PII-041 - A CASE OF HEPATOTOXICITY DURING COMBINATION AXITINIB AND PEMBROLIZUMAB THERAPY IN A CYP3A4 AND CYP3A5 DUAL POOR METABOLIZER

T. Smith¹, Y. Gafari², J. Leighty³, N. Powell⁴, T. Skaar⁵, T. Shugg⁵; ¹Indiana University School of Medicine, Indianapolis, IN, USA, ²Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA, ³Indiana University School of Medicine, Indianapolis, IN, United States, ⁴Indiana University School of Medicine, Indianapolis, IN, US, ⁵Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, US.

Background: Axitinib and pembrolizumab are commonly given as combination therapy to treat advanced renal cell carcinoma. Both agents can cause hepatotoxicity, and the incidence of Grade 3-4 hepatotoxicity during combination therapy is 5-10%. Axitinib is a Cytochrome P450 3A (CYP3A) substrate, and co-administration with strong CYP3A inhibitors has been shown to increase axitinib exposure 2.1-fold.

Methods: A 68-year-old male who experienced treatment-limiting hepatotoxicity during combination axitinib and pembrolizumab therapy was identified at our institutional molecular tumor board. The patient presented to the emergency room 10 days after initiating therapy with nausea/vomiting, diarrhea, and lack of appetite. Laboratory tests revealed the patient had elevated aspartate aminotransferase (4.5x the upper limit of normal), alanine aminotransferase (2.8x elevated), alkaline phosphatase (1.7x elevated), and bilirubin (1.6x elevated), and the decision was made to discontinue therapy. The patient had germline clinical short-read whole exome sequencing (WES; Ashion Analytics) performed as part of their tumor board clinical workup, and Aldy v3.3 was used to extract genotypes for CYP3A4 and CYP3A5 from WES data. To phase variants identified in CYP3A4 and to confirm variants in both genes, Oxford Nanopore long-read whole genome sequencing (WGS) and a clinically-valid genotyping panel were performed, respectively.

Results: Short-read WES revealed that the patient was heterozygous for the CYP3A4*10 (rs4986908) and CYP3A4*22 (rs35599367) variants and homozygous for the CYP3A5*3 (rs776746) variant. Clinical genotyping confirmed the CYP3A5*3/*3 diplotype, which predicts a poor metabolizer phenotype, and confirmed heterozygosity of the CYP3A4*22 allele; however, the rare CYP3A4*10 allele was not included on the panel. As shown in Figure 1, long-read WGS demonstrated that the patient carried the CYP3A4*10 and CYP3A4*22 on separate gene copies, predicting that the patient is a CYP3A4 poor metabolizer.

Conclusion: The patient’s poor metabolizer phenotypes for CYP3A4 and CYP3A5 likely contributed to their treatment-limiting hepatotoxicity during combination therapy with axitinib and pembrolizumab. Long-read WGS was an effective technology for phasing the CYP3A4*10 and CYP3A4*22 variants.