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

Abstract

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.

Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma

“…Importantly, recent studies are pointing to specific mechanisms through which some of the actors of the coagulation cascade may regulate tumor-specific adaptive immunity and antigen presentation [ 45 ]. Actioning the coagulome based on this rationale might be a promising strategy to boost the efficacy of the immune system, especially in cancer patients receiving immune checkpoint blockers [ 46 ].…”

Hemostasis and tumor immunity

“…Although the results of this clinical analysis are intriguing 31 and suggest that FXa inhibitors could augment antitumor immunotherapy, they must be interpreted with caution. The study was entirely retrospective in nature.…”

“…Patients receiving FXa inhibitors had a significantly better response to ICI therapy than those not receiving any anticoagulant. 31 Interestingly, patients receiving vitamin K antagonists had a similar response to therapy as those patients receiving no anticoagulation, but patients receiving heparins had a worse response than those not receiving any anticoagulation.…”

“…Consistent with these results, recent clinical analyses suggested a link between the use of FXa inhibitors and improved outcomes in patients receiving ICI therapy. 31 This retrospective study analyzed 280 patients with metastatic melanoma receiving ICI therapy. Of these, 76 were treated concomitantly with anticoagulation with 29 receiving heparins, 20 receiving vitamin K antagonists, and 27 receiving small‐molecule FXa inhibitors (rivaroxaban, edoxaban, or apixaban).…”

Targeting coagulation to unlock antitumor immunity?

“…Indeed, specific targeting of coagulation factors, such as FXa, might be required to achieve superior antitumor immune stimulation, as suggested by recent preliminary clinical studies suggesting that the DOAC rivaroxaban boosts the effects of ICB in malignant melanomas. 10 Finally, the coagulation cascade is a source of clinical biomarkers, many of which are broadly-available in clinics to monitor hemostasis. The existence of a rich, active interplay between coagulation and the TME, as discussed elsewhere, 1 opens the enticing possibility that coagulation/fibrinolysis biomarkers might be revisited to non-invasively explore the TME and the immune characteristics of human tumors.…”