Could Retsevmo® ▼ (selpercatinib) prolong QT interval?

Selpercatinib and Prolonged QT Interval

Warnings and Precautions

Selpercatinib can cause concentration-dependent QT interval prolongation. Review of ECG data showed 6.2% of patients had >500 msec maximum post‑baseline QTcF value, and 17.5% of patients had a >60 msec maximum increase from baseline in QTcF intervals.¹

At the time of the last post-baseline measurement, increase in QTc value >60 msec was reported in 2.6% of patients.¹

Patients should have a QTcF interval of ≤470 ms and serum electrolytes within normal range before starting selpercatinib treatment. ¹

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.

Electrocardiograms and serum electrolytes should be monitored in all patients

• after 1 week of selpercatinib treatment

• at least monthly for the first 6 months and

• otherwise as clinically indicated.¹

Monitor the QT interval with ECGs more frequently when selpercatinib is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval.¹

Withhold and reduce dose or permanently discontinue selpercatinib based on the toxicity severity.¹

Dose Modifications Due to QT Prolongation

Dose modification by weight for AEs is presented in Table 1.

Table 1.  Recommended Selpercatinib Dose Reductions for Adverse Reactions¹

Dose Reduction	Patients Weighing Less Than 50 kg	Patients Weighing 50 kg or Greater
First	80 mg orally twice daily	120 mg orally twice daily
Second	40 mg orally twice daily	80 mg orally twice daily
Third	40 mg orally once daily	Not Applicable

Dose modification recommendations specific to QT prolongation are presented in Table 2.

Table 2. Dose Management for QT Interval Prolongation¹

Observed Toxicity	Dose Modification
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.

Abbreviation: QTcF = QT interval corrected for heart rate (Fridericia method).

Use With Drugs That Prolong QTc

Selpercatinib should be used with caution in combination with CYP3A4 inhibitors or other drugs known to prolong QTc.¹

CYP3A4 Inhibitors

Monitor the QT interval more frequently when selpercatinib is concomitantly administered with a strong CYP3A inhibitors or drugs known to prolong QTc interval. ¹

Avoid coadministration of strong CYP3A4 inhibitors with selpercatinib. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the selpercatinib as seen in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume selpercatinib at the dose taken prior to initiating the CYP3A4 inhibitor.

Table 3. Recommended Selpercatinib Dosage for Concomitant Use of Strong CYP3A Inhibitors ¹

Current Selpercatinib Dosage	Recommended Selpercatinib Dosage
120 mg orally twice daily	40 mg orally twice daily
160 mg orally twice daily	80 mg orally twice daily

Abbreviation: CYP = cytochrome P450.

Clinical Trial Experience

LIBRETTO-001 is a multicenter, open-label, phase 1/2 study of selpercatinib administered orally to patients with RET fusion-positive solid tumors, RET-mutant MTC, and other tumors with RET activation.^2-4

There were no reports of

• torsade de pointes

• sudden death

• ventricular tachycardia

• ventricular fibrillation, or

• ventricular flutter during the study.

No patient discontinued treatment due to QT prolongation.¹

In the data-cut off of March 2020 (N=746), in the overall population, ECG QT prolonged was reported in 18% of patients (4% grade 3/4), with 14% considered related to selpercatinib. Severity of the related events was reported to be

• grade 1 (6%)

• grade 2 (5%)

• grade 3 (3%), and

• no grade 4.^1,5

Review of ECG data showed 6.2% of patients had >500 msec maximum post baseline QTcF value, and 17.5% of patients had a >60 msec maximum increase from baseline in QTcF intervals.

At the time of the last post-baseline measurement, increase in QTc value >60 msec was reported in 2.6% of patients.¹

During the study, 12-lead ECGs were performed during screening (in triplicate) and

• before the first dose (triplicate, up to 4 hours before dose)

• 2 and 4 hours (triplicate) after the first dose, and

• at the eighth day dose.⁵

Triplicate ECGs were obtained 2 hours postdose (±10 minutes) every 28 days after the first dose for 6 months. Additional ECGs could have been performed if clinically indicated.⁵

Selpercatinib has not been studied in patients with clinically significant active cardiovascular disease or recent MI. Study exclusion criteria included

• clinically significant active cardiovascular disease or history of MI within 6 months prior to planned start of LOXO-292, and

• prolongation of the QTcF interval >470 ms on at least 2 out of 3 consecutive ECGs and mean QTcF >470 ms on all 3 ECGs during screening. 

Correction of suspected drug-induced QTcF prolongation could be attempted at the Investigator’s discretion if clinically safe to do so.⁵

In patients in the December 2019 data cut-off, QTcF prolongation was manageable by 

• dose interruptions (15 patients)

• dose reductions (16 patients), or

• no action taken with selpercatinib (84 patients).

 There were no patients who discontinued treatment due to QT prolongation.⁵

References

1. Retsevmo [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Phase 1/2 study of LOXO-292 in patients with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). ClinicalTrials.gov identifier: NCT03157128. Updated July 2, 2020. Accessed January 25, 2020. https://www.clinicaltrials.gov/ct2/show/NCT03157128

3. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. https://dx.doi.org/10.1056/NEJMoa2005651

4. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. https://dx.doi.org/10.1056/NEJMoa2005653

5. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

AE = adverse event

CYP = cytochrome P450

ECG = electrocardiogram

MI = myocardial infarction

MTC = medullary thyroid cancer

QTc = corrected QT interval

QTcF = QT interval corrected for heart rate (Fridericia method)

RET = rearranged during transfection

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.