Evaluation of cabozantinib (cabo) in combination with direct oral anticoagulants (DOAC) or low molecular weight heparin (LMWH) in renal cell carcinoma (RCC).
Authors: Mesleh Shayeb Akram , Urman Danielle , Dizman Nazli , Meza Luis A , Sivakumar Akhilesh , Gan Chun Loo , Dzimitrowicz Hannah Elizabeth , Zhang Tian , Barata Pedro C. , Bilen Mehmet Asim , Gao Xin , Heng Daniel Yick Chin , Pal Sumanta K. , Kaymakcalan Marina D. , McGregor Bradley Alexander , Choueiri Toni K. , McKay Rana R. 
Published: March 2021

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Background: Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. Despite cabo improving RCC outcomes, VTE management in these patients remains a challenge, partly due to poor understanding of cabo safety profile and drug interactions with anticoagulants. Recent anti-Xa DOAC studies demonstrated comparable efficacy and safety with LMWH for VTE treatment in patients with cancer. Thus far, cabo clinical trials have largely allowed concurrent LMWH use but not DOACs. Herein, we investigated the hemostasis safety profile of cabo with different anticoagulants in patients with RCC. Methods: We performed a retrospective multicenter study (7 sites) of patients with advanced RCC receiving treatment with cabo. Patients were allocated into three groups: cabo with concomitant use (at least 1 week) of 1) DOACs (anti-Xa inhibitors), 2) LMWH, or 3) no anticoagulant. Primary endpoint was to evaluate the rate of major bleeding events (defined per the International Society of Hemostasis and Thrombosis criteria) in the above groups. Secondary endpoint was rate of new/recurrent VTE while on anticoagulation. Overall comparison between groups was analyzed by Fisher exact test. If a difference was found, then pairwise comparison was done. Results: Between 2016-2020, 172 patients with RCC received cabo (DOAC 50, LMWH 18, and no anticoagulant 104). At initiation, cabo median dose was 60 mg but 45% had dose reduction. Median age was 63 [IQR 57-69]. Most were males (77%), had clear cell histology (81.5%), underwent nephrectomy (76.7%), and had intermediate IMDC risk disease (59%). Cabo was first, second, and subsequent line of therapy in 19.8%, 34.9%, and 45.3% of patients, respectively. The table below shows major bleeding and VTE events between groups. An overall difference of major bleeding was found between the three groups comparison ( p=0.009). There was no difference in major bleeding events between patients who received DOAC vs LMWH ( p=0.28) and DOAC vs no anticoagulant ( p=0.1) but there was a difference between LMWH vs no anticoagulant ( p=0.02). Two patients died from bleeding (one in LMWH and one in DOAC group). Conclusions: This study highlights the first reported real world experience of cabo with different anticoagulants in patients with advanced RCC. Cabo use with a DOAC had a similar bleeding risk in comparison to patients not receiving any anticoagulation. In carefully selected patients, DOACs can be considered as concurrent medications in those receiving cabo. Given the low number of patients receiving LMWH, it is difficult to draw conclusions from this group. Data are currently being updated to expand subjects receiving DOAC and LMWH in our cohort. [Table: see text]