Dirk Schadendorf1, Georgina V Long2, Daniil Stroiakovski3, Boguslawa Karaszewska4, Axel Hauschild5, Evgeny Levchenko6, Vanna Chiarion-Sileni7, Jacob Schachter8, Claus Garbe9, Caroline Dutriaux10, Helen Gogas11, Mario Mandalà12, John B A G Haanen13, Céleste Lebbé14, Andrzej Mackiewicz15, Piotr Rutkowski16, Jean-Jacques Grob17, Paul Nathan18, Antoni Ribas19, Michael A Davies20, Ying Zhang21, Mathilde Kaper21, Bijoyesh Mookerjee21, Jeffrey J Legos21, Keith T Flaherty22, Caroline Robert23. 1. Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany; German Cancer Consortium, 69117 Heidelberg, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. 2. Melanoma Institute Australia, The University of Sydney, NSW, Australia; Mater Hospital, North Sydney, NSW, Australia; Royal North Shore Hospital, St Leonards, NSW, Australia. 3. Moscow City Oncology Hospital No 62, Moscow 143423, Russia. 4. Przychodnia Lekarska KOMED, Wojska Polskiego 6, 62-500 Konin, Poland. 5. Department of Dermatology, University Medical Center Schleswig-Holstein, Arnold-Heller-Straße 3, 24105 Kiel, Germany. 6. Petrov Research Institute of Oncology, 68 Leningradskaya Street, Saint Petersburg 197758, Russia. 7. Melanoma and Esophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Via Gattamelata 64, 35128 Padova, Italy. 8. Oncology Division, Sheba Medical Center, Tel HaShomer, Emek HaEla St 1, Ramat Gan, Israel. 9. Department of Dermatology, University of Tübingen, Geschwister-Scholl-Platz, 72074 Tübingen, Germany. 10. Service de Dermatologie et Dermatologie Pédiatrique, Hôpital Saint-André, 1 Rue Jean Burguet, 33000 Bordeaux, France. 11. First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens 157 72, Greece. 12. Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. 13. Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. 14. APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France. 15. Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary Street, 61-866 Poznań, Poland. 16. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Wawelska 15B, 02-034 Warsaw, Poland. 17. Department of Dermatology, University Hospital Center, Timone Hospital, Aix Marseille University, 264 Rue St Pierre, 13885 Marseille Cedex 05, France. 18. Mount Vernon Cancer Centre, Rickmansworth Road, HA6 2RN Northwood, UK. 19. Department of Medicine, Hematology/Oncology, UCLA Medical Center, 100 UCLA Medical Plaza, Suite 550, Los Angeles, CA, USA. 20. Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, TX, USA. 21. Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover 07936, NJ, USA. 22. Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston 02114, MA, USA. 23. Department of Medical Oncology, Dermatology Service, Gustave Roussy Comprehensive Cancer Center and Faculty of Medicine, University Paris-South, F-94805, Villejuif, France.
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.
RCT Entities:
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.
Authors: Cigdem Atay; Taekyoung Kwak; Sergio Lavilla-Alonso; Laxminarasimha Donthireddy; Allison Richards; Valerie Moberg; Shari Pilon-Thomas; Michael Schell; Jane L Messina; Vito W Rebecca; Min Xiao; Jiufeng Tan; Gao Zhang; Jeffrey S Weber; Meenhard Herlyn; Amod A Sarnaik; Dmitry I Gabrilovich Journal: Clin Cancer Res Date: 2019-02-14 Impact factor: 12.531
Authors: Inês Pires da Silva; Kevin Y X Wang; James S Wilmott; Jeff Holst; Matteo S Carlino; John J Park; Camelia Quek; Matthew Wongchenko; Yibing Yan; Graham Mann; Douglas B Johnson; Jennifer L McQuade; Rajat Rai; Richard F Kefford; Helen Rizos; Richard A Scolyer; Jean Y H Yang; Georgina V Long; Alexander M Menzies Journal: Clin Cancer Res Date: 2019-01-10 Impact factor: 12.531
Authors: Antoni Ribas; Adil Daud; Anna C Pavlick; Rene Gonzalez; Karl D Lewis; Omid Hamid; Thomas F Gajewski; Igor Puzanov; Matthew Wongchenko; Isabelle Rooney; Jessie J Hsu; Yibing Yan; Erica Park; Grant A McArthur Journal: Clin Cancer Res Date: 2019-11-15 Impact factor: 12.531
Authors: Axel Hauschild; James Larkin; Antoni Ribas; Brigitte Dréno; Keith T Flaherty; Paolo A Ascierto; Karl D Lewis; Edward McKenna; Qian Zhu; Yong Mun; Grant A McArthur Journal: JAMA Oncol Date: 2018-10-01 Impact factor: 31.777