Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study
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Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study. / Wagner, Nikolaus B; Lenders, Max M; Kühl, Kathrin; Reinhardt, Lydia; André, Fiona; Dudda, Milena; Ring, Natalie; Ebel, Chiara; Stäger, Ramon; Zellweger, Caroline; Lang, Roland; Paar, Michael; Gussek, Philipp; Richtig, Georg; Stürmer, Suzan H; Kimeswenger, Susanne; Oellinger, Angela; Forschner, Andrea; Leiter, Ulrike; Weide, Benjamin; Gassenmaier, Maximilian; Schraag, Amadeus; Klumpp, Bernhard; Hoetzenecker, Wolfram; Berking, Carola; Richtig, Erika; Ziemer, Mirjana; Mangana, Johanna; Terheyden, Patrick; Loquai, Carmen; Nguyen, Van Anh; Gebhardt, Christoffer; Meier, Friedegund; Diem, Stefan; Cozzio, Antonio; Flatz, Lukas; Röcken, Martin; Garbe, Claus; Eigentler, Thomas K.
In: J IMMUNOTHER CANCER, Vol. 9, No. 5, e002350, 05.2021.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study
AU - Wagner, Nikolaus B
AU - Lenders, Max M
AU - Kühl, Kathrin
AU - Reinhardt, Lydia
AU - André, Fiona
AU - Dudda, Milena
AU - Ring, Natalie
AU - Ebel, Chiara
AU - Stäger, Ramon
AU - Zellweger, Caroline
AU - Lang, Roland
AU - Paar, Michael
AU - Gussek, Philipp
AU - Richtig, Georg
AU - Stürmer, Suzan H
AU - Kimeswenger, Susanne
AU - Oellinger, Angela
AU - Forschner, Andrea
AU - Leiter, Ulrike
AU - Weide, Benjamin
AU - Gassenmaier, Maximilian
AU - Schraag, Amadeus
AU - Klumpp, Bernhard
AU - Hoetzenecker, Wolfram
AU - Berking, Carola
AU - Richtig, Erika
AU - Ziemer, Mirjana
AU - Mangana, Johanna
AU - Terheyden, Patrick
AU - Loquai, Carmen
AU - Nguyen, Van Anh
AU - Gebhardt, Christoffer
AU - Meier, Friedegund
AU - Diem, Stefan
AU - Cozzio, Antonio
AU - Flatz, Lukas
AU - Röcken, Martin
AU - Garbe, Claus
AU - Eigentler, Thomas K
N1 - © 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.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - Antibodies, Monoclonal, Humanized/adverse effects
KW - Cell Proliferation
KW - Europe
KW - Female
KW - Humans
KW - Immune Checkpoint Inhibitors/adverse effects
KW - Male
KW - Melanoma/diagnostic imaging
KW - Middle Aged
KW - Neoplasm Staging
KW - Nivolumab/adverse effects
KW - Predictive Value of Tests
KW - Programmed Cell Death 1 Receptor/antagonists & inhibitors
KW - Reproducibility of Results
KW - Retrospective Studies
KW - Risk Assessment
KW - Risk Factors
KW - Skin Neoplasms/diagnostic imaging
KW - Time Factors
KW - Tomography, X-Ray Computed
KW - Treatment Outcome
U2 - 10.1136/jitc-2021-002350
DO - 10.1136/jitc-2021-002350
M3 - SCORING: Journal article
C2 - 33986126
VL - 9
JO - J IMMUNOTHER CANCER
JF - J IMMUNOTHER CANCER
SN - 2051-1426
IS - 5
M1 - e002350
ER -