Selpercatinib

Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Danger

H341 (50%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]

P203, P260, P264, P270, P273, P280, P308+P316, P318, P319, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Selpercatinib exerts anti-tumour activity in specific cancers through inhibition of mutated forms of RET tyrosine kinases. Due to its increased specificity for RET over other tyrosine kinases, selpercatinib is thought to have an improved safety profile compared to other multi-kinase inhibitors. Despite this, selpercatinib treatment is associated with hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, risk of impaired wound healing, and embryo-fetal toxicity; some patients may also exhibit hypersensitivity to selpercatinib.

Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase containing extracellular, transmembrane, and intracellular domains whose activity is required for normal kidney and nervous system development. Constitutive RET activation is primarily achieved through chromosomal rearrangements producing 5' fusions of dimerizable domains to the 3' _RET_ tyrosine kinase domain, such as _KIF5B-RET_ and _CCDC6-RET_, resulting in constitutive dimerization and subsequent autophosphorylation. Constitutive activation leads to increased downstream signalling and is associated with tumour invasion, migration, and proliferation. Selpercatinib is a direct RET kinase inhibitor, exhibiting IC₅₀ values between 0.92 and 67.8 nM depending on the exact _RET_ genotype. Information based on natural as well as induced resistance mutations and molecular modelling suggests that selpercatinib directly inhibits RET autophosphorylation by competing with ATP for binding. Various single amino acid mutations at position 810 inhibit selpercatinib binding without significantly altering ATP binding, potentially leading to treatment failures. Selpercatinib is also reported to inhibit other tyrosine kinase receptors, including VEGFR1, VEGFR3, FGFR1, FGFR2, and FGFR3, at clinically relevant concentrations. The significance of these effects is not well studied.