Abstract 42P
Background
Repotrectinib is a novel ROS1/TRK tyrosine kinase inhibitor that was recently approved by the United States Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic ROS1-positive non-small cell lung cancer. As the incidence of venous thromboembolism is estimated to be 3- to 5-fold higher in patients harbouring ROS1-rearrangement (Chiari et al. Clin Lung Cancer 2020), we reviewed all possible drug-drug interactions (DDIs) between antithrombotic agents and repotrectinib.
Methods
Data from FDA Product Information of repotrectinib (Augtyro®) was used to assess the DDI potential with antithrombotic agents (ATC code B01A). Repotrectinib acts as a moderate CYP3A inducer (midazolam AUC and Cmax decreased by 69% and 48%, resp.). Although data are currently lacking, we hypothesize that repotrectinib is also a moderate P-gp inducer, analogous to sotorasib. Recommendations for DDI management were constructed using a modified “traffic light” system developed by the University of Liverpool to classify DDIs. These were either “no or minimal interaction expected; no action” (green); “clinically relevant interaction expected; action needed” (orange); or “severe interaction expected, do not co-administer” (red).
Results
FDA’s Product Information does not contain specific recommendations for combining repotrectinib with antithrombotic agents. We, therefore, applied extrapolations based on the known DDI potential of repotrectinib. A clinically relevant interaction is expected with apixaban, betrixaban, dabigatran, edoxaban, phenprocoumon, rivaroxaban, ticagrelor and warfarin. These patients should be closely monitored for reduced efficacy of the antithrombotic agent. The remaining 18 antithrombotic agents are not expected to be involved in a DDI. All DDI pairs, as well as DDIs between repotrectinib and other co-medications, will be included in an online tool (www.DDIManager.co).
Conclusions
Repotrectinib may be involved in a DDI with a number of widely-used antithrombotic agents, including all directly-acting oral anticoagulants (DOACs). An online tool can guide clinicians to manage DDIs between repotrectinib and relevant co-medications.
Legal entity responsible for the study
The authors.
Funding
RadboudUMC.
Disclosure
D. Burger: Non-Financial Interests, Personal, Member of Board of Directors: Global DDI Solutions; Financial Interests, Institutional, Funding, GlobalDDISolutions: AstraZeneca, Pfizer. J. Leentjens: Financial Interests, Institutional, Research Grant: BMS-Pfizer, Viatris, and AstraZeneca. A.J. van der Wekken: Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Takeda; Financial Interests, Institutional, Advisory Board: AstraZeneca, Janssen, Lilly, Roche, and Takeda; Financial Interests, Institutional, Funding: from AstraZeneca, BMS, Lilly, Pfizer, and Roche. R. ter Heine: Financial Interests, Institutional, Research Grant: Amgen. All other authors have declared no conflicts of interest.