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

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 -