RETEVMO Capsule Ref.[10397] Active ingredients: Selpercatinib

Exposure-Response Relationship

Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology

The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (C_max) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.

The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. Steady-state selpercatinib AUC and C_max 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%)] C_max was 2,980 (53%) ng/mL and AUC_0-24h was 51,600 (58%) ng*h/mL.

Absorption

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

Effect of Food

No clinically significant differences in selpercatinib AUC or C_max were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects.

Distribution

The apparent volume of distribution (V_ss/F) 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 (CL/F) 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. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma.

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).

Specific Populations

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

No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (15 years to 90 years), sex, or mild or moderate renal impairment (CLcr ≥30 mL/min as estimated by Cockcroft-Gault). The effect of severe renal impairment (CLcr <30 mL/min) on selpercatinib pharmacokinetics has not been adequately studied.

Patients with Hepatic Impairment

The selpercatinib AUC_0-INF increased by 7%, 32%, and 77% in subjects 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 ), moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, respectively, compared to subjects with normal hepatic function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC_0-INF and C_max when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC_0-INF and C_max when RETEVMO was administered with food (Table 7).

Table 7. Change in Selpercatinib Exposure After Coadministration with PPI:

¹ High-fat meal: approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; approximately 800 to 1000 calories total
² Low-fat meal: approximately 390 calories and 10 g of fat

H2 Receptor Antagonists: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the RETEVMO dose (administered fasting).

Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC_0-INF by 133% and C_max by 30%.

Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC by 60-99% and C_max by 46-76%.

Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC_0-INF by 87% and C_max by 70%.

Moderate CYP3A Inducers: Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the selpercatinib AUC by 40-70% and C_max by 34-57%.

Weak CYP3A Inducers: Coadministration of multiple doses of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and C_max by 26%.

CYP2C8 Substrates: Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC_0-INF by 188% and C_max by 91%.

CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A) increased the midazolam AUC_0-INF by 54% and C_max by 39%.

P-glycoprotein (P-gp) Inhibitors: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampin (P-gp inhibitor).

MATE1 Substrates: No clinically significant differences in glucose levels were observed when metformin (MATE1 substrate) was coadministered with selpercatinib.

In Vitro Studies

CYP Enzymes: Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.

Transporter Systems: Selpercatinib inhibits MATE1, P-gp, and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Adverse Effects (6.1)]. Selpercatinib is a substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.

Carcinogenicity studies have not been conducted with selpercatinib. Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation. Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the C_max at the human dose of 160 mg twice daily.

In general toxicology studies, male rats and minipigs exhibited testicular degeneration which was associated with luminal cell debris and/or reduced luminal sperm in the epididymis at selpercatinib exposures approximately 0.4 (rat) and 0.1 (minipig) times the clinical exposure by AUC at the recommended human dose. In a dedicated fertility study in male rats, administration of selpercatinib at doses up to 30 mg/kg/day (approximately twice the clinical exposure by AUC at the 160 twice daily dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display a dose-dependent increase in testicular germ cell depletion and spermatid retention at doses ≥3 mg/kg (~0.2 times the clinical exposure by AUC at the 160 twice daily dose) accompanied by altered sperm morphology at 30 mg/kg.

In a dedicated fertility study in female rats treated with selpercatinib for 15 days before mating to Gestational Day 7, there were decreases in the number of estrous cycles at a dose of 75 mg/kg (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). While selpercatinib did not have clear effects on mating performance or ability to become pregnant at any dose level, half of females at the 75 mg/kg dose level had 100% nonviable embryos. At the same dose level in females with some viable embryos there were increases in post-implantation loss. In the general toxicology study in minipigs, there were findings of decreased or absent corpora lutea, decreased number and size of follicles and stromal proliferation at a selpercatinib dose of 15 mg/kg (approximately 0.3 times to the human exposure by AUC at the 160 mg twice daily clinical dose). Corpora luteal cysts were present in the minipig at selpercatinib doses ≥2 mg/kg (approximately 0.07 times the human exposure by AUC at the 160 mg twice daily clinical dose).

14.1 Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer

The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive NSCLC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and patients with advanced or metastatic NSCLC without prior systemic therapy in separate cohorts. Identification of a RET gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), or fluorescence in situ hybridization (FISH). Adult patients received RETEVMO 160 mg orally twice daily until unacceptable toxicity or disease progression. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1.

Metastatic RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy

Efficacy was evaluated in 105 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001.

The median age was 61 years (range: 23 to 81); 59% were female; 52% were White, 38% were Asian, 4.8% were Black, and 3.8% were Hispanic/Latino. ECOG performance status was 0-1 (98%) or 2 (2%) and 98% of patients had metastatic disease. Patients received a median of 3 prior systemic therapies (range 1-15); 55% had prior anti-PD-1/PD-L1 therapy. RET fusions were detected in 90% of patients using NGS (81.9% tumor samples; 7.6% blood or plasma samples), 8.6% using FISH, and 1.9% using PCR.

Efficacy results for RET fusion-positive NSCLC are summarized in Table 8.

Table 8. Efficacy Results in LIBRETTO-001 (Metastatic RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy):

¹ Confirmed overall response rate assessed by BICR
² Based on observed duration of response
NE = not estimable

For the 58 patients who received an anti-PD-1 or anti-PD-L1 therapy, either sequentially or concurrently with platinum-based chemotherapy, an exploratory subgroup analysis of ORR was 66% (95% CI: 52%, 78%) and the median DOR was 12.5 months (95% CI: 8.3, NE).

Among the 105 patients with RET fusion-positive NSCLC, 11 had measurable CNS metastases at baseline as assessed by BIRC. No patients received radiation therapy (RT) to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 10 of these 11 patients; all responders had a DOR of ≥ 6 months.

Treatment-naïve RET Fusion-Positive NSCLC

Efficacy was evaluated in 39 patients with treatment-naïve RET fusion-positive NSCLC enrolled into a cohort of LIBRETTO-001.

The median age was 61 years (range 23 to 86); 56% were female; 72% were White, 18% were Asian, and 8% were Black. ECOG performance status was 0-1 in all patients (100%) and all patients (100%) had metastatic disease. RET fusions were detected in 92% of patients using NGS (69% tumor samples; 23% in blood) and 8% using FISH.

Efficacy results for treatment naïve RET fusion-positive NSCLC are summarized in Table 9.

Table 9. Efficacy Results in LIBRETTO-001 (Treatment-Naïve Metastatic RET Fusion-Positive NSCLC):

¹ Confirmed overall response rate assessed by BICR
² Based on observed duration of response
NE = not estimable

14.2 RET-Mutant Medullary Thyroid Cancer

The efficacy of RETEVMO was evaluated in patients with RET-mutant MTC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic RET-mutant MTC who had been previously treated with cabozantinib or vandetanib (or both) and patients with advanced or metastatic RET-mutant MTC who were naïve to cabozantinib and vandetanib in separate cohorts.

RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib

Efficacy was evaluated in 55 patients with RET-mutant advanced MTC who had previously treated with cabozantinib or vandetanib enrolled into a cohort of LIBRETTO-001.

The median age was 57 years (range: 17 to 84); 66% were male; 89% were White, 7% were Hispanic/Latino, and 1.8% were Black. ECOG performance status was 0-1 (95%) or 2 (5%) and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1-8). RET mutation status was detected in 82% of patients using NGS (78% tumor samples; 4% blood or plasma), 16% using PCR, and 2% using an unknown test. The protocol excluded patients with synonymous, frameshift or nonsense RET mutations; the specific mutations used to identify and enroll patients are described in Table 10.

Table 10. Mutations used to Identify and Enroll Patients with RET-Mutant MTC in LIBRETTO-001:

¹ Somatic or germline mutations; protein change
² Extracellular cysteine mutations involving cysteine residues 609, 611, 618, 620, 630, and 634
³ Other included: K666N (1), D631_L633delinsV (2), D631_L633delinsE (5), D378_G385delinsE (1), D898_E901del (2), A883F (4), E632_L633del (4), L790F (2), T636_V637insCRT(1), D898_E901del + D903_S904delinsEP (1)
⁴ One patient also had a M918T mutation

Efficacy results for RET-mutant MTC are summarized in Table 11.

Table 11. Efficacy Results in LIBRETTO-001 (RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib):

¹ Confirmed overall response rate assessed by BICR
² Based on observed duration of response
NE = not estimable

Cabozantinib and Vandetanib-naïve RET-Mutant MTC

Efficacy was evaluated in 88 patients with RET-mutant MTC who were cabozantinib and vandetanib treatment-naïve enrolled into a cohort of LIBRETTO-001.

The median age was 58 years (range: 15 to 82) with two patients (2.3%) aged 12 to 16 years; 66% were male; and 86% were White, 4.5% were Asian, and 2.3% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3.4%). All patients (100%) had metastatic disease and 18% had received 1 or 2 prior systemic therapies (including 8% kinase inhibitors, 4.5% chemotherapy, 2.3% anti-PD1/PD-L1 therapy, and 1.1% radioactive iodine). RET mutation status was detected in 78.4% of patients using NGS (76.1 % tumor samples; 2.3% blood samples), 18.2% using PCR, and 3.4% using an unknown test. The mutations used to identify and enroll patients are described in Table 10.

Efficacy results for cabozantinib and vandetanib-naïve RET-mutant MTC are summarized in Table 12.

Table 12. Efficacy Results in LIBRETTO-001 (Cabozantinib and Vandetanib-naïve RET-Mutant MTC):

¹ Confirmed overall response rate assessed by BICR
² Based on observed duration of response
NE = not estimable

14.3 RET Fusion-Positive Thyroid Cancer

The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive thyroid cancer enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 27 patients with RET fusion-positive thyroid cancer who were radioactive iodine (RAI)-refractory (if RAI was an appropriate treatment option) and were systemic therapy naïve and patients with RET fusion-positive thyroid cancer who were RAI-refractory and had received sorafenib, lenvatinib, or both, in separate cohorts.

The median age was 54 years (range 20 to 88); 52% were male; 74% were White, 11% were Hispanic/Latino, 7.4% were Asian, and 3.7% were Black. ECOG performance status was 0-1 (89%) or 2 (11%). All (100%) patients had metastatic disease with primary tumor histologies including papillary thyroid cancer (78%), poorly differentiated thyroid cancer (11%), anaplastic thyroid cancer (7%) and Hurthle cell thyroid cancer (4%). Patients had received a median of 3 prior therapies (range 1-7). RET fusion-positive status was detected in 93% of patients using NGS tumor samples and in 7% using blood samples.

Efficacy results for RET fusion-positive thyroid cancer are summarized in Table 13.

Table 13. Efficacy Results in LIBRETTO-001 (RET Fusion-Positive Thyroid Cancer):

¹ Confirmed overall response rate assessed by BICR
² Based on observed duration of response
NE = not estimable