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

Autor: Schadendorf D; Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany; German Cancer Consortium, 69117 Heidelberg, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de., Long GV; Melanoma Institute Australia, The University of Sydney, NSW, Australia; Mater Hospital, North Sydney, NSW, Australia; Royal North Shore Hospital, St Leonards, NSW, Australia., Stroiakovski D; Moscow City Oncology Hospital No 62, Moscow 143423, Russia., Karaszewska B; Przychodnia Lekarska KOMED, Wojska Polskiego 6, 62-500 Konin, Poland., Hauschild A; Department of Dermatology, University Medical Center Schleswig-Holstein, Arnold-Heller-Straße 3, 24105 Kiel, Germany., Levchenko E; Petrov Research Institute of Oncology, 68 Leningradskaya Street, Saint Petersburg 197758, Russia., Chiarion-Sileni V; Melanoma and Esophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Via Gattamelata 64, 35128 Padova, Italy., Schachter J; Oncology Division, Sheba Medical Center, Tel HaShomer, Emek HaEla St 1, Ramat Gan, Israel., Garbe C; Department of Dermatology, University of Tübingen, Geschwister-Scholl-Platz, 72074 Tübingen, Germany., Dutriaux C; Service de Dermatologie et Dermatologie Pédiatrique, Hôpital Saint-André, 1 Rue Jean Burguet, 33000 Bordeaux, France., Gogas H; First Department of Medicine, 'Laiko' General Hospital, National and Kapodistrian University of Athens, Athens 157 72, Greece., Mandalà M; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy., Haanen JBAG; Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Lebbé C; APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France., Mackiewicz A; Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary Street, 61-866 Poznań, Poland., Rutkowski P; Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Wawelska 15B, 02-034 Warsaw, Poland., Grob JJ; Department of Dermatology, University Hospital Center, Timone Hospital, Aix Marseille University, 264 Rue St Pierre, 13885 Marseille Cedex 05, France., Nathan P; Mount Vernon Cancer Centre, Rickmansworth Road, HA6 2RN Northwood, UK., Ribas A; Department of Medicine, Hematology/Oncology, UCLA Medical Center, 100 UCLA Medical Plaza, Suite 550, Los Angeles, CA, USA., Davies MA; Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, TX, USA., Zhang Y; Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover 07936, NJ, USA., Kaper M; Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover 07936, NJ, USA., Mookerjee B; Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover 07936, NJ, USA., Legos JJ; Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover 07936, NJ, USA., Flaherty KT; Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston 02114, MA, USA., Robert C; Department of Medical Oncology, Dermatology Service, Gustave Roussy Comprehensive Cancer Center and Faculty of Medicine, University Paris-South, F-94805, Villejuif, France.
Jazyk: angličtina
Zdroj: European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2017 Sep; Vol. 82, pp. 45-55. Date of Electronic Publication: 2017 Jun 22.
DOI: 10.1016/j.ejca.2017.05.033
Abstrakt: 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.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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