Treatment with therapeutic anticoagulation is not associated with immunotherapy response in advanced cancer patients

Abstract

Background Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct. Methods We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010–2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5). Results Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05). Conclusion AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.

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

“…This finding was unexpected because randomized trials showed that the application of LMWH and DOACs reduced the risk of VTE in cancer patients and may thus also reduce the risk of VTE-associated mortality [29][30][31]. However, our data are consistent with previous studies and randomized phase III trials [32], which found no association of concomitant AC with prolonged survival in patients with NSCLC [16] or other advanced solid cancer entities [19,21]. Although the cancer-specific risk of VTE in the pre-ICI era was found to be smaller in melanoma patients [33], melanoma patients treated with ICI show similar rates of TEE-and VTE-associated mortality as compared to patients with other advanced cancers [27,34,35], providing a biological rationale for AC therapy [21].…”

“…Despite the robust preclinical data, these findings have not been translated into the clinical setting. With few exceptions in tumor subtypes, AC, in general, does not appear to be associated with an improved outcome in tumor patients [19,20]. Investigating the role of AC in the outcome of patients with non-small-cell lung cancer (NSCLC) who have received anti-PD-1 or anti-PD-1-ligand (PD-L1) treatment, Nichetti et al found no effect of AC on the progression-free survival (PFS) or overall survival (OS) [16].…”

“…Investigating the role of AC in the outcome of patients with non-small-cell lung cancer (NSCLC) who have received anti-PD-1 or anti-PD-1-ligand (PD-L1) treatment, Nichetti et al found no effect of AC on the progression-free survival (PFS) or overall survival (OS) [16]. AC at any time in combination with ICI also showed no benefit in a larger cohort of advanced cancer patients [19]. However, given the strong heterogeneity of patients in terms of the primary tumor localization, the question as to whether the use of AC in general and the application of FXa or thrombin inhibitors more specifically might impact the outcome of ICI treatment might be better addressed in defined tumor entities with unmet clinical needs in improvements of ICI therapy.…”

Thrombotic Complications Associated with Immune Checkpoint Inhibitors

“…It is of great interest whether this finding can be translated into a clinical setting. However, a recent retrospective study showed no difference in response rates, progression-free or overall survival in patients receiving ICIs and therapeutic anticoagulation compared to patients who were not on anticoagulation [52]. Of note, anticoagulation included in this study was not limited to factor X inhibitors (including dabigatran, rivaroxaban, apixaban, enoxaparin, and warfarin).…”

“…Of note, anticoagulation included in this study was not limited to factor X inhibitors (including dabigatran, rivaroxaban, apixaban, enoxaparin, and warfarin). Moreover, the cohort of patients on anticoagulation in the study was significantly older, with poorer performance status, and a higher percentage had lung cancer, all of which were poor prognostic factors [52]. The authors performed a multivariable analysis to adjust for confounders and reached the same conclusions, but residual confounding could be present.…”