Sevabertinib

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Serum aminotransferase elevations are common during sevabertinib therapy, but clinically apparent liver injury has not been reported. Among 268 patients treated with the approved dose in the prelicensure trials, ALT elevations arose in 37% of patients which were above 5 times the upper limit of normal (ULN) in 2.3%. Bilirubin elevations occurred in 12% of patients and alkaline phosphatase in 22%, all of which were mild-to-moderate in degree. The elevations arose after a median of 1.4 months of therapy (range 0.2 to 14.5 months) and were generally transient and asymptomatic, resolving with dose interruption or reduction. Liver related adverse events led to temporary interruption of sevabertinib in approximately 4% of patients, dose reduction in 4%, and permanent discontinuation in less than 1%. Two patients had both ALT and bilirubin elevations , but on clinical review other causes of liver abnormalities were found, and neither case was judged to be due to sevabertinib. Because of the frequency of liver test abnormalities, the product label includes a warning about liver injury and recommends monitoring of liver tests before starting sevabertinib, every 2 weeks during the first month of therapy, and monthly thereafter. Sevabertinib has been in general use for a short time and its safety profile in larger populations has yet to be defined.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Sevabertinib (BAY 2927088) is an oral, reversible tyrosine kinase inhibitor (TKI) developed for the treatment of non-small cell lung cancer (NSCLC). It is specifically designed to target tumours harbouring activating mutations in the HER2 (ERBB2) tyrosine kinase domain (TKD), a genetic driver found in a subset of NSCLC patients. The drug is active against a broad spectrum of HER2 alterations, including exon 20 insertions and various point mutations. Sevabertinib functions as a dual inhibitor that targets both HER2 and the epidermal growth factor receptor (EGFR). By reversibly binding to these kinases, sevabertinib inhibits the phosphorylation of HER2, thereby blocking the activation of downstream signalling pathways critical for tumor growth and survival. In vitro studies demonstrate that this inhibition suppresses the proliferation of cancer cells that either over-express wild-type HER2 or harbor specific HER2 mutations.

The mean (CV%) Cmax is 902 (45%) ng/mL and total systemic exposure (AUC) is 6,640 (50%) ng x h/mL. The Cmax 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). Drug accumulation is approximately 1.7-fold for AUC and 1.3-fold for Cmax at the approved recommended dosage. Drug steady state is achieved within three days. Sevabertinib median (min, max) time to maximum concentrations (Tmax) is approximately 2 hours (0.5, 8.2 hours) after a single dose. Sevabertinib Cmax 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).