Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials

Publication date: September 2017
Source:European Journal of Cancer, Volume 82
Author(s): Dirk Schadendorf, Georgina V. Long, Daniil Stroiakovski, Boguslawa Karaszewska, Axel Hauschild, Evgeny Levchenko, Vanna Chiarion-Sileni, Jacob Schachter, Claus Garbe, Caroline Dutriaux, Helen Gogas, Mario Mandalà, John B.A.G. Haanen, Céleste Lebbé, Andrzej Mackiewicz, Piotr Rutkowski, Jean-Jacques Grob, Paul Nathan, Antoni Ribas, Michael A. Davies, Ying Zhang, Mathilde Kaper, Bijoyesh Mookerjee, Jeffrey J. Legos, Keith T. Flaherty, Caroline Robert
AimUnderstanding 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.MethodsThree-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.ResultsLong-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.ConclusionUsing 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.



http://ift.tt/2rGXvVX