 1.74] 0.8494 Presence of brain metastasis * No 579 (67.6) 1 (=reference) - - Yes 275 (32.1) 1.38 [1.11 - 1.71] 0.0043 Missing 2 (0.23) - - - * Factors included in the RTA. Conclusions This is to date the largest prospective study in advanced BRAFV600-mutant melanoma pts treated with D+T. The study was carried out in conditions close to the real-world. We confirm findings of registration trials that LDH, ECOG and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor. Editorial acknowledgement Jone Iriondo-Alberdi (PhD) from ITEC Services. Legal entity responsible for the study Novartis Pharma S.A.S. (France). Funding Novartis Pharma S.A.S. (France). Disclosure P. Saiag: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bristol-Myers Squibb; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Sharp & Dohme ; Travel / Accommodation / Expenses: Merck Serono; Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche-Genentech; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Novartis. C. Robert: Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme ; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Participation to Boards and Steering Committees: Pierre Fabre. J.J. Grob: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Incyte. L. Mortier: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: GSK/Novartis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Leo; Honoraria (self): Merck Serono; Honoraria (self): Sanofi; Honoraria (self): Pierre Fabre; Honoraria (self): Novartis. C. Lebbe: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Amgen; Honoraria (self): Merck; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Incyte. S. Mansard: Advisory / Consultancy: Novartis. F. Grange: Advisory / Consultancy: Novartis. E. Neidhardt: Travel / Accommodation / Expenses: BMS. T. Lesimple: Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy: Incyte; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (self): Roche. C. Bedane: Advisory / Consultancy: Novartis. S. Dalac-Rat: Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pierre Fabre. C. Nardin: Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD. A. Szenik: Full / Part-time employment: Novartis. A. Denden: Full / Part-time employment: Novartis. C. Dutriaux: Honoraria (self), Advisory / Consultancy: Novartis. All other authors have declared no conflicts of interest.