(250) The Risk of Posterior Reversible Encephalopathy Syndrome (PRES) with Tyrosine Kinase Inhibitors: A Disproportionality Analysis from Vigibase and AERS Databases

Saturday, August 27, 2022

8:00 AM – 6:00 PM CEST

Location: Hall C

Publication Number: 924

Presenting Author(s)

Luis G. Velez-Nandayapa, MD
– PhD Student in Pharmacoepidemiology, University of Basel, University of Basel, Z�rich, Z�rich, Switzerland

Co-Author(s)

Anusmita Das
– Safety Signal Detection & MQM, Novartis, India
Amit Saxena
– Safety Signal Detection & MQM, Novartis, India
Vishaka Parulekar, MD
– Patient Safety Oncology, Novartis, Hyderabad, India, India
Naveen Chhabra, MD
– Patient Safety Oncology, Novartis, Hyderabad, India, India
Miguel Izquierdo, MD
– Clinical Development Oncology, Novartis, Basel, Switzerland, Switzerland
Pierre de Zeeuw, MD
– Patient Safety Oncology, Novartis, Basel, Switzerland, Switzerland
Edwin Schaart
– Patient Safety Oncology, Novartis, New Jersey, United States
Johannes Eisinger, MD
– Patient Safety Oncology, Novartis, Basel, Switzerland, Switzerland

Background: PRES is a clinical radiologic syndrome characterized by headache, seizure, altered consciousness and visual disturbances. PRES has been associated with sepsis, malignant hypertension, transplants, and the use of chemotherapeutic agents, immunosuppressants, or cytotoxic treatments for malignant neoplasms, but its pathogenesis remains poorly understood.

Objectives: To quantify disproportionate reporting (Disp-Rep) for the risk of PRES for 41 tyrosine kinase inhibitors (TKIs) in 3 groups: 1) Anti-angiogenic (AA) TKIs; 2) Non-anti-angiogenic (NAA) TKIs & 3) Control group of 3 drugs associated to PRES.

Methods: We used the Vigibase and AERS databases, with data up to Mar2022 and Dec2021. Cases were identified using MedDRA (v24.1) and the PT PRES. Empirical Bayes Geometric Means (EBGM) were calculated to quantify Disp-Rep. We considered the lower bound of the 90% confidence interval, EB05 > 2, as the threshold for claiming disproportionate reporting. We studied 3 groups of drugs: 1) a positive control group (non-TKIs associated with PRES: cyclosporine, tacrolimus and bevacizumab) and groups of TKIs: 2) AA TKIs (16 drugs) & 3) NAA TKIs (25 drugs). Drugs were identified by non-proprietary name.

Results: We retrieved 1,991 cases of PRES in Vigibase and 2,551 in AERS. In Vigibase, Disp-Rep with EBGM [90%CI, EB05-EB95] was confirmed for the positive control group: tacrolimus 34.54 [32.43-36.76] cyclosporine 32.48 [30.21-34.88], and bevacizumab 22.94 [21.0-25.02]. Disp-Rep was observed for 10 of 16 AA TKIs: lenvatinib 41.24 [32.62-51.56], axitinib 41.12 [33.77-49.68], pazopanib 14.22 [11.07-17.87], sunitinib 8.63 [6.98-10.61], cabozantinib 7.6 [5.28-10.8], regorafenib 5.98 [4.07-8.56], ponatinib 5.55 [3.42-8.65], sorafenib 4.06 [2.9-5.55], vandetanib 5.7 [2.72-14.2] and tivozanib 23.56 [2.7-128.78]. Few AA TKIs were observed with no Disp-Rep (EB05 < 2): acalabrutinib, dacomitinib, neratinib, nintedanib, ripretinib and selpercatinib. No Dis-Rep (EB05 < 2) was observed for any of the NAA TKIs: afatinib, alectinib, avapritinib, bosutinib, brigatinib, ceritinib, crizotinib, dabrafenib, dasatinib, entrectinib, erlotinib, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, lapatinib, lorlatinib, nilotinib, osimertinib, pemigatinib, pexidartinib, pralsetinib, tucatinib and zanubrutinib. The analysis in AERS did not show Dis-Rep for vandetanib and tivozanib.

Conclusions: All TKIs with confirmed Disp-Rep were from the AA group. This finding suggests a potential class effect for the event of PRES for AA TKIs.
Our results however, should be interpreted with caution as disproportionality analyses are hypothesis generating rather than hypothesis testing. Further analysis are planned to better understand this potential class effect.