Retevmo selpercatinib 40 mg Tablet, Coated, 60-count — NDC 0002-5340-60 (Billing 00002-5340-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC 50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable.

In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentration than VEGFR3. Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T.

In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion positive tumor.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics The pharmacokinetics of selpercatinib capsules were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. The capsule and tablet dosage forms of selpercatinib are bioequivalent. 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 For both the capsule and tablet dosage forms 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 203 L.

Protein binding of selpercatinib is 96% 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 (9.6 k… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC 50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable.

In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentration than VEGFR3. Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T.

In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion positive tumor.

12.3Pharmacokinetics The pharmacokinetics of selpercatinib capsules were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. The capsule and tablet dosage forms of selpercatinib are bioequivalent. 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 For both the capsule and tablet dosage forms 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 203 L.

Protein binding of selpercatinib is 96% 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 (9.6 kg to 179 kg). No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (2 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR ≥15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied.

Pediatric patients The exposures of selpercatinib in pediatric patients are comparable to those in adult patients administered at the recommended dosages. Patients with Hepatic Impairment The selpercatinib AUC 0-INF increased 1.1-fold in subjects with mild (total bilirubin ≤ ULN with AST > ULN or total bilirubin > 1 to 1.5 × ULN with any AST), 1.3-fold in subjects with moderate (total bilirubin > 1.5 to 3 × ULN and any AST), and 1.8-fold in subjects with severe (total bilirubin > 3 to 10 × ULN and any AST) hepatic impairment, 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 14 ). Table 14: 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 1,000 calories total.

2 Low-fat meal: approximately 390 calories and 10 g of fat. Selpercatinib AUC 0-INF Selpercatinib C max RETEVMO fasting Reference Reference RETEVMO fasting + PPI ↓ 69% ↓ 88% RETEVMO with a high-fat meal 1 + PPI ↑ 2% ↓ 49% RETEVMO with a low-fat… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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.

14 CLINICAL STUDIES

14.1RET Fusion-Positive Non-Small Cell Lung Cancer LIBRETTO-001 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 locally advanced (stage III who were not candidates for surgical resection or definitive chemoradiation) 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), fluorescence in situ hybridization (FISH) or other local testing methods. Adult patients received RETEVMO 160 mg orally twice daily until unacceptable toxicity or disease progression; patients enrolled in the dose escalation phase were permitted to adjust their dose to 160 mg twice daily. 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.

RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy Efficacy was evaluated in 247 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); 57% were female; 44% were White, 48% were Asian, 4.9% were Black or African American; and 2.8% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3%) and 97% of patients had metastatic disease.

Patients received a median of 2 prior systemic therapies (range 1–15); 58% had prior anti-PD1/PD-L1 therapy. RET fusions were detected in 94% of patients using NGS (84.6% tumor samples; 9.3% blood or plasma samples), 4.0% using FISH, 1.6% using PCR and 0.4% by other local testing methods. Efficacy results for previously treated RET fusion-positive NSCLC are summarized in Table 15 .

Table 15: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy) 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable RETEVMO (n = 247) Overall Response Rate 1 (95% CI) 61% (55%, 67%) Complete response 7.3% Partial response 54% Duration of Response Median in months (95% CI) 28.6 (20, NE) % with ≥ 12 months 2 63% For the 144 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 63% (95% CI: 54%, 70%) and the median DOR was 28.6 months (95% CI: 14.8, NE).

Among the 247 patients with previously treated RET fusion-positive NSCLC, 16 had measurable CNS metastases at baseline as assessed by BIRC. One patient received radiation therapy (RT) to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 14 of these 16 patients; 39% of responders had an intracranial DOR of ≥ 12 months.

Treatment-naïve RET Fusion-Positive NSCLC Efficacy was evaluated in 69 patients with treatment-naïve RET fusion-positive NSCLC enrolled into a cohort of LIBRETTO-001. The median age was 63 years (range 23 to 92); 62% were female; 70% were White, 19% were Asian, and 6% were Black or African American. ECOG performance status was 0-1 (94%) or 2 (6%) and 99% of patients had metastatic disease.

RET fusions were detected in 91% of patients using NGS (60.9% tumor samples; 30.4% in blood), 7.2% using FISH and 1.4% using PCR. Efficacy results for treatment naïve RET fusion-positive NSCLC are summarized in Table 16 . Table 16: Efficacy Results in LIBRETTO-001 (Treatment-Naïve RET Fusion-Positive NSCLC) 1 Confirmed overall response rate assessed by BIRC.

2 Based on observed duration of response. NE = not estimable RETEVMO… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice when administered by daily oral gavage at doses of up to 60 mg/kg. 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 160 mg twice daily clinical 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 clinical 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 clinical 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 a 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea 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).