Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study.

Abstract

BACKGROUND:

Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies.

METHODS:

MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB-IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR.

RESULTS:

Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036).

CONCLUSIONS:

High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.

• Authors: Nikolaus B Wagner, Max M Lenders, Kathrin Kühl, Lydia Reinhardt, Fiona André, Milena Dudda, Natalie Ring, Chiara Ebel, Ramon Stäger, Caroline Zellweger, Roland Lang, Michael Paar, Philipp Gussek, Georg Richtig, Suzan H Stürmer, Susanne Kimeswenger, Angela Oellinger, Andrea Forschner, Ulrike Leiter, Benjamin Weide, Maximilian Gassenmaier, Amadeus Schraag, Bernhard Klumpp, Wolfram Hoetzenecker, Carola Berking, Erika Richtig, Mirjana Ziemer, Johanna Mangana, Patrick Terheyden, Carmen Loquai, Van Anh Nguyen, Christoffer Gebhardt, Friedegund Meier, Stefan Diem, Antonio Cozzio, Lukas Flatz, Martin Röcken, Claus Garbe, Thomas K Eigentler
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 9 Issue 5 (05 2021) ISSN: 2051-1426 [Electronic] England
• PMID: 33986126 (Publication Type: Journal Article, Multicenter Study, Validation Study)
• Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antibodies, Monoclonal, Humanized
• Immune Checkpoint Inhibitors
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Nivolumab
• pembrolizumab

Topics

• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• Cell Proliferation
• Europe
• Female
• Humans
• Immune Checkpoint Inhibitors (adverse effects, therapeutic use)
• Male
• Melanoma (diagnostic imaging, drug therapy, immunology, secondary)
• Middle Aged
• Neoplasm Staging
• Nivolumab (adverse effects, therapeutic use)
• Predictive Value of Tests
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology)
• Reproducibility of Results
• Retrospective Studies
• Risk Assessment
• Risk Factors
• Skin Neoplasms (diagnostic imaging, drug therapy, immunology, pathology)
• Time Factors
• Tomography, X-Ray Computed
• Treatment Outcome