TY - JOUR
TI - Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials
AU - Schadendorf, D.
AU - Long, G.V.
AU - Stroiakovski, D.
AU - Karaszewska, B.
AU - Hauschild, A.
AU - Levchenko, E.
AU - Chiarion-Sileni, V.
AU - Schachter, J.
AU - Garbe, C.
AU - Dutriaux, C.
AU - Gogas, H.
AU - Mandalà, M.
AU - Haanen, J.B.A.G.
AU - Lebbé, C.
AU - Mackiewicz, A.
AU - Rutkowski, P.
AU - Grob, J.-J.
AU - Nathan, P.
AU - Ribas, A.
AU - Davies, M.A.
AU - Zhang, Y.
AU - Kaper, M.
AU - Mookerjee, B.
AU - Legos, J.J.
AU - Flaherty, K.T.
AU - Robert, C.
JO - EUROPEAN JOURNAL OF CANCER
PY - 2017
VL - 82
TODO - null
SP - 45-55
PB - Elsevier Ireland Ltd
SN - null
TODO - 10.1016/j.ejca.2017.05.033
TODO - dabrafenib;  lactate dehydrogenase;  trametinib;  antineoplastic agent;  dabrafenib;  imidazole derivative;  lactate dehydrogenase;  oxime;  protein kinase inhibitor;  pyridone derivative;  pyrimidinone derivative;  trametinib, Article;  cancer survival;  clinical outcome;  follow up;  human;  intention to treat analysis;  metastatic melanoma;  overall survival;  phase 3 clinical trial (topic);  prediction;  priority journal;  progression free survival;  randomized controlled trial (topic);  retrospective study;  treatment duration;  adult;  aged;  clinical trial;  controlled study;  female;  male;  melanoma;  metabolism;  metastasis;  middle aged;  pathology;  phase 3 clinical trial;  predictive value;  prognosis;  randomized controlled trial;  risk factor;  survival analysis, Adult;  Aged;  Antineoplastic Combined Chemotherapy Protocols;  Female;  Humans;  Imidazoles;  L-Lactate Dehydrogenase;  Male;  Melanoma;  Middle Aged;  Neoplasm Metastasis;  Oximes;  Predictive Value of Tests;  Prognosis;  Protein Kinase Inhibitors;  Pyridones;  Pyrimidinones;  Risk Factors;  Survival Analysis
TODO - Aim Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)–randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit. Methods Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables. Results Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months. Conclusion Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses. © 2017 Elsevier Ltd
ER -