RET-mutant medullary thyroid cancer

Active Ingredient: Selpercatinib

Indication for Selpercatinib

Population group: only adolescents (12 years - 18 years old) , adults (18 years old or older)
Therapeutic intent: Curative procedure

Selpercatinib as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with advanced RET-mutant medullary thyroid cancer (MTC).

For this indication, competent medicine agencies globally authorize below treatments:

For patients weighting <50 kg 120 mg twice daily and for patients weighting ≥50 kg 160 mg twice daily

For:

Dosage regimens

Regimen A: In case that patient weight is ≤ 50 kg, oral, 120 milligrams selpercatinib, 2 times daily.

Regimen B: In case that patient weight is ≥ 50 kg, oral, 160 milligrams selpercatinib, 2 times daily.

Detailed description

The presence of a RET gene fusion should be confirmed by a validated test prior to initiation of treatment with selpercatinib.

The recommended dose of selpercatinib based on body weight is:

  • Less than 50 kg: 120 mg twice daily.
  • 50 kg or greater: 160 mg twice daily.

If a patient vomits or misses a dose, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken.

Treatment should be continued until disease progression or unacceptable toxicity.

The current selpercatinib dose should be reduced by 50% if co-administering with a strong CYP3A inhibitor. If the CYP3A inhibitor is discontinued, the selpercatinib dose should be increased (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor.

Based on results from a preclinical study, open growth plates in adolescent patients should be monitored. Dose interruption or discontinuation should be considered based on the severity of any growth plate abnormalities and an individual risk-benefit assessment.

Dose adjustments

Management of some adverse reactions may require dose interruption and/or dose reduction. Selpercatinib dose modifications are summarised in Table 1 and Table 2.

Table 1. Recommended dose modifications for selpercatinib for adverse reactions based on body weight:

Dose modification Adults and adolescents ≥50 KgAdults and adolescents <50 Kg
Starting dose 160 mg orally twice daily 120 mg orally twice daily
First dose reduction 120 mg orally twice daily80 mg orally twice daily
Second dose reduction 80 mg orally twice daily 40 mg orally twice daily
Third dose reduction 40 mg orally twice daily Not applicable

Table 2. Recommended dose modifications for adverse reactions:

Adverse drug
reaction (ADR)
 Dose modification
Increased ALT or
AST
Grade 3 or Grade 4• Suspend dose until toxicity resolves
to baseline.
Resume at a dose reduced by
2 levels.
• If after at least 2 weeks selpercatinib
is tolerated without recurrent
increased ALT or AST, increase
dosing by 1 dose level.
• If selpercatinib is tolerated without
recurrence for at least 4 weeks,
increase to dose taken prior to the
onset of Grade 3 or 4 increased AST
or ALT.
• Permanently discontinue
selpercatinib if Grade 3 or 4 ALT or
AST increases recur despite dose
modifications.
Hypersensitivity All Grades• Suspend dose until toxicity resolves
and begin corticosteroids at a dose of
1 mg/kg.
Resume selpercatinib at 40 mg twice
daily while continuing steroid
treatment. Discontinue selpercatinib
for recurrent hypersensitivity.
• If after at least 7 days, selpercatinib
is tolerated without recurrent
hypersensitivity, incrementally
increase the selpercatinib dose by
1 dose level each week, until the
dose taken prior to the onset of
hypersensitivity is reached. Taper
steroid dose after selpercatinib has
been tolerated for at least 7 days at
the final dose.
QT interval
prolongation
Grade 3• Suspend dose for QTcF intervals
>500 ms until the QTcF returns to
<470 ms or baseline.
• Resume selpercatinib treatment at
the next lower dose level.
Grade 4• Permanently discontinue
selpercatinib if QT prolongation
remains uncontrolled after two dose
reductions or if the patient has signs
or symptoms of serious arrhythmia.
Hypertension Grade 3• Patient blood pressure should be
controlled before starting treatment.
• Selpercatinib should be suspended
temporarily for medically significant
hypertension until controlled with
antihypertensive therapy. Dosing
should be resumed at the next lower
dose if clinically indicated.
Grade 4• Selpercatinib should be discontinued
permanently if medically significant
hypertension cannot be controlled.
Haemorrhagic
events
Grade 3 or Grade 4• Selpercatinib should be suspended
until recovery to baseline.
• Discontinue selpercatinib for severe
or life-threatening haemorrhagic
events.
Interstitial lung
disease
(ILD)/Pneumonitis
Grade 2• Withhold selpercatinib until
resolution.
• Resume at a reduced dose.
• Discontinue selpercatinib for
recurrent ILD/pneumonitis
Grade 3 or Grade 4• Discontinue selpercatinib.
Other adverse
reactions
Grade 3 or Grade 4• Selpercatinib should be suspended
until recovery to baseline.
• Discontinue selpercatinib for severe
or life-threatening events

Elderly

No dose adjustment is required based on age.

No overall differences were observed in the treatment emergent adverse events or effectiveness of selpercatinib between patients who were ≥65 years of age and younger patients. Limited data are available in patients ≥75 years.

Dosage considerations

It can be taken with or without food.

Patients should take the doses at approximately the same time every day.

Retsevmo must be accompanied by a meal if used concomitantly with a proton pump inhibitor.

Retsevmo should be administered 2 hours before or 10 hours after H2 receptor antagonists.

Active ingredient

Selpercatinib

Selpercatinib is an inhibitor of the rearranged during transfection (RET) receptor tyrosine kinase. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET protein resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T.

Read more about Selpercatinib

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