Selpercatinib

Selpercatinib is an inhibitor of the rearranged during transfection (RET) receptor tyrosine kinase. Certain point mutations in RET, or in-frame fusions of RET with various partners, produce constitutively active RET proteins that act as oncogenic drivers and promote proliferation of tumour cells.

Mechanism of Action

• RET inhibition: selpercatinib inhibited wild-type RET and multiple mutated RET isoforms, and also VEGFR1 and VEGFR3, with IC50 values from 0.92 to 67.8 nM. It inhibited FGFR1, 2 and 3 only at higher concentrations that are still clinically achievable.
• Activity in RET-driven models: in cell and animal models with constitutively active RET from fusions or mutations (including CCDC6-RET, KIF5B-RET, RET V804M and RET M918T) it showed anti-tumour activity, also in mice with an intracranially implanted RET fusion-positive tumour.
• Resistance: it is thought to compete with ATP at the kinase site; amino-acid changes at position 810 of RET reduce its binding and may cause treatment failure.
• Cardiac electrophysiology: in a thorough QT study in 32 healthy subjects, no large change (more than 20 ms) in QTcF occurred at concentrations like those with therapeutic dosing. Exposure-response analysis indicated that supratherapeutic concentrations could raise QTc by more than 20 ms.

Pharmacokinetics

• Absorption: rapid, with tmax about 2 hours after a 160 mg dose and absolute bioavailability of 73.2% (range 60.2–81.5%). A high-fat meal raised AUC by 9% and lowered Cmax by 14%, which is not clinically relevant. Steady state is reached in about 7 days, with a median accumulation ratio of 3.4-fold at 160 mg twice daily; mean steady-state Cmax is 2,980 ng/mL and AUC0–24h 51,600 ng·h/mL. The hard capsules and film-coated tablets are bioequivalent.
• Distribution: apparent volume of distribution at steady state 203.1 L in adult patients; 96% bound to plasma proteins in vitro, independent of concentration; blood-to-plasma ratio 0.7.
• Metabolism: predominantly by CYP3A4. After a radiolabelled dose, unchanged selpercatinib made up 86% of the radioactive components in plasma.
• Elimination: after a single radiolabelled 160 mg dose in healthy subjects, most radioactivity was recovered in faeces (about 69%, 14% as unchanged drug) and the rest in urine (about 24%, 12% unchanged). Half-life and clearance are given in section 5.2 of the SmPC.
• Special populations: clearance and volume of distribution rise with body weight. Exposure is higher in hepatic impairment (adults with severe impairment take a lower dose, see Administration and Dosage); renal impairment needs no dose adjustment.

Retsevmo is used as monotherapy; the hard capsules and the film-coated tablets have the same indications.

In adults

• Non-small cell lung cancer (NSCLC): advanced RET fusion-positive NSCLC not previously treated with a RET inhibitor.

In adults and paediatric patients 2 years of age and older

• Thyroid cancer: advanced RET fusion-positive thyroid cancer in patients who are radioactive iodine-refractory (if radioactive iodine is appropriate).
• Medullary thyroid cancer (MTC): advanced RET-mutant MTC.
• Solid tumours: advanced RET fusion-positive solid tumours, when treatment options not targeting RET provide limited clinical benefit or have been exhausted.

For each indication the RET alteration is confirmed by a validated test before treatment (see Administration and Dosage).

• Hypersensitivity to selpercatinib or to any of the excipients.

The safety data come from 1,188 patients in three studies (LIBRETTO-001, LIBRETTO-431 and LIBRETTO-531). The most common serious reactions (≥1.0%) were pneumonia (5.3%), haemorrhage (2.4%), abdominal pain (2.1%), decreased blood sodium (2.0%), diarrhoea (1.5%), hypersensitivity (1.4%), vomiting (1.3%), increased blood creatinine (1.3%), pyrexia (1.3%), urinary tract infections (1.3%), and increased ALT and AST (1.0% each). Treatment was permanently stopped because of adverse events in 8.8% of patients; the most common reactions behind this were increased ALT (0.7%), fatigue (0.5%) and increased AST (0.4%).

Very common (≥1/10): urinary tract infections, pneumonia, hypothyroidism, decreased appetite, headache, dizziness, QT prolongation on the electrocardiogram, hypertension, haemorrhage, diarrhoea, dry mouth, abdominal pain, constipation, nausea, vomiting, stomatitis, rash, erectile dysfunction, oedema, fatigue, pyrexia. Laboratory changes: raised AST, ALT, creatinine, alkaline phosphatase and total bilirubin; decreased calcium, sodium, potassium, magnesium, albumin, lymphocyte, white blood cell, neutrophil and platelet counts, and haemoglobin.

Common (≥1/100 to <1/10): hypersensitivity, interstitial lung disease or pneumonitis, chylothorax, chylous ascites, epiphysiolysis of the femoral head (seen in 6.4% of paediatric patients under 18 years).

Not known: Stevens-Johnson syndrome (from post-marketing reports).

Grade 3 or higher hypertension, raised AST and ALT, decreased lymphocyte count and decreased sodium were themselves very common. Serious and sometimes fatal haemorrhage, interstitial lung disease, hypersensitivity and severe skin reactions are described under Special Instructions.

Selpercatinib is broken down by CYP3A4 and is a substrate of P-glycoprotein (P-gp) and BCRP, although these transporters do not appear to limit its absorption.

• Strong CYP3A and/or P-gp inhibitors (ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole, nefazodone): itraconazole raised AUC by 130% and Cmax by 30%. If co-administration is unavoidable, the selpercatinib dose is reduced by 50%.
• Strong CYP3A4 inducers (carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St John’s wort): rifampicin lowered AUC by about 87% and Cmax by 70%. Avoid.
• Sensitive CYP2C8 substrates: selpercatinib raised repaglinide AUC by about 188%. Avoid sensitive CYP2C8 substrates, for example repaglinide, paclitaxel, sorafenib, rosiglitazone, montelukast and buprenorphine.
• Sensitive CYP3A4 substrates: selpercatinib raised midazolam AUC by about 54%. Avoid sensitive CYP3A4 substrates, for example alfentanil, buspirone, midazolam, triazolam, simvastatin and lovastatin.
• Acid-reducing medicines: selpercatinib dissolves less at higher pH. With a proton pump inhibitor, take selpercatinib with a meal, because omeprazole lowered exposure only in the fasted state. Take selpercatinib 2 hours before or 10 hours after an H2 receptor antagonist.
• P-gp and BCRP substrates: dabigatran exposure rose by about 38% (AUC) and rosuvastatin by about 80%. Use caution with sensitive P-gp substrates (such as fexofenadine, dabigatran etexilate, colchicine, saxagliptin and, with its narrow therapeutic index, digoxin) and BCRP substrates (such as rosuvastatin and prazosin).
• MATE1 substrates: selpercatinib inhibits MATE1 and may raise serum creatinine by reducing its tubular secretion.
• Levothyroxine: selpercatinib may block the conversion of levothyroxine (T4) to triiodothyronine (T3), so the response to levothyroxine can be insufficient and liothyronine may be needed.
• QT-prolonging medicines: ECGs are done more often (see Special Instructions).
• Interaction studies have only been performed in adults.

Therapy should be initiated and supervised by a physician experienced in anti-cancer therapies. Before treatment, a RET gene mutation (MTC) or fusion (all other tumour types) is confirmed with a CE-marked in vitro diagnostic for that purpose or, if none is available, an alternative validated test. Retsevmo is for oral use, at about the same time every day.

• Hard capsules: swallowed whole (not opened, crushed or chewed), with or without food. Tablets are available for paediatric patients who cannot swallow capsules.
• Film-coated tablets: swallowed whole (not crushed, chewed or split), with or without food. If the larger tablets are hard to swallow, several of the smaller tablets can be taken to reach the dose.
• With a proton pump inhibitor, take it with a meal; with an H2 receptor antagonist, take it 2 hours before or 10 hours after.

Recommended Dose

• 12 years and older, by body weight: under 50 kg, 120 mg twice daily; 50 kg or more, 160 mg twice daily.
• 2 to under 12 years, by body surface area (BSA): 0.45–0.65 m², 40 mg three times daily; 0.66–1.08 m², 80 mg twice daily; 1.09–1.52 m², 120 mg twice daily; 1.53 m² or more, 160 mg twice daily. Retsevmo is not recommended below 0.45 m².
• Treatment continues until disease progression or unacceptable toxicity.
• With a strong CYP3A inhibitor: reduce the current dose by 50%; after stopping the inhibitor, return to the earlier dose after 3–5 half-lives of the inhibitor.

Dose Adjustments for Side Effects

• Dose steps (each step is one dose level; stop permanently if three reductions are not tolerated): adults and adolescents 50 kg or more, 160, 120, 80, then 40 mg twice daily; under 50 kg, 120, 80, then 40 mg twice daily. Children 2 to under 12 years: BSA 1.53 m² or more, 160, 120, 80, then 40 mg twice daily; BSA 1.09–1.52 m², 120 mg twice daily, 80 mg twice daily, 40 mg twice daily, then 40 mg once daily; BSA 0.66–1.08 m², 80 mg twice daily, 40 mg twice daily, then 40 mg once daily; BSA 0.45–0.65 m², 40 mg three times daily, 40 mg twice daily, then 40 mg once daily. After the last step, treatment is stopped permanently.
• Raised ALT or AST, grade 3 or 4: suspend until baseline, resume 2 levels lower, then step back up if tolerated; stop permanently if it recurs despite dose changes.
• Hypersensitivity (any grade): suspend, start corticosteroids (1 mg/kg), resume at 40 mg twice daily with the steroid, then raise by one level a week once tolerated for 7 days; stop permanently if it recurs.
• QT prolongation: for grade 3 (QTcF above 500 ms), suspend until QTcF is below 470 ms (440 ms or less under 12 years) or at baseline, then resume one level lower; for grade 4, stop permanently if it stays uncontrolled after two reductions or there are signs of serious arrhythmia.
• Hypertension: for grade 3, suspend until controlled and resume one level lower if clinically indicated; for grade 4, stop permanently if it cannot be controlled.
• Haemorrhage: grade 3, suspend until baseline and resume at a reduced dose (stop permanently if it recurs); grade 4, stop permanently.
• Interstitial lung disease or pneumonitis: grade 2, withhold until resolved and resume at a reduced dose (stop if it recurs); grade 3 or 4, stop.
• Other grade 3 or 4 reactions: suspend until baseline, resume at a reduced dose; stop permanently if grade 4 recurs.

Special Populations

• Elderly: no dose adjustment; no overall differences from younger patients, and limited data from 75 years.
• Renal impairment: no adjustment in mild, moderate or severe impairment; no data in end-stage renal disease or dialysis.
• Hepatic impairment: close monitoring; no adjustment in mild (Child-Pugh A) or moderate (Child-Pugh B) impairment. Adults with severe impairment (Child-Pugh C) take 80 mg twice daily. It has not been studied in patients under 18 years with hepatic impairment; in severe impairment treatment starts with caution. Children under 12 years with severe impairment start by BSA: 0.45–0.65 m², 40 mg once daily; 0.66–1.52 m², 40 mg twice daily; 1.53 m² or more, 80 mg twice daily.
• Children: not for use under 2 years (no data). Open growth plates in adolescents should be monitored, and interruption or stopping considered by the severity of any abnormality and an individual risk-benefit assessment.

Missed or Vomited Dose

Take the next dose at its scheduled time; do not take an extra dose.

Efficacy Across Tumour Types

The benefit was shown in single-arm trials in a relatively small number of patients with RET fusions, on response rate and duration, in a limited number of tumour types. For RET fusion-positive solid tumours, selpercatinib should be used only when there are no treatment options of established clinical benefit, or these have been exhausted.

Interstitial Lung Disease and Pneumonitis

Severe, life-threatening or fatal cases have occurred. Patients are monitored for respiratory symptoms; with acute or worsening symptoms (dyspnoea, cough, fever) selpercatinib is withheld and ILD is investigated.

Liver Enzymes

ALT and AST are checked before starting, every 2 weeks for the first 3 months, monthly for the next 3 months and then as indicated.

Hypertension

Blood pressure is controlled before starting, monitored during treatment and treated as needed. Selpercatinib is stopped permanently if medically significant hypertension cannot be controlled.

QT Interval Prolongation

Use caution in congenital or acquired long QT syndrome or other conditions that predispose to arrhythmias. Before starting, QTcF should be 470 ms or less (440 ms or less under 12 years) and electrolytes normal. ECG and electrolytes are checked after 1 week and at least monthly for the first 6 months, then as indicated, and more often with QT-prolonging medicines. Hypokalaemia, hypomagnesaemia and hypocalcaemia are corrected.

Hypothyroidism

Thyroid function is measured at baseline and monitored periodically. Patients may respond poorly to levothyroxine because selpercatinib can block conversion of T4 to T3.

Hypersensitivity

Most events occurred in NSCLC patients previously treated with anti-PD-1/PD-L1 immunotherapy. Signs include fever, rash, and joint or muscle pain with falling platelets or raised aminotransferases. Selpercatinib is suspended and steroids started; it is stopped permanently for recurrence.

Haemorrhage

Serious, including fatal, haemorrhagic events have occurred. Selpercatinib is stopped permanently for life-threatening or recurrent severe haemorrhage.

Tumour Lysis Syndrome

Cases have been observed. Risk factors are high tumour burden, chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine; these patients are monitored closely and prophylaxis, including hydration, is considered.

Femoral Head Epiphysiolysis in Paediatric Patients

Epiphysiolysis of the femoral head has been reported in patients under 18 years. Patients are monitored for symptoms and treated medically or surgically as appropriate.

Severe Cutaneous Adverse Reactions

Stevens-Johnson syndrome, which can be life-threatening or fatal, has been reported. Patients should seek medical advice at once if signs appear; selpercatinib is withdrawn immediately and, after such a reaction, must never be restarted.

Strong CYP3A4 Inducers

Avoid, because of the risk of reduced efficacy.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use highly effective contraception during treatment and for at least one week after the last dose; men with female partners of childbearing potential should use effective contraception for the same period.
• Pregnancy: no data; animal studies showed reproductive toxicity. Not recommended in pregnancy or in women of childbearing potential not using contraception; use only if the benefit justifies the risk to the foetus.
• Breastfeeding: not known whether it passes into milk; a risk to the infant cannot be excluded. Stop breastfeeding during treatment and for at least one week after the last dose.
• Fertility: no human data; animal findings suggest male and female fertility may be compromised. Both men and women should seek advice on fertility preservation before treatment.

Effect on Driving

Retsevmo may have a minor influence on the ability to drive and use machines. Be cautious if fatigue or dizziness occurs.

Retsevmo hard capsules and film-coated tablets do not require any special storage conditions. The capsules are supplied in plastic (HDPE) bottles or PCTFE/PVC–aluminium blister cards. Not all pack sizes may be marketed.

3 years (hard capsules and film-coated tablets).

Prescription only (Rx), subject to restricted medical prescription. Treatment is started and supervised by a physician experienced in anti-cancer therapies. Retsevmo is taken by mouth at home, so it is supplied to the patient or to the treating clinic on prescription.