Selpercatinib

Selpercatinib should be used with caution in patients with such conditions as congenital long QT syndrome or acquired long QT syndrome or other clinical conditions that predispose to arrhythmias.

Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval. Selpercatinib may require dose interruption or modification.

Selpercatinib increased the C_max and AUC of repaglinide (a substrate of CYP2C8) by approximately 91% and 188% respectively. Therefore, coadministration with sensitive CYP2C8 substrates (e.g., odiaquine, cerivastatin, enzalutamide, paclitaxel, repaglinide, torasemide, sorafenib, rosiglitazone, buprenorphine, selexipag, dasabuvir and montelukast), should be avoided.

Selpercatinib is an in vitro inhibitor of P-gp and BCRP. In vivo, selpercatinib increased C_max and AUC of rosuvastatin, a BCRP substrate, by 71% and 80%, respectively. Caution should be used when taking a BCRP substrate (e.g., rosuvastatin, prazosin).

Selpercatinib inhibits the renal transporter multidrug and toxin extrusion protein 1 (MATE1). In vivo interactions of selpercatinib with clinically relevant substrates of MATE1, such as creatinine, may occur.

Selpercatinib increased C_max and AUC of midazolam (a CYP3A4 substrate) by approximately 39% and 54%, respectively. Therefore, concomitant use with sensitive CYP3A4 substrates, (e.g., alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, tipranavir, triazolam, vardenafil), should be avoided.

Close monitoring of patients with impaired hepatic function is important. No dose adjustment is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Adults with severe (Child-Pugh class C) hepatic impairment should be dosed with 80 mg selpercatinib twice daily. The use of selpercatinib has not been studied in patients under 18 years of age with hepatic impairment. Treatment in patients under 18 years of age with severe hepatic impairment should be initiated with caution, and dosing adjustments should be guided by clinical judgment and individual patient tolerability. For paediatric patients under 12 years of age with severe hepatic impairment, the recommended starting dose is shown in the following table.

Recommended starting dose for paediatric patients under 12 years with severe hepatic impairment:

Selpercatinib is an in vitro inhibitor of P-gp and BCRP. In vivo, selpercatinib increased C_max and AUC of dabigatran, a P-gp substrate, by 43% and 38%, respectively. Therefore, caution should be used when taking a sensitive P-gp substrate (e.g., fexofenadine, dabigatran etexilate, colchicine, saxagliptin), and particularly those with a narrow therapeutic index (e.g., digoxin).

Co-administration of a single 160 mg selpercatinib dose with itraconazole, a strong CYP3A inhibitor, increased the C_max and AUC of selpercatinib by 30% and 130%, respectively, compared to selpercatinib given alone. If strong CYP3A and/or P-gp inhibitors, including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole and nefazodone, have to be coadministered, the dose of selpercatinib should be reduced.

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.

Concomitant use of strong CYP3A4 inducers should be avoided due to the risk of decreased efficacy of selpercatinib.

Co-administration of rifampicin, a strong CYP3A4 inducer resulted in a decrease of approximately 87% and 70% in selpercatinib AUC and C_max, respectively, compared to selpercatinib alone, therefore the concomitant use of strong CYP3A4 inducers including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's Wort (Hypericum perforatum), should be avoided.

There are no data in patients with end stage renal disease, or in patients on dialysis.

Coadministration with multiple daily doses of omeprazole (a proton pump inhibitor) decreased selpercatinib AUC_0-INF and C_max when selpercatinib was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC_0-INF and C_max when selpercatinib was administered with food.

No human data on the effect of selpercatinib on fertility are available. Based on findings from animal studies, male and female fertility may be compromised by treatment with selpercatinib. Both men and women should seek advice on fertility preservation before treatment.

Selpercatinib could inhibit D2 deiodinase and thereby decrease the conversion of levothyroxine (T4) to liothyronine (T3). Patients could therefore have an insufficient response to substitution with levothyroxine and supplementation with liothyronine may be needed.

There are no available data from the use of selpercatinib in pregnant women. Studies in animals have shown reproductive toxicity. Selpercatinib is not recommended during pregnancy and in women of childbearing potential not using contraception. It should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus.

It is unknown whether selpercatinib is excreted in human milk. A risk to breast-fed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with selpercatinib and for at least one week after the last dose.

Women of childbearing potential/Contraception in females and males

Women of childbearing potential have to use highly effective contraception during treatment and for at least one week after the last dose of selpercatinib. Men with female partners of childbearing potential should use effective contraception during treatment and for at least one week after the last dose of selpercatinib.

Fertility

No human data on the effect of selpercatinib on fertility are available. Based on findings from animal studies, male and female fertility may be compromised by treatment with selpercatinib. Both men and women should seek advice on fertility preservation before treatment.

Selpercatinib may have minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue or dizziness during treatment with selpercatinib.

Summary of the safety profile

The integrated frequency of adverse drug reactions (ADRs) reported in patients treated with selpercatinib from an open-label, multicentre, dose-escalation phase ½ study (LIBRETTO-001) and from two open-label, multicentre, randomised phase 3 comparative studies (LIBRETTO-431 and LIBRETTO-531) are summarised. The most common (≥1.0%) serious adverse drug reactions (ADRs) are pneumonia (5.3%), haemorrhage (2.4%), abdominal pain (2.1%), blood sodium decreased (2.0%), diarrhoea (1.5%), hypersensitivity (1.4%), vomiting (1.3%), blood creatinine increased (1.3%), pyrexia (1.3%), urinary tract infections (1.3%), ALT increased (1.0%) and AST increased (1.0%).

Permanent discontinuation of selpercatinib for treatment emergent adverse events, regardless of attribution occurred in 8.8% of patients. The most common ADRs resulting in permanent discontinuation (3 or more patients) were increased ALT (0.7%), fatigue (0.5%), increased AST (0.4%), blood bilirubin increased (0.3%), pneumonia (0.3%), thrombocytopenia (0.3%), haemorrhage (0.3%), and hypersensitivity (0.3%).

Tabulated list of adverse drug reactions

The integrated frequency and severity of ADRs reported in patients treated with selpercatinib in Study LIBRETTO-001, Study LIBRETTO-431, and Study LIBRETTO-531 are shown in Table 1.

The ADRs are classified according to the MedDRA system organ class and frequency. Frequency groups are defined by the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000), and not known (cannot be estimated from available data).

Median time on treatment with selpercatinib was 30.09 months (Study LIBRETTO-001), 16.7 months (Study LIBRETTO-431), and 14.9 months (Study LIBRETTO-531).

Table 1. Adverse drug reactions in patients receiving selpercatinib (N=1188):

^a Urinary tract infections includes urinary tract infection, cystitis, urosepsis, escherichia urinary tract infection, escherichia pyelonephritis, kidney infection, nitrite urine present, pyelonephritis, urethritis, urinary tract infection bacterial and urogenital infection fungal.
^b Pneumonia includes pneumonia, lung infection, pneumonia aspiration, empyema, lung consolidation, pleural infection, pneumonia bacterial, pneumonia staphylococcal, atypical pneumonia, lung abscess, pneumocystis jirovecii pneumonia, pneumonia pneumococcal, pneumonia respiratory syncytial viral, infectious pleural effusion, and pneumonia viral.
^c Hypersensitivity reactions were characterised by a maculopapular rash often preceded by a fever with associated arthralgias/myalgias during the patient's first cycle of treatment (typically between Days 7-21).
^d Hypersensitivity includes drug hypersensitivity and hypersensitivity.
^e Headache includes headache, sinus headache and tension headache.
^f Dizziness includes dizziness, vertigo, presyncope and dizziness postural.
^g Electrocardiogram QT prolonged includes electrocardiogram QT prolonged and Electrocardiogram QT interval abnormal.
^h Hypertension includes hypertension and blood pressure increased.
ⁱ Haemorrhage includes epistaxis, haemoptysis, contusion, haematuria, rectal haemorrhage, vaginal haemorrhage, cerebral haemorrhage, traumatic haematoma, blood urine present, conjunctival haemorrhage, ecchymosis, gingival bleeding, haematochezia, petechiae, blood blister, spontaneous haematoma, abdominal wall haematoma, anal haemorrhage, angina bullosa haemorrhagica, disseminated intravascular coagulation, eye haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haemorrhage intracranial, haemorrhage subcutaneous, haemorrhoidal haemorrhage, hepatic haematoma, intra-abdominal haemorrhage, mouth haemorrhage, oesophageal haemorrhage, pelvic haematoma, periorbital haematoma, periorbital haemorrhage, pharyngeal haemorrhage, pulmonary contusion, purpura, retroperitoneal haematoma, skin haemorrhage, subarachnoid haemorrhage, diverticulum intestinal haemorrhagic, eye haematoma, haematemesis, haemorrhage, haemorrhagic stroke, hepatic haemorrhage, laryngeal haemorrhage, lower gastrointestinal haemorrhage, melaena, menorrhagia, occult blood positive, post procedural haemorrhage, postmenopausal haemorrhage, retinal haemorrhage, scleral haemorrhage, subdural haemorrhage, traumatic haemothorax, tumour haemorrhage, upper gastrointestinal haemorrhage, uterine haemorrhage, vessel puncture site haematoma, haemarthrosis and haematoma.
^j Interstitial lung disease/pneumonitis includes interstitial lung disease, pneumonitis, radiation pneumonitis, restrictive pulmonary disease, acute respiratory distress syndrome, alveolitis, bronchiolitis, langerhans' cell
histiocytosis, pulmonary radiation injury, cystic lung disease, lung infiltration and lung opacity.
^k Diarrhoea includes diarrhoea, anal incontinence, defaecation urgency, frequent bowel movements and gastrointestinal hypermotility.
^l Dry mouth includes dry mouth and mucosal dryness.
^m Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and gastrointestinal pain.
ⁿ Vomiting includes vomiting, retching and regurgitation.
° Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation and oral mucosal blistering.
^p Chylous ascites includes chylous ascites and ascites chylous (MedDRA LLTs).
^q Rash includes rash, rash maculo-papular, dermatitis, skin exfoliation, rash macular, rash erythematous, urticaria, dermatitis allergic, exfoliative rash, rash papular, rash morbilliform, rash pruritic, rash vesicular, butterfly rash, rash follicular, rash generalised, rash pustular and skin reaction.
^r From post-marketing data.
^s Epiphysiolysis of the femoral head has been commonly observed (6.4%) in paediatric patients (<18 years of age) treated with selpercatinib (n=47).
^t Erectile dysfunction has been very commonly observed (12.4%) in male patients treated with selpercatinib in clinical trials (n=986)
^u Oedema includes oedema peripheral, face oedema, periorbital oedema, swelling face, localised oedema, peripheral swelling, generalised oedema, eyelid oedema, eye swelling, lymphoedema, oedema genital, scrotal swelling, angioedema, eye oedema, oedema, scrotal oedema, skin oedema, swelling, orbital oedema, testicular swelling, vulvovaginal swelling, orbital swelling, penile oedema, periorbital swelling and swelling of eyelid.
^v Fatigue includes fatigue, asthenia and malaise.
^w Based on laboratory assessments. Percentage is calculated based on the number of patients with baseline assessment and at least one post-baseline assessment as the denominator.

Description of selected adverse reactions in patients receiving selpercatinib

Aminotransferase elevations (AST/ALT increased)

Based on laboratory assessment, ALT and AST elevations were reported in 59.4% and 61% patients, respectively. Grade 3 or 4 ALT or AST elevations were reported in 14.1% and 9.5% patients respectively.

The median time to first onset was: AST increase 4.7 weeks (range: 0.7, 227.9), ALT increase 4.4 weeks (range: 0.9, 186.1) in LIBRETTO-001, AST increase 5.1 weeks (range: 0.7, 88.1), ALT increase 5.1 weeks (range: 0.7, 110.9) in LIBRETTO-431, and AST increase 6.1 weeks (range: 0.1, 85.1), ALT increase 6.1 weeks (range: 0.1, 85.1) in LIBRETTO-531.

Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase.

QT interval prolongation

In the 837 patients in study LIBRETTO-001 who had ECGs, review of data showed 8.1% of patients had >500 msec maximum post-baseline QTcF value, and 21.6% of patients had a >60 msec maximum increase from baseline in QTcF intervals. In the 156 patients in LIBRETTO-431 who had ECGs, 5.1% of patients had >500 msec maximum post-baseline QTcF value, and 16.7% of patients had a >60 msec maximum increase from baseline in QTcF intervals. In the 191 patients in LIBRETTO-531 who had ECGs, 3.7% of patients had >500 msec maximum post-baseline QTcF value, and 17.8% of patients had a >60 msec maximum increase from baseline in QTcF intervals.

In LIBRETTO-001, LIBRETTO-431 and LIBRETTO-531 studies, there were no reports of torsades de pointes, events of Grade ≥3 or clinically significant treatment-emergent arrhythmias, ventricular tachycardia, ventricular fibrillation, or ventricular flutter. Fatal events of sudden death and cardiac arrest were reported in patients with significant cardiac history. Across all studies, two patients (0.2%) discontinued selpercatinib treatment due to QT prolongation. Selpercatinib may require dose interruption or modification.

Hypertension

In the 837 patients who had blood pressure measurements in study LIBRETTO-001, the median maximum increase from baseline systolic pressure was 32 mm Hg (range: –15, +100). Diastolic blood pressure results were similar, but the increases were of lesser magnitude. In LIBRETTO-001, only 10.3% of patients retained their baseline grade during treatment, 40.7% had an increasing shift of 1 grade, 38.5% of 2 grades, and 9.8% of 3 grades. A treatment emergent adverse event of hypertension was reported in 44.8% patients with history of hypertension (28.2% with grade 3, 4) and 41.7% of patients without history of hypertension (14.1% with grade 3, 4).

In the 154 patients treated with selpercatinib who had blood pressure measurements in LIBRETTO-431, 23.4% of patients treated with selpercatinib retained their baseline grade during treatment, 49.4% had an increasing shift of 1 grade, 22.7% had an increasing shift of 2 grades, and 3.3% had an increasing shift of 3 grades.

In the 192 patients treated with selpercatinib who had blood pressure measurements in LIBRETTO- 531, 20.8% of patients treated with selpercatinib retained their baseline grade during treatment, 43.8% had an increasing shift of 1 grade, 27.6% had an increasing shift of 2 grades, and 6.8% had an increasing shift of 3 grades.

Overall, a total of 19.8% of patients in LIBRETTO-001, 20.3% of patients in LIBRETTO-431, and 19.2% of patients in LIBRETTO-531 displayed treatment-emergent Grade 3 hypertension (defined as maximum systolic blood pressure greater than 160 mm Hg). Grade 4 treatment emergent hypertension was reported in 0.1% of patients in LIBRETTO-001, and no reports in LIBRETTO-431 and LIBRETTO-531.

Two patients (0.2%) permanently discontinued treatment due to hypertension in LIBRETTO-001, and no patients in LIBRETTO-431 and LIBRETTO-531. Dose modification is recommended in patients who develop hypertension. Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy.

Hypersensitivity

Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or increased aminotransferase.

In study LIBRETTO-001, 24.0% (201/837) of patients treated with selpercatinib had previously received anti-PD-1/PD-L1 immunotherapy. Hypersensitivity occurred in a total of 5.7% (48/837) of patients receiving selpercatinib, including Grade 3 hypersensitivity in 1.9% (16/837) of patients. Of the 48 patients with hypersensitivity in LIBRETTO-001, 54.2% (26/48) had NSCLC and had received prior anti-PD-1/PD-L1 immunotherapy.

Grade 3 hypersensitivity occurred in 3.5% (7/201) of the patients previously treated with anti-PD-1/PD-L1 immunotherapy in LIBRETTO-001.

In LIBRETTO-001, the median time to onset was 1.9 weeks (range: 0.7 to 203.9 weeks): 1.7 weeks in patients with previous anti-PD-1/PD-L1 immunotherapy and 4.4 weeks in patients who were anti-PD-1/PD-L1 immunotherapy naïve.

Study LIBRETTO-431 enrolled patients with advanced or metastatic NSCLC. Hypersensitivity occurred in a total of 1.9% (3/158) of patients receiving selpercatinib, including Grade 3 hypersensitivity in 0.6% (1/158) of patients. In an integrated analysis of patients with NSCLC receiving selpercatinib who were previously treated with anti-PD-1/PD-L1 therapy based on studies LIBRETTO-001 and LIBRETTO-431 (N=205), hypersensitivity occurred in 16.6% of patients, including ≥Grade 3 hypersensitivity in 5.9% of patients.

Study LIBRETTO-531 enrolled patients with advanced or metastatic MTC. Hypersensitivity occurred in 1 patient (0.5% [1/193]) receiving selpercatinib. This 1 patient experienced Grade 3 hypersensitivity.

Selpercatinib may require dose interruption or modification.

Haemorrhages

Grade ≥3 haemorrhagic events occurred in 2.5% of patients treated with selpercatinib across studies LIBRETTO-001, LIBRETTO-431 and LIBRETTO-531. In LIBRETTO-001 this included 4 (0.5%) patients with fatal haemorrhagic events, two cases of cerebral haemorrhage, and one case each of tracheostomy site haemorrhage, and haemoptysis. No fatal haemorrhagic events were reported in patients treated with selpercatinib in LIBRETTO-431 or LIBRETTO-531. The median time to onset 15 was 34.1 weeks (range: 0.1 week to 234.6 weeks) in LIBRETTO-001, 16.8 weeks (range: 1.1 to 94.1 weeks) in LIBRETTO-431, and 10.7 weeks (range: 1.0 to 124.1 weeks) in LIBRETTO-531. Selpercatinib should be discontinued permanently in patients with life-threatening or recurrent severe haemorrhage.

Additional information on special populations

Paediatric patients

There were 3 patients <18 years (range: 15-17) of age with RET-mutant MTC in LIBRETTO-001. There were 11 patients <18 years (range 2-17) of age with RET-mutant MTC, 13 patients <18 years (range 6–17) of age with RET fusion-positive thyroid cancer, and 6 patients <18 years (range 5–15) of age with RET altered solid tumours, of which 3 were patients with RET fusion positive solid tumours in LIBRETTO-121. There was 1 patient 12 years of age with RET-mutant MTC in LIBRETTO-531. Cases of epiphysiolysis of the femoral head have been reported in patients <18 years of age treated with selpercatinib. No other unique safety findings in children aged less than 18 years have been identified.

Tabulated list of adverse drug reactions in LIBRETTO-121

The frequency and severity of ADRs reported in patients ≤21 years of age treated with selpercatinib in Study LIBRETTO-121 are shown in Table 2.

The ADRs are classified according to the MedDRA system organ class and frequency. Frequency groups are defined by the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000), and not known (cannot be estimated from available data).

Median time on treatment with selpercatinib was 30.26 months.

Table 2. Adverse drug reactions in patients receiving selpercatinib in Study LIBRETTO-121 (n=36):

^# Among the 36 patients in LIBRETTO-121, 31 patients were less than 18 years of age, and 5 patients were between 18 and 21 years of age.
^a Urinary tract infections include urinary tract infection and cystitis.
^b Pneumonia includes pneumonia and pneumonia respiratory syncytial viral.
^c Hypersensitivity reactions were characterized by a maculopapular rash often preceded by a fever with associated arthralgias/myalgias during the patient's first cycle of treatment (typically between Days 7-21).
^d Hypersensitivity includes drug hypersensitivity and hypersensitivity.
^e Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased and thyroglobulin increased.
^f Electrocardiogram QT prolonged includes electrocardiogram QT prolonged and electrocardiogram QRS complex prolonged.
^g Haemorrhage includes epistaxis, haematuria, activated partial thromboplastin time prolonged, anal haemorrhage, blood urine present, haemoptysis, menorrhagia and mouth haemorrhage.
^h Diarrhoea includes diarrhoea and anal incontinence.
ⁱ Abdominal pain includes abdominal pain, abdominal pain upper and abdominal discomfort.
^j Rash includes rash maculo-papular, rash, rash erythematous and urticaria.
^k Musculoskeletal pain includes arthralgia, pain in extremity, back pain, non-cardiac chest pain, bone pain, musculoskeletal chest pain, musculoskeletal pain and neck pain.
^l Erectile dysfunction in male patients treated with selpercatinib. Denominator adjusted due to gender-specific event for males (n=19)
^m Fatigue includes fatigue, asthenia and malaise.
ⁿ Oedema includes face oedema, oedema peripheral, periorbital oedema, generalised oedema, localised oedema and swelling.
° Based on laboratory assessments. Percentage is calculated based on the number of patients with baseline assessment and at least one post-baseline assessment as the denominator.

Elderly

In patients receiving selpercatinib, 24.7% were ≥65-74 years of age, 8.6% were 75-84 years of age, and 1.0% ≥85 years of age in study LIBRETTO-001. In study LIBRETTO-431, 26.6% of patients receiving selpercatinib were ≥65-74 years of age, 9.5% were 75-84 years of age and 1.3% were ≥85 years of age. In study LIBRETTO-531, 20.2% of patients receiving selpercatinib were ≥65-74 years of age, 5.2% were 75-84 years of age and none were ≥85 years of age. The frequency of serious adverse events reported was higher in patients ≥65-74 years (58.0%), 75-84 years (62.5%), and ≥85 years (100.0%), than in patients <65 years (46.7%) of age in LIBRETTO-001 and in LIBRETTO-431, ≥65-74 years (38.1%), 75-84 years (46.7%), ≥85 years (50.0%), than in patients <65 years (31.3%) of age. In LIBRETTO-531 the frequency of serious adverse events reported was higher in patients 75-84 years (50%) than in patients <65 years (20.8%) and 65-74 years (17.9%).

In study LIBRETTO-001 the frequency of adverse events (AE) leading to discontinuation of selpercatinib was higher in patients ≥65-74 years (10.1%), 75-84 years (19.4%), and ≥85 years (37.5%), than in patients <65 years of age (7.6%). In study LIBRETTO-431, the frequency of AE leading to discontinuation of selpercatinib was higher in patients ≥65-74 years (14.3%), 75-84 years (20.0%) than in patients <65 years (7.1%) of age. No patients ≥85 years of age discontinued selpercatinib due to AE. In LIBRETTO-531, the frequency of AE leading to discontinuation of selpercatinib was higher in patients 75-84 years (10%), and ≥65-74 years (7.7%) than in patients <65 years (3.5%).