Caroline Robert1, Keith Flaherty2, Paul Nathan3, Peter Hersey4, Claus Garbe5, Mohammed Milhem6, Lev Demidov7, Peter Mohr8, Jessica C Hassel9, Piotr Rutkowski10, Reinhard Dummer11, Jochen Utikal12, Felix Kiecker13, James Larkin14, Anthony D'Amelio15, Bijoyesh Mookerjee15, Dirk Schadendorf16. 1. Department of Dermatology, Institut Gustave Roussy, Villejuif, France. Electronic address: Caroline.ROBERT@gustaveroussy.fr. 2. Massachusetts General Hospital Cancer Center, Boston, MA, USA. 3. Mount Vernon Cancer Centre, Northwood, United Kingdom. 4. University of Sydney, Sydney, Australia. 5. University Medical Center, Tübingen, Germany. 6. University of Iowa Hospital and Clinics, Iowa City, IA, USA. 7. N. N. Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russian Federation. 8. Elbe Klinikum Buxtehude, Buxtehude, Germany. 9. University Hospital Heidelberg, Heidelberg, Germany. 10. Maria Sklodowska-Curie Institute Oncology Center, Warsaw, Poland. 11. University Hospital Zurich, Zurich, Switzerland. 12. German Cancer Research Center (DKFZ) and University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. 13. Charité-Universitätsmedizin, Berlin, Germany. 14. Royal Marsden Hospital, London, United Kingdom. 15. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 16. University Hospital Essen, Essen, Germany.
Abstract
BACKGROUND: Primary findings from the METRIC (TMT212A2301) study demonstrated that trametinib improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in patients with unresectable or metastatic cutaneous melanoma with a BRAF V600 E/K mutation. However, clinical data characterising the long-term use of these therapies in combination with BRAF inhibitors or as monotherapies are limited. METHODS: In this open-label, phase 3 study, 322 patients with BRAF V600E/K-mutant metastatic melanoma were randomised in a 2:1 ratio to receive trametinib (2 mg orally, once daily; n = 214) or chemotherapy (dacarbazine [1000 mg/m2] or paclitaxel [175 mg/m2] intravenously, every 3 weeks; n = 108). Patients who progressed on chemotherapy were allowed to cross over and receive trametinib. Five-year results of efficacy and safety analyses are reported. RESULTS: The median PFS was 4.9 months in the trametinib arm versus 1.5 months in the chemotherapy arm (hazard ratio, 0.54; 95% confidence interval, 0.41-0.73). Landmark OS rates for trametinib versus chemotherapy arms at 1 year, 2 years and 5 years were 60.9% versus 49.6%, 32.0% versus 29.4% and 13.3% versus 17.0%, respectively. Most patients (n = 70 [65%]) from the chemotherapy arm crossed over to the trametinib arm early in their treatment. No unexpected adverse events were reported. CONCLUSIONS: This 5-year follow-up of patients with BRAF V600E/K-mutant metastatic melanoma on a targeted therapy demonstrates that long-term use of trametinib is possible with no new or unexpected adverse events. Some patients experienced long-term survival benefit with trametinib monotherapy (METRIC ClinicalTrials.gov number, NCT01245062.).
RCT Entities:
BACKGROUND: Primary findings from the METRIC (TMT212A2301) study demonstrated that trametinib improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in patients with unresectable or metastatic cutaneous melanoma with a BRAF V600 E/K mutation. However, clinical data characterising the long-term use of these therapies in combination with BRAF inhibitors or as monotherapies are limited. METHODS: In this open-label, phase 3 study, 322 patients with BRAF V600 E/K-mutant metastatic melanoma were randomised in a 2:1 ratio to receive trametinib (2 mg orally, once daily; n = 214) or chemotherapy (dacarbazine [1000 mg/m2] or paclitaxel [175 mg/m2] intravenously, every 3 weeks; n = 108). Patients who progressed on chemotherapy were allowed to cross over and receive trametinib. Five-year results of efficacy and safety analyses are reported. RESULTS: The median PFS was 4.9 months in the trametinib arm versus 1.5 months in the chemotherapy arm (hazard ratio, 0.54; 95% confidence interval, 0.41-0.73). Landmark OS rates for trametinib versus chemotherapy arms at 1 year, 2 years and 5 years were 60.9% versus 49.6%, 32.0% versus 29.4% and 13.3% versus 17.0%, respectively. Most patients (n = 70 [65%]) from the chemotherapy arm crossed over to the trametinib arm early in their treatment. No unexpected adverse events were reported. CONCLUSIONS: This 5-year follow-up of patients with BRAF V600 E/K-mutant metastatic melanoma on a targeted therapy demonstrates that long-term use of trametinib is possible with no new or unexpected adverse events. Some patients experienced long-term survival benefit with trametinib monotherapy (METRIC ClinicalTrials.gov number, NCT01245062.).
Authors: Christopher P Vellano; Michael G White; Miles C Andrews; Manoj Chelvanambi; Russell G Witt; Joseph R Daniele; Mark Titus; Jennifer L McQuade; Fabio Conforti; Elizabeth M Burton; Matthew J Lastrapes; Gabriel Ologun; Alexandria P Cogdill; Golnaz Morad; Peter Prieto; Alexander J Lazar; Yanshuo Chu; Guangchun Han; M A Wadud Khan; Beth Helmink; Michael A Davies; Rodabe N Amaria; Jeffrey J Kovacs; Scott E Woodman; Sapna Patel; Patrick Hwu; Michael Peoples; Jeffrey E Lee; Zachary A Cooper; Haifeng Zhu; Guang Gao; Hiya Banerjee; Mike Lau; Jeffrey E Gershenwald; Anthony Lucci; Emily Z Keung; Merrick I Ross; Laura Pala; Eleonora Pagan; Rossana Lazcano Segura; Qian Liu; Mikayla S Borthwick; Eric Lau; Melinda S Yates; Shannon N Westin; Khalida Wani; Michael T Tetzlaff; Lauren E Haydu; Mikhila Mahendra; XiaoYan Ma; Christopher Logothetis; Zachary Kulstad; Sarah Johnson; Courtney W Hudgens; Ningping Feng; Lorenzo Federico; Georgina V Long; P Andrew Futreal; Swathi Arur; Hussein A Tawbi; Amy E Moran; Linghua Wang; Timothy P Heffernan; Joseph R Marszalek; Jennifer A Wargo Journal: Nature Date: 2022-06-15 Impact factor: 69.504