Introduction

Selpercatinib is an oral selective inhibitor of the tyrosine kinase receptor encoded by RET (rearranged during transfection), a proto-oncogene which is mutated or altered in many cancers such a medullary thyroid cancer and non-small cell lung cancer. Serum aminotransferase elevations are common during therapy with selpercatinib and can lead to dose modifications or drug discontinuation, but clinically apparent liver injury with jaundice has not been described with its use.

Background

Selpercatinib (sel per’ca ti nib) is an orally available, small molecule inhibitor of the tyrosine kinase receptor encoded by the proto-oncogene RET (rearranged during transfection), which is mutated or altered in several cancers including non-small cell lung cancer (NSCLC) and medullary thyroid cancer. The RET encoded tyrosine kinase receptor leads to stimulation of cell growth and proliferation which when overexpressed can become a cancer promoter by stimulating tumor cell proliferation, invasion and migration. Alterations in the RET gene, either mutations or RET fusions, are found in several forms of cancer, including 70% of medullary thyroid cancers and a small proportion of other forms of thyroid cancer and NSCLC. Therapy with selpercatinib has been shown to result in objective responses (either complete or partial) in a high proportion of patients with NSCLC and thyroid cancers with RET alterations. Selpercatinib was granted accelerated approved in the United States in 2020 for adults and children (aged 12 years or older) with advanced, unresectable or metastatic NSCLC, medullary thyroid cancer and thyroid cancers harboring RET mutations or RET gene fusions. Indications were subsequently extended to include adults with refractory, advanced solid tumors harboring a RET fusion. Selpercatinib is available in capsules of 40 and 80 mg under the brand name Retevmo. The recommended dose is 160 mg twice daily in adults and children weighing 50 kg or greater, and 120 mg twice daily in those weighing less than 50 kg. Side effects are common and arise in almost all patients treated with selpercatinib and can include dry mouth, diarrhea, systemic arterial hypertension, fatigue, constipation, nausea, poor appetite, myalgia, arthralgia, edema, anemia, elevations in serum creatinine, uric acid, and aminotransferase levels. Uncommon but potentially severe adverse events include interstitial lung disease, severe hypertension, prolongation of the QTc interval, hemorrhagic events, tumor lysis syndrome, impaired wound healing, hypersensitivity reactions, and embryo-fetal toxicity.

Hepatotoxicity

In the prelicensure clinical trials of selpercatinib in patients with thyroid and non-small cell lung cancer, liver test abnormalities were frequent although usually mild. Some degree of ALT elevation arose in up to 55% of selpercatinib treated patients and were above 5 times the upper limit of normal (ULN) in 10% to 12%, arising mostly within the first few months of therapy; the median onset was at 6 weeks but with a range of 1 day to more than 2 years. In the preregistration trials that enrolled 531 patients, serum aminotransferase elevations led to dose interruptions and modifications in 5% to 6% but complete discontinuation in less than 1% of patients. ALT levels were closely monitored and did not lead to clinically apparent liver injury with jaundice or deaths from liver disease. Thus, selpercatinib therapy is associated with a high rate of transient serum enzyme elevations but has not been definitely linked to instances of clinically apparent liver injury with jaundice. The product label for selpercatinib recommends monitoring for routine liver tests before, at 2 week intervals during the first 3 months of therapy, and monthly thereafter as clinically indicated.

Likelihood score: E* (unproven but suspect cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the serum aminotransferase elevations during selpercatinib therapy is unknown, but the pattern of abnormalities and response to dose adjustments suggests some degree of low level, direct hepatotoxicity. Selpercatinib is metabolized in the liver via the cytochrome P450 system, largely CYP 3A4, and is susceptible to drug-drug interactions with agents that inhibit or induce the CYP enzyme reactivity.

Outcome and Management

Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation of selpercatinib therapy until serum enzymes return to normal or near normal values. In patients with clinically apparent liver injury and jaundice, restarting therapy should be done with caution. Cross sensitivity to liver injury is uncommon among the tyrosine kinase inhibitors, but there is no information on shared adverse event sensitivity of selpercatinib with other RET inhibitors such as pralsetinib or other antineoplastic protein kinase inhibitors.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

Related Drugs: Pralsetinib