Sevabertinib

Sevabertinib is a reversible kinase inhibitor of human epidermal growth factor receptor 2 (HER2). It also exhibits activity against epidermal growth factor receptor (EGFR).

In vitro, sevabertinib inhibited the phosphorylation of HER2 and downstream signaling in cancer cells with HER2 alterations and proliferation of cancer cells overexpressing wild-type HER2 or harboring HER2 mutations.

In vivo, sevabertinib demonstrated antitumor activity in subcutaneous mouse xenograft models derived from human NSCLC tumors harboring an activating HER2 exon 20 mutation.

Exposure-Response Relationship

Higher sevabertinib exposure, across the dose range of 10 to 80 mg total daily dose (0.25 to 2 times the recommended dosage), was associated with an increased incidence of diarrhea (all grade and Grade ≥3) and rash.

Cardiac Electrophysiology

At 2 times the maximum recommended dose, a mean increase in the QTc interval >20 ms was not observed.

Sevabertinib pharmacokinetics were observed at steady state in patients with advanced NSCLC harboring activating HER2 or EGFR mutations at the approved recommended dosage and are presented as mean (CV%), unless otherwise specified.

Sevabertinib maximum concentration (C_max) is 902 (45%) ng/mL and total systemic exposure (AUC) is 6,640 (50%) ng*h/mL. Sevabertinib C_max and AUC increase in a dose-proportional manner across the dose range of 10 mg to 80 mg (0.25 to 2 times the approved recommended total daily dose). Sevabertinib accumulation is approximately 1.7-fold for AUC and 1.3-fold for C_max at the approved recommended dosage. Steady state is achieved within 3 days.

Absorption

Sevabertinib median (min, max) time to maximum concentrations (T_max) is approximately 2 hours (0.5, 8.2 hours) after a single dose.

Effect of Food

Sevabertinib C_max decreases by 56% and AUC decreases by 28% with a high-fat meal (1000 calories, 50% fat) in healthy subjects. No clinically significant differences in sevabertinib pharmacokinetics were observed following administration of a low-fat meal (400 calories, 25% fat).

Distribution

Sevabertinib apparent volume of distribution is 28 L (42%). Sevabertinib plasma protein binding is 95%. The blood-to-plasma concentration ratio is 0.6.

Elimination

Sevabertinib effective half-life is approximately 8 hours (33%) with an apparent clearance of 3.1 L/hour (38%).

Metabolism

Sevabertinib is primarily metabolized by CYP3A (major), CYP1A1 (minor), and glucuronidation (minor).

Excretion

After a single oral dose of radiolabeled sevabertinib 40 mg to healthy subjects, approximately 84% of the dose was recovered in feces (14% unchanged) and approximately 10% in urine (1.3% unchanged).

Specific Populations

No clinically significant effects in the pharmacokinetics of sevabertinib were observed based on age (18 to 91 years), race (27% White, 65% Asian, 2.7% Black/African American), sex, body weight (29 to 155 kg), smoking status, eGFR 30 to <90 mL/min, or mild hepatic impairment (AST > ULN and total bilirubin ≤ ULN; or total bilirubin >1 to 1.5× ULN and any AST). The effect of severe renal impairment (eGFR 15 to <30 mL/min), end-stage renal disease (eGFR <15 mL/min), moderate hepatic impairment (total bilirubin >1.5 to 3× ULN and any AST) or severe hepatic impairment (total bilirubin >3× ULN and any AST) on sevabertinib pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies

Strong CYP3A Inhibitors: Sevabertinib AUC increased 2.3-fold and C_max 1.6-fold following concomitant use of itraconazole (strong CYP3A inhibitor) 200 mg once daily.

Strong CYP3A Inducers: Sevabertinib AUC decreased by 79% and C_max by 57% following concomitant use of carbamazepine (strong CYP3A inducer) 600 mg once daily.

CYP3A Substrates: Midazolam (CYP3A substrate) AUC increased 2-fold and C_max 1.8-fold following concomitant use of sevabertinib 20 mg twice daily.

P-gp Substrates: Dabigatran etexilate (P-gp substrate) AUC increased 1.4-fold following concomitant use of sevabertinib 20 mg twice daily.

BCRP Substrates: Rosuvastatin (BCRP substrate) AUC increased 1.3-fold and C_max 1.4-fold following concomitant use of sevabertinib 20 mg twice daily.

Other Drugs: No clinically significant differences in sevabertinib pharmacokinetics were observed when used concomitantly with esomeprazole (proton pump inhibitor).

In Vitro studies

CYP450 Enzymes: Sevabertinib inhibits CYP1A1 and CYP2C8 but does not inhibit CYP2A6, CYP2C9, CYP1A2, CYP2B6, CYP2D6, CYP2C19, or CYP2E1. Sevabertinib does not induce CYP1A2, CYP2B6, or CYP2C19.

Transporter Systems: Sevabertinib is a substrate of P-gp, and BCRP. Sevabertinib inhibits MATE1 and MATE2-K but does not inhibit OATP1B1, OATP1B3, MRP2, OAT1, OAT3, OCT1, or OCT2.