L Khoja1, E G Atenafu2, S Suciu3, S Leyvraz4, T Sato5, E Marshall6, U Keilholz7, L Zimmer8, S P Patel9, S Piperno-Neumann10, J Piulats11, T T Kivelä12, C Pfoehler13, S Bhatia14, P Huppert15, L B J Van Iersel16, I J M De Vries17, N Penel18, T Vogl19, T Cheng20, G Fiorentini21, F Mouriaux22, A Tarhini23, P M Patel24, R Carvajal25, A M Joshua26. 1. Department of Medical Oncology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge; AstraZeneca UK, Clinical Discovery Unit, Early Clinical Development, IMED Biotech Unit, Melbourn, UK. 2. Department of Biostatistics, University Health Network, Toronto, Canada. 3. EORTC Headquarters, Brussels, Belgium. 4. Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. 5. Department of Medical Oncology, Thomas Jefferson University, Philadelphia, USA. 6. Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. 7. Charité-Universitätsmedizin, Berlin. 8. Department of Dermatology, University Hospital, University Duisburg-Essen, Germany & German Cancer Consortium (DKTK), Heidelberg, Germany. 9. Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA. 10. Department of Medical Oncology, Institut Curie, Paris, France. 11. Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), IDIBELL, Barcelona, Spain. 12. Ocular Oncology Service, Department of Ophthalmology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland. 13. Department of Dermatology, Saarland University Medical School, Hamburg, Germany. 14. Division of Medical Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, USA. 15. Department of Diagnostic and Interventional Radiology, Darmstadt, Germany. 16. Department of Medical Oncology, Maastricht University Medical Centre, Maastricht. 17. Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands. 18. Centre Oscar Lambret, Lille, France. 19. Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Johann Wolfgang Goethe-University, Frankfurt, Germany. 20. Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Canada. 21. Oncology Unit, Azienda Ospedaliera 'Ospedali Riuniti Marche Nord', Pesaro, Italy. 22. University of Rennes, INSERM, Department of Ophthalmology, CHU Rennes, Rennes, France. 23. UPMC Hillman Cancer Center, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, USA. 24. Academic Unit of Oncology, Division of Cancer & Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK. 25. Division of Hematology/Oncology, Columbia University Medical Center, New York, USA. 26. Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney; Melanoma Institute of Australia, Sydney, Australia. Electronic address: Anthony.joshua@svha.org.au.
Abstract
BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
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