FDA Approves RETEVMO (Selpercatinib) for the Treatment of Adult Patients with Metastatic RET Fusion-positive Non-small Cell Lung Cancer as well as the Treatment of Adult and Pediatric Patients 12 Years of Age and Older with Advanced or Metastatic RET-mutant Medullary Thyroid Cancer or RET Fusion-positive Thyroid Cancer


On May 8, 2020, the U.S. Food and Drug Administration (FDA) approved RETEVMO (selpercatinib) for the treatment of:

  • Adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC)

     

  • Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy

     

  • Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

 

These indications were approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

The approved recommended dosage of RETEVMO based on body weight is:

  • Less than 50 kg: 120 mg orally twice daily

     

  • 50 kg or greater: 160 mg orally twice daily

Additional information regarding dosage and administration, including dosage modifications for adverse reactions, as well as important warnings and precautions about hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: Selpercatinib is a kinase inhibitor that inhibits wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3.

     

  • General PK: Steady-state selpercatinib AUC and Cmax increased in a slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily (0.06 to 1.5 times the maximum recommended total daily dosage). Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib (coefficient of variation (CV%)) Cmax was 2,980 (53%) ng/mL and AUC0-24h was 51,600 (58%) ng*h/mL.

     

  • Absorption: The median Tmax of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects.

     

  • Distribution: The apparent volume of distribution of selpercatinib is 191 L. Protein binding of selpercatinib is 97% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7.

     

  • Elimination: The apparent clearance of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects.

     

  • Metabolism: Selpercatinib is metabolized predominantly by CYP3A4.

     

  • Excretion: Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged).

     

  • Cardiac Electrophysiology: The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) after administration of RETEVMO 160 mg twice daily. The increase in QTc was concentration-dependent.

 

Drug Interactions

  • Acid-Reducing Agents: Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food when coadministered with a PPI, take RETEVMO 2 hours before or 10 hours after administration of an H2 receptor antagonist, or take RETEVMO 2 hours before or 2 hours after administration of a locally-acting antacid. Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations, which may reduce RETEVMO anti-tumor activity.

 

  • Strong CYP3A Inhibitors: Avoid concomitant use of strong CYP3A inhibitors with RETEVMO. If concomitant use cannot be avoided, reduce the RETEVMO dosage from 120 mg orally twice daily to 40 mg orally twice daily or from 160 mg orally twice daily to 80 mg orally twice daily and monitor the QT interval with ECGs more frequently. Concomitant use of RETEVMO with a strong CYP3A inhibitor increases selpercatinib plasma concentrations, which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation.

     

  • Moderate CYP3A Inhibitors: Avoid concomitant use of moderate CYP3A inhibitors with RETEVMO. If concomitant use cannot be avoided, reduce the RETEVMO dosage from 120 mg orally twice daily to 80 mg orally twice daily or from 160 mg orally twice daily to 120 mg orally twice daily and monitor the QT interval with ECGs more frequently. Concomitant use of RETEVMO with a moderate CYP3A inhibitor increases selpercatinib plasma concentrations, which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation.

     

  • Strong and Moderate CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO. Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations, which may reduce RETEVMO anti-tumor activity.

     

  • CYP2C8 and CYP3A Substrates: Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations, which may increase the risk of adverse reactions related to these substrates.

     

  • Drugs that Prolong QT Interval: Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval. RETEVMO is associated with QTc interval prolongation.

 

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (15 years to 90 years), or sex.

  • Body Weight: The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (27 kg to 177 kg).

     

  • Renal Impairment: No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance (CLcr) ≥ 30 mL/min, estimated by Cockcroft-Gault). The recommended dosage has not been established for patients with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease.

     

  • Hepatic Impairment: Reduce the recommended dosage of RETEVMO for patients with severe (total bilirubin greater than 3 to 10 times upper limit of normal (ULN) and any AST) hepatic impairment from 120 mg or 160 mg orally twice daily to 80 mg orally twice daily. No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment. Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment.

     

  • Lactation: Advise women not to breastfeed during treatment with RETEVMO and for 1 week after the final dose because of the potential for serious adverse reactions in breastfed children. There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production.

Efficacy and Safety

Efficacy of RETEVMO was demonstrated in a multicenter, open-label, multi-cohort clinical trial that enrolled patients with advanced or metastatic RET fusion-positive NSCLC, patients with advanced or metastatic RET-mutant MTC, and patients with advanced RET fusion-positive thyroid cancer. The major efficacy outcome measures were confirmed overall response rate and duration of response as determined by a blinded independent review committee according to RECIST v1.1. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions, including laboratory abnormalities, (≥ 25%) were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation.

Full prescribing information is available at https://go.usa.gov/xvssr.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.