Retevmo

Uses

Retevmo is a RET receptor tyrosine kinase inhibitor for the treatment of RET-driven non-small cell lung cancer, medullary thyroid cancer, and thyroid cancer in appropriate patient populations.

Retevmo is indicated for the treatment of RET fusion-positive non-small cell lung cancer in adult patients. Retevmo is also indicated for the systemic treatment of advanced or metastatic RET-mutant medullary thyroid cancer and for the systemic treatment of RET fusion-positive radioactive iodine-refractory thyroid cancer in both adult and pediatric patients aged 12 and over.

Retevmo is currently approved for these indications under an accelerated approval scheme and continued approval may be contingent on future confirmatory trials.

Retevmo is also used to associated treatment for these conditions: Advanced RET-fusion thyroid cancer, Advanced RET-mutant medullary thyroid cancer, Metastatic RET-fusion Non Small Cell Lung Cancer, Metastatic RET-fusion thyroid cancer, Metastatic RET-mutant medullary thyroid cancer

How Retevmo works

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.

Retevmo 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.

Retevmo 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.

Toxicity

Toxicity information regarding selpercatinib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hepatotoxicity, hypertension, prolonged QT interval, and hemorrhaging. Symptomatic and supportive measures are recommended.

Food Interaction

• Take with or without food. Patients on proton pump inhibitors should take selpercatinib with food.

[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of selpercatinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Inhibition of hepatic CYP450 3A4 may also contribute.

The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors.

When selpercatinib was coadministered with multiple doses of itraconazole, a potent CYP450 3A4 inhibitor, selpercatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 30% and 133%, respectively.

Based on pharmacokinetic modeling, administration of selpercatinib with multiple doses of the moderate CYP450 3A4 inhibitors diltiazem, fluconazole, or verapamil is predicted to increase selpercatinib Cmax by 46% to 76% and AUC by 60% to 99%.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to selpercatinib may increase the risk of serious adverse effects such as QT interval prolongation, liver transaminase and bilirubin elevations, hypertension, hemorrhage, edema, and hypersensitivity reactions (e.g., fever, rash, arthralgias
MANAGEMENT: Patients should limit or avoid consumption of grapefruit and grapefruit juice during treatment with selpercatinib.

Retevmo Hypertension interaction

[Moderate] Retevmo may cause hypertension and therapy should not be initiated in patients with uncontrolled hypertension.

Care should be exercised when using this agent in hypertensive patients.

Optimize blood pressure before starting treatment.

It is recommended to monitor blood pressure after 1 week, and regularly as clinically indicated.

Initiate or adjust anti-hypertensive therapy as appropriate.

Withhold, reduce dose, or permanently discontinue treatment based on the severity.

Retevmo Disease Interaction

Moderate: bleeding, hypertension, liver dysfunction, Selpercatinib – arrhythmias, Selpercatinib – renal dysfunction

Volume of Distribution

Retevmo has an apparent volume of distribution of 191 L; the volume of distribution increases with increasing body weight.

Elimination Route

In patients with locally advanced or metastatic solid tumours receiving 160 mg of selpercatinib twice daily, steady-state was achieved after approximately 7 days, with a C_max of 2,980 (CV 53%) and AUC_0-24h of 51,600 (CV 58%). The absolute bioavailability is between 60 and 82% (mean 73%), and the median t_max is two hours. Food has no apparent effect on the AUC or C_max of selpercatinib. Patients with hepatic impairment display a concomitant increase in AUC_0-INF for mild (7%), moderate (32%), and severe (77%) impairment.

Half Life

Retevmo has a half-life of 32 hours in healthy individuals.

Clearance

Retevmo has an apparent clearance of 6L/h; the clearance increases with increasing body weight.

Elimination Route

Retevmo administered as a single 160 mg dose in healthy individuals was primarily recovered in feces (69%, 14% unchanged) and urine (24%, 12% unchanged).

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