(172) Pembrolizumab and The Potential Risk of Cholestasis: A Review of Pharmacovigilance Data

Publication Number: 503

Background: Pembrolizumab is humanized monoclonal antibody works as antineoplastic agent which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cells and potentiates its anti-tumor responses. Cholestasis is a liver disease that occurs when the flow of bile from the liver is reduced or blocked. Bile is fluid produced by liver that aids in the digestion of food, especially fats.

Objectives: The aim of this review is to evaluate the potential risk of cholestasis that been reported with pembrolizumab and suggest regulatory recommendations if required.

Methods: We performed a comprehensive signal review by assessing the causality of case-reports available in national and global case-reports databases. Reviewers also searched for additional evidences from literature and measured disproportional analysis (data-mining) for this drug/adverse reaction combination.

Results:
Case Review: The number of resulted cases are 63 globally. The reviewers have selected and assessed the causality for top quality reported cases (33 ICSRs). Out of 33 assessed ICSRs, 18 reports revealed positive association (1 certain, 10 probable and 7 possible) with 14 positive dechallenges (adverse reaction abated after stopping the medication).

Data Mining: The disproportionality of the observed and the expected reporting rate for drug/adverse drug reaction pair is estimated using information component (IC). Positive IC reflects higher statistical association while negative values indicates less statistical association. The results of (IC= 2.2) revealed a positive statistical association for the drug/ADR combination, meaning “cholestasis” with the use of “pembrolizumab” has been observed more than expected compared to other medications available in WHO database.

Literature: This signal was detected from phase 3 double-blind trial entitled (Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma). Cholestasis was one of the identified serious adverse events. Additionally, a case report was found in literature. A 48-year-old male patient diagnosed with lung adenocarcinoma. The patient was treated with pembrolizumab as second-line therapy. Eleven days after the second administration of pembrolizumab, he developed cholestatic liver injury.

Conclusions: The weighted cumulative evidence identified from the reported cases, data mining and literature are sufficient to support a causal association between pembrolizumab and the risk of cholestasis. Health regulators and health care professionals must be aware of this potential risk and it is advisable to monitor any signs or symptoms in treated patients.