Sarah Knispel1, Maximilian Gassenmaier2, Alexander M Menzies3, Carmen Loquai4, Douglas B Johnson5, Cindy Franklin6, Ralf Gutzmer7, Jessica C Hassel8, Carsten Weishaupt9, Thomas Eigentler2, Bastian Schilling10, Patrick Schummer10, Judith Sirokay11, Felix Kiecker12, Carina N Owen13, Maria I Fleischer4, Christopher Cann5, Katharina C Kähler14, Peter Mohr15, Leonie Bluhm15, Dennis Niebel11, Kai-Martin Thoms16, Simone M Goldinger17, Lydia Reinhardt18, Friedegund Meier18, Carola Berking19, Raphael Reinhard20, Laura Susok21, Paolo A Ascierto22, Konstantin Drexler23, Claudia Pföhler24, Julia Tietze25, Lucie Heinzerling19, Elisabeth Livingstone1, Selma Ugurel1, Georgina V Long3, Andreas Stang26, Dirk Schadendorf1, Lisa Zimmer27. 1. Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 2. Department of Dermatology, University Hospital Tübingen, Tübingen, Germany. 3. Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia. 4. Department of Dermatology, University Medical Center Mainz, Mainz, Germany. 5. Vanderbilt University Medical Center, Nashville, USA. 6. Department of Dermatology and Venereology, Skin Cancer Center at the Center of Integrated Oncology (CIO) Köln Bonn, University Hospital of Cologne, Cologne, Germany. 7. Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. 8. Skin Cancer Center, Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. 9. Department of Dermatology, University Hospital of Muenster, Muenster, Germany. 10. Department of Dermatology, University Hospital Würzburg, Würzburg, Germany. 11. Department of Dermatology, University Hospital Bonn, Bonn, Germany. 12. Department of Dermatology, University Hospital Charité Berlin, Berlin, Germany. 13. Melanoma Institute Australia, The University of Sydney, Sydney, Australia. 14. Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. 15. Department of Dermatology, Elbe-Klinikum Buxtehude, Buxtehude, Germany. 16. Department of Dermatology, University Medical Center Goettingen, Göttingen, Germany. 17. Department of Dermatology, University Hospital Zürich, Zürich, Switzerland. 18. Department of Dermatology, Skin Cancer Center at the National Center for Tumor Diseases, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. 19. Department of Dermatology, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen - Metropolitan Region of Nuremberg, Deutsches Zentrum Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany. 20. Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Mannheim, Germany. 21. Department of Dermatology, St. Josef-Hospital Bochum, Bochum, Germany. 22. Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy. 23. Department of Dermatology, University Hospital Regensburg, Regensburg, Germany. 24. Department of Dermatology, Saarland University Medical School, Homburg/Saar, Germany. 25. Department of Dermatology, University Hospital Rostock, Rostock, Germany. 26. Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany. 27. Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Electronic address: lisa.zimmer@uk-essen.de.
Abstract
BACKGROUND: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. METHODS: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. RESULTS: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. CONCLUSIONS: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.
BACKGROUND: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanomapatients with elevated LDH because prospective studies in this area are lacking. METHODS: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanomapatients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. RESULTS: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. CONCLUSIONS: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.
Authors: Lauretta Levati; Cristian Bassi; Simona Mastroeni; Laura Lupini; Gian Carlo Antonini Cappellini; Laura Bonmassar; Ester Alvino; Simona Caporali; Pedro Miguel Lacal; Maria Grazia Narducci; Ivan Molineris; Federica De Galitiis; Massimo Negrini; Giandomenico Russo; Stefania D'Atri Journal: Cancers (Basel) Date: 2022-07-29 Impact factor: 6.575