Bleeding in Lung Cancer Patients Receiving Therapeutic Anticoagulation While Being Treated with VEGF and EGFR Inhibitors

Background: The safety of concurrent anticoagulation and treatment with vascular endothelial growth factor inhibitors (VEGFi) and epidermal growth factor receptor inhibitors (EGFRi) is largely uncertain. Many VEGF and EGFR inhibitors have black box warnings and/or risk profiles including bleeding events, thus complicating decisions regarding administration of concomitant anticoagulation (AC). Our aim was to assess the rates of major and non-major bleeding events among patients receiving AC with VEGFi or EGFRi and compare those rates with patients receiving AC with chemotherapy alone (without VEGFi or EGFRi).

Methods: In a retrospective cohort study, patients with lung cancer receiving AC (excluding prophylactic-dose low-molecular-weight-heparin [LMWH]) from 2012 to 2022 at Memorial Sloan Kettering Cancer Center (MSKCC) were assessed for major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) events as defined by the International Society on Thrombosis and Haemostasis (ISTH). Patients were identified using diagnostic codes and prescription data and were indexed on the first day of concurrent AC and anti-neoplastic therapy. The first 295 patients were reviewed via manual chart review. The subsequent 202 patients were reviewed using the CEDARS platform (Mantha et al, 2024), which uses natural language processing (NLP) to identify potential bleeding events that are then adjudicated by a physician, to identify CRNMB and MB outcomes over a 15-month period. Patients were censored for MB, discontinuation of AC or antineoplastic therapy (60 days after last prescription), end of 12-month follow-up, or death. The study exposure was type of anti-neoplastic therapy in the first 30 days post-index including chemotherapy alone (chemo), EGFRi with or without chemotherapy (EGFRi±chemo), and VEGFi with or without chemotherapy (VEGFi±chemo).

Results: The study included 497 patients with a median age of 66.1 years (IQR 58.8-73.3 years) and consisting of 293 (59%) females and 204 (41%) males. A total of 248 (50%) patients received AC with a direct oral anticoagulant, 240 (48%) with LMWH, and 9 (2%) with a vitamin K antagonist. The majority had stage 4 cancer and the median follow-up was 5.79 months.

Cancer treatment groups included 206 (41%) chemotherapy alone, 193 (39%) EGFRi±chemo (168 EGFRi alone), and 98 (20%) VEGFi±chemo (28 VEGFi alone). The cumulative incidences for MB in the full cohort was 5.1% (95% CI 3.3-7.5%) at 6-months and 8.2% (95% CI 5.4-12%) at 12-months. The 12-month cumulative incidences of MB were 8.8% for the chemo-alone group, 8.1% for the EGFRi±chemo group, and 7.4% for the VEGFi±chemo group (p=0.91 for differences between the groups). The 12-month cumulative incidences of CRNMB were 17% for the chemo-alone group, 20% for the EGFRi±chemo group, and 16% for the VEGFi±chemo group (p=0.35).

Across all treatment groups at 12-months there were 28 MB. This included 4 (1.9%) GI hemorrhages in the chemo-alone group, 3 (1.5%) in the EGFRi±chemo group, and 0 in the VEGFi±chemo group. Similarly, there were 4 (1.9%) cases of intracranial hemorrhage in the chemo-alone group, compared with 4 (2.0%) in the EGFRi±chemo group, and 1 (1.0%) in the VEGFi±chemo group.

Conclusions: Utilizing an NLP platform to help identify cases of hemorrhage, we observed that the risks of both CRNMB and MB with therapy regimens including VEGF and EGFR inhibitors appear similar to chemotherapy alone. This data should reassure clinicians that therapeutic anticoagulation can be administered to lung cancer patients being treated with VEGF or EGFR inhibitors without substantial increased risk of bleeding when compared to anticoagulating patients on chemotherapy alone.