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Article

Anticoagulation with Factor Xa Inhibitors Is Associated with Improved Overall Response and Progression-Free Survival in Patients with Metastatic Malignant Melanoma Receiving Immune Checkpoint Inhibitors—A Retrospective, Real-World Cohort Study

1
Department of Dermatology, University Medical Center of the Johannes-Gutenberg University Mainz, 55131 Mainz, Germany
2
Center for Thrombosis and Hemostasis, University Medical Center of the Johannes-Gutenberg University Mainz, 55131 Mainz, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Joseph G Crompton
Cancers 2021, 13(20), 5103; https://doi.org/10.3390/cancers13205103
Received: 28 August 2021 / Revised: 3 October 2021 / Accepted: 9 October 2021 / Published: 12 October 2021
(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)
The advent of immune checkpoint inhibitors (ICI) improved the prognosis for patients with advanced melanoma. However, many patients do not benefit from ICI therapy due to primary and acquired resistance. Observations in murine systems suggested that coagulation factor Xa impedes anti-tumor immunity and that the oral FXa-inhibitor (FXa-i) rivaroxaban might synergize with ICI. In this retrospective study, we could demonstrate that concomitant treatment with anticoagulants did not impact the objective response rate, progression-free survival, or overall survival of stage IV melanoma patients who were treated with ICI. Remarkably, however, patients receiving concomitant treatment with FXa-i during initial ICI therapy showed a significantly improved objective response rate and progression-free survival as compared to patients not receiving anticoagulation or patients treated with other anticoagulants, such as heparins or vitamin K antagonists. Hence, our data suggest that FXa-i may augment ICI therapy, while patients who received FXa-i were not more likely to encounter bleeding complications.
Immune checkpoint inhibitors (ICI) significantly improved the prognosis of advanced melanoma patients. However, many patients do not derive long-term benefit from ICI therapy due to primary and acquired resistance. In this regard, it has been shown that coagulation factors contribute to cancer immune evasion and might therefore promote resistance to ICI. In particular, recent observations in murine systems demonstrated that myeloid-derived factor Xa (FXa) impedes anti-tumor immunity in the tumor microenvironment and that the oral FXa inhibitor (FXa-i) rivaroxaban synergizes with ICI. The synergistic effect of FXa inhibitors with clinical ICI therapy is unknown. We performed a retrospective study of 280 metastatic melanoma patients who were treated with ICI and stratified them for concomitant anticoagulation (AC) by medical chart review. Data on baseline patient characteristics, specific AC treatment, ICI therapy, other tumor-targeting therapies, and clinical outcomes were analyzed. Of 280 patients who received ICI, 76 received concomitant AC during initial ICI therapy. Patients on AC were treated either with heparins (n = 29), vitamin K antagonists (VKA) (n = 20), or FXa-i (n = 27). Patients requiring AC during ICI therapy showed no significantly reduced objective response rate (ORR) (p = 0.27), or progression-free (PFS; median PFS 4 vs. 4 months; p = 0.71) or overall survival (OS; median OS: 39 vs. 51 months; p = 0.31). Furthermore, patients who underwent AC did not show significantly more bleeding complications (p = 0.605) than those who were not anticoagulated. Remarkably, stratification of patients by the class of AC revealed that patients receiving FXa-i were more likely to obtain CR (26.9 vs. 12.6%, p = 0.037), and showed better ORR (69.2 vs. 36.4%, p = 0.005), PFS (median PFS: 12 months vs. 3 months; p = 0.006), and OS (median OS not reached vs. 42 months; p = 0.09) compared to patients not receiving FXa-i. Patient demographics and tumor characteristics in this patient subcohort did not significantly differ from patients not on FXa-i. In summary, our study provides first clinical evidence that the clinical application of FXa-i may enhance the efficacy of ICI therapy via the restoration of anti-tumor immunity, while patients who received FXa-i were not more likely to encounter bleeding complications. View Full-Text
Keywords: immunotherapy; immune checkpoint inhibitors; anticoagulation; factor Xa inhibitors; advanced melanoma; anti-tumor immunity; thromboprophylaxis; thromboembolic events immunotherapy; immune checkpoint inhibitors; anticoagulation; factor Xa inhibitors; advanced melanoma; anti-tumor immunity; thromboprophylaxis; thromboembolic events
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MDPI and ACS Style

Haist, M.; Stege, H.; Pemler, S.; Heinz, J.; Fleischer, M.I.; Graf, C.; Ruf, W.; Loquai, C.; Grabbe, S. Anticoagulation with Factor Xa Inhibitors Is Associated with Improved Overall Response and Progression-Free Survival in Patients with Metastatic Malignant Melanoma Receiving Immune Checkpoint Inhibitors—A Retrospective, Real-World Cohort Study. Cancers 2021, 13, 5103. https://doi.org/10.3390/cancers13205103

AMA Style

Haist M, Stege H, Pemler S, Heinz J, Fleischer MI, Graf C, Ruf W, Loquai C, Grabbe S. Anticoagulation with Factor Xa Inhibitors Is Associated with Improved Overall Response and Progression-Free Survival in Patients with Metastatic Malignant Melanoma Receiving Immune Checkpoint Inhibitors—A Retrospective, Real-World Cohort Study. Cancers. 2021; 13(20):5103. https://doi.org/10.3390/cancers13205103

Chicago/Turabian Style

Haist, Maximilian, Henner Stege, Saskia Pemler, Jaqueline Heinz, Maria Isabel Fleischer, Claudine Graf, Wolfram Ruf, Carmen Loquai, and Stephan Grabbe. 2021. "Anticoagulation with Factor Xa Inhibitors Is Associated with Improved Overall Response and Progression-Free Survival in Patients with Metastatic Malignant Melanoma Receiving Immune Checkpoint Inhibitors—A Retrospective, Real-World Cohort Study" Cancers 13, no. 20: 5103. https://doi.org/10.3390/cancers13205103

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