Sunvozertinib

Based on findings from animal studies and its mechanism of action, sunvozertinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of sunvozertinib in pregnant women to inform a drug-associated risk. Oral administration of sunvozertinib to pregnant animals during the period of organogenesis resulted in structural abnormalities at concentrations below the human exposure at the recommended dose based on AUC. Advise pregnant women and females of reproductive potential 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 sunvozertinib or its metabolites in human milk or their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with sunvozertinib and for 2 weeks after the last dose.

Carcinogenesis

Carcinogenicity studies have not been conducted with sunvozertinib.

Mutagenesis

Sunvozertinib was not genotoxic in the bacterial reverse mutation (Ames) assay, an in vitro chromosome aberration assay, or an in vivo micronucleus assay in rats.

Impairment of Fertility

Fertility studies have not been conducted with sunvozertinib. In repeat-dose toxicology studies of up to 4-weeks duration in dogs, oral administration of sunvozertinib caused vaginal epithelial atrophy and degeneration of the seminiferous tubule in the testes at doses as low as 8 mg/kg/day (≥0.2 times the human exposure at the recommended dose based on AUC). The reversibility of the findings in females was not assessed. The findings in males were reversible.

Clinical trials experience

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 populations described in WARNINGS AND PRECAUTIONS reflect exposure to sunvozertinib as a single agent at a dose of 200 mg orally once daily in 121 patients with locally advanced or metastatic NSCLC from two clinical trials WU-KONG1 (NCT03974022) and WU-KONG2 (n=3). Among 121 patients who received sunvozertinib, 56% were exposed for 6 months or longer and 28% were exposed for greater than one year. In this pooled safety population, the most common (≥20%) adverse reactions were diarrhea, rash, decreased appetite, stomatitis, fatigue, nausea, paronychia, vomiting, constipation, musculoskeletal pain, pruritus, dry skin, urinary tract infection, abdominal pain and decreased weight. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, increased lipase, decreased hemoglobin, increased amylase, increased creatine kinase, decreased neutrophils, decreased potassium, increased aspartate aminotransferase, increased alanine aminotransferase, decreased sodium, increased magnesium, and increased alkaline phosphatase.

EGFR Exon 20 Insertion Mutation-Positive Locally Advanced or Metastatic NSCLC Previously Treated with Platinum-Based Chemotherapy

The safety of sunvozertinib was evaluated in WU-KONG1B in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in a multinational, open-label, dose randomization clinical trial. Eligible patients must have had disease progression on or after platinum-based chemotherapy and received sunvozertinib 200 mg orally once daily until disease progression or intolerable toxicity. The median age of patients who received sunvozertinib was 62 years (range: 35-88); 67% were females; 65% were Asian and 33% were White; 97% were not of Hispanic or Latino ethnicity.

Serious adverse reactions occurred in 41% of patients who received sunvozertinib. Serious adverse reactions in ≥2% of patients who received sunvozertinib were pneumonia (9%); dyspnea (4.4%); and pancreatitis, device related infection and rash (2.2% each). Fatal adverse reactions occurred in 2.2% of patients who received sunvozertinib including thrombosis (1.1%) and COVID-19 infection (1.1%).

Permanent discontinuation of sunvozertinib due to adverse reactions occurred in 8% of patients. Adverse reactions leading to treatment discontinuation of sunvozertinib in ≥2% of patients were pneumonia and rash (2.2% each).

Dosage interruption of sunvozertinib due to adverse reactions occurred in 48% of patients. Adverse reactions requiring dosage interruption of sunvozertinib in ≥5% of patients were vomiting (9%), pneumonia (8%), and rash (8%).

Dose reduction of sunvozertinib due to adverse reactions occurred in 23% of patients. Adverse reactions requiring dose reduction of sunvozertinib in ≥3% of patients were rash (4.4%) and diarrhea (3.3%).

Table 1 summarizes the adverse reactions in WU-KONG1B.

Table 1. Adverse Reactions (≥10%) in Patients with Locally Advanced or Metastatic NSCLC Who Received Sunvozertinib in WU-KONG1B:

¹ NCI CTCAE v5.0.
^* Grouped Terms

Clinically relevant adverse reactions in <10% of patients who received sunvozertinib were: cough, dizziness, dyspnea, dry eye and keratitis.

Table 2 summarizes the laboratory abnormalities in WU-KONG1B.

Table 2. Selected Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Locally Advanced or Metastatic NSCLC Who Received Sunvozertinib in WU-KONG1B:

¹ The denominator used to calculate the rate varied from 89 to 90 based on the number of patients with a baseline and at least one post-treatment value.
² NCI CTCAE v5.0

Other Clinical Trials Experience

The following adverse reactions occurred following administration of sunvozertinib: Interstitial Lung Disease (ILD)/Pneumonitis.