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

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. DaviesYing Zhang, Mathilde Kaper, Bijoyesh Mookerjee, Jeffrey J. Legos, Keith T. Flaherty, Caroline Robert

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)45-55
Number of pages11
JournalEuropean Journal of Cancer
Volume82
DOIs
Publication statusPublished - Sep 1 2017

Keywords

  • Dabrafenib
  • Melanoma
  • Multivariate analysis
  • Trametinib
  • Vemurafenib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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