Sevabertinib

Based on findings from animal studies and its mechanism of action, sevabertinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of sevabertinib in pregnant women to inform a drug-associated risk. In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures ≥0.18 times the human exposure based on area under the curve (AUC) at the clinical dose of 20 mg twice daily. Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no data on the presence of sevabertinib or its metabolites in human milk or their effects on a breastfed child or on milk production. In rats, sevabertinib or its metabolites are excreted in milk (see Data). Because of the potential for serious adverse reactions in breastfed children from sevabertinib, advise women not to breastfeed during treatment with sevabertinib and for 1 week after the last dose.

Carcinogenesis

Carcinogenicity studies have not been conducted with sevabertinib.

Mutagenesis

Sevabertinib was not genotoxic in a bacterial reverse mutation (Ames) and an in vitro micronucleus assay, or an in vivo micronucleus assay in rats.

Impairment of Fertility

Fertility studies have not been conducted with sevabertinib.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population in the WARNINGS AND PRECAUTIONS reflects exposure to sevabertinib at 20 mg orally twice daily in 268 patients with locally advanced or metastatic NSCLC harboring HER2 and/or other mutations from the SOHO-01 study. Among 268 patients who received sevabertinib, 35% were exposed for greater than 6 months and 12% were exposed for greater than 1 year. In this pooled safety population, the most common (>20%) adverse reactions were diarrhea, rash, stomatitis, and paronychia. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased potassium, increased lipase, decreased lymphocyte count, decreased sodium, increased amylase, increased ALT, and increased AST.

The safety of sevabertinib at 20 mg orally twice daily was evaluated in 136 patients with locally advanced or metastatic NSCLC harboring HER2 activating mutations who had received prior systemic therapy in the SOHO-01 study. Among 136 patients who received sevabertinib, 46% were exposed greater than 6 months and 15% were exposed for greater than 1 year. The median age of patients who received sevabertinib was 62 years (range: 29 to 91); 63% female; 65% Asian, 27% White, 3.7% Black or African American; and 2.2% were of Hispanic or Latino ethnicity.

The most common adverse reactions (>20%) in patients who received sevabertinib were diarrhea, rash, paronychia, stomatitis, and nausea. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were potassium decreased, lipase increased, lymphocyte count decreased, sodium decreased, amylase increased, aspartate aminotransferase (AST) increased, and alanine aminotransferase (ALT) increased.

Serious adverse reactions occurred in 31% of patients who received sevabertinib. Serious adverse reactions in ≥2% of patients were diarrhea (6%), pneumonia (3.7%), dyspnea (2.2%), and pleural effusion (2.2%).

Permanent discontinuation of sevabertinib due to an adverse reaction occurred in 3.7% of patients. Adverse reactions which resulted in permanent discontinuation were corneal epithelial microcysts, hepatic function abnormal, electrocardiogram QT prolonged, pain in extremity and dyspnea (0.7%, 1 patient each).

Dosage interruptions of sevabertinib due to an adverse reaction occurred in 46% of patients. Adverse reactions which resulted in dosage interruptions in >3% of patients were diarrhea, hypokalemia, nausea, decreased appetite, and pneumonia.

Dose reductions of sevabertinib due to adverse reactions occurred in 28% of patients. Adverse reactions which resulted in dose reductions in >2% of patients were diarrhea, rash, and hypokalemia.

Table 1 summarizes the adverse reactions in SOHO-01 (Groups D and E).

Table 1. Adverse Reactions (≥10%) in Patients with NSCLC with HER2 Activating Mutations Who Received Sevabertinib in SOHO-01 (Groups D and E):

^* Graded per NCI CTCAE version 5.
^† All were Grade 3, except for dyspnea (0.7%, Grade 4).
^‡ Includes diarrhea, enterocolitis.
^§ Includes cheilitis, mouth ulceration, mucosal inflammation, stomatitis.
^¶ Includes abdominal pain, abdominal pain upper.
^# Includes dermatitis acneiform, eczema, eczema asteatotic, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash maculopapular, rash pruritic, rash pustular, skin exfoliation.
^Þ Includes ingrowing nail, nail disorder, onychoclasis, onycholysis, onychomadesis, paronychia.
^ß Includes dry skin, xeroderma.
^à Includes asthenia, fatigue.
^è Includes blindness unilateral, cataract, conjunctivitis, conjunctivitis allergic, corneal epithelial microcysts, dry eye, eye discharge, eye pain, lacrimation increased, ocular hyperemia, ocular hypertension, ocular toxicity, vision blurred, visual acuity reduced, visual impairment, xerophthalmia.
^ð Includes dyspnea, dyspnea exertional.

Clinically relevant adverse reactions in <10% of patients who received sevabertinib included edema (8%), cardiac arrhythmia (6%; includes arrhythmia, atrioventricular block complete, electrocardiogram QT prolonged, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia) and alopecia (3.7%).

Table 2 summarizes the laboratory abnormalities observed in SOHO-01 (Groups D and E).

Table 2. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with NSCLC with HER2 Activating Mutations in SOHO-01 (Groups D and E):

^* The denominator used to calculate the rate varied from 103 to 135 based on the number of patients with a baseline value and at least one post-treatment value.
^† Graded per NCI CTCAE version 5 using only numeric values.
^‡ All were Grade 3, except for calcium decreased (0.7%, Grade 4) and amylase increased (1.5%; Grade 4)
^§ Graded per NCI CTCAE version 4.03 using only numeric values.

Laboratory abnormalities in <20% of patients who received sevabertinib include blood bilirubin increased (14%; all were Grades 1 and 2).