Zidesamtinib

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies and its mechanism of action, zidesamtinib can cause etal harm when administered to a pregnant woman. There are no available data on zidesamtinib use in pregnant women to inform a drug-associated risk. Oral administration of zidesamtinib to pregnant rats during the period of organogenesis resulted in embryo-fetal mortality, alterations to growth, and structural abnormalities at maternal exposures approximately equivalent to the human exposure at the recommended dose based on AUC. 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 zidesamtinib or its metabolites in human milk or their effects on a 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 zidesamtinib and for 1 week after the last dose.

Carcinogenesis

Carcinogenicity studies with zidesamtinib were not conducted.

Mutagenesis

Zidesamtinib was genotoxic in the in vivo rat micronucleus assays. Zidesamtinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro assay in human lymphoblastoid TK6 cells. Zidesamtinib did not induce DNA strand breaks in the comet assay in liver.

Impairment of Fertility

Dedicated fertility studies were not conducted with zidesamtinib. In a 13-week repeat dose toxicity study with oral administration of zidesamtinib in rats, adverse effects in reproductive organs included hemorrhage and inflammation of the ovaries with dilation and inflammation of the oviduct in females at doses ≥3 mg/kg/day (≥1.7 times the human exposure at the recommended dose based on AUC) and spermatid retention and tubular degeneration in the testis in males at doses ≥6 mg/kg/day (approximately equivalent to the human exposure at the recommended dose based on AUC). Findings in males were reversible, whereas the reversibility in females was not assessed.

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 reflects exposure to zidesamtinib in 446 patients with ROS1-positive NSCLC (n=432) and other solid tumors (n=14) who received zidesamtinib at a dose of 100 mg orally once daily until disease progression or unacceptable toxicity in ARROS-1. Among 446 patients who received zidesamtinib, 44% were exposed for 6 months or longer and 14% were exposed for greater than one year. In this pooled safety population, the most common (≥15%) adverse reactions included: edema (38%), peripheral neuropathy (25%), constipation (17%), fatigue (16%), dyspnea (15%). The most common Grade 3 or 4 laboratory abnormalities (≥2%), were increased lipase (8%), increased creatine phosphokinase (CPK) (4%), increased triglycerides (3.5%), decreased lymphocytes (2.7%), and decreased hemoglobin (2.3%).

Previously Treated ROS1-positive NSCLC

The safety of zidesamtinib was evaluated in ARROS-1. Patients received zidesamtinib 100 mg orally once daily until disease progression or unacceptable toxicity. Among the 432 patients who received zidesamtinib, 44% were exposed to zidesamtinib for 6 months or longer, and 15% were exposed for greater than 1 year.

The median age of patients who received zidesamtinib was 58 years (range: 26 to 87); 62% female; 41% White, 41% Asian, 3.7% Black or African American, 0.2% American Indian or Alaska Native, 14% other races, multiple races or race unknown, and 4.6% of patients were of Hispanic or Latino ethnicity.

Serious adverse reactions occurred in 22% of patients who received zidesamtinib. Serious adverse reactions in ≥2% of patients included pneumonia (6%) and dyspnea (2.5%). Fatal adverse reactions occurred in 2.3% of patients who received zidesamtinib, including pneumonia (0.5%), cerebrovascular accident (0.2%), COVID-19 (0.2%), dyspnea (0.2%), infectious pleural effusion (0.2%), influenza (0.2%), myocardial infarction (0.2%), myocarditis (0.2%), and respiratory failure (0.2%).

Permanent discontinuation of zidesamtinib due to an adverse reaction occurred in 2.3% of patients. Adverse reactions resulting in permanent discontinuation of zidesamtinib occurring in ≥2 patients were pneumonia (0.7%) and pneumonitis (0.5%).

Dosage interruptions of zidesamtinib due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥1% of patients included pneumonia (4.6%), increased creatine phosphokinase level (3.0%), peripheral neuropathy (1.9%), peripheral edema (1.6%), COVID-19 (1.4%), and dyspnea and elevated alanine aminotransferase level (each in 1.2%).

Dose reductions of zidesamtinib due to an adverse reaction occurred in 10% of patients. Adverse reactions which required dosage reduction in ≥1% of patients included peripheral edema (1.9%) and peripheral neuropathy (1.2%).

Table 1 summarizes the adverse reactions that occurred in the ARROS-1 trial.

Table 1. Adverse Reactions (≥10%) in Patients with ROS1-Positive NSCLC Who Received Zidesamtinib in ARROS-1:

¹ Based on NCI CTCAE v5.0
^* Grouped term

Clinically relevant adverse reactions in <10% of patients receiving zidesamtinib were cognitive disorders, psychiatric disorders, stomatitis, ataxia, ILD/pneumonitis, QTc prolongation, pancreatitis, and ankle fracture.

Table 2 summarizes the laboratory abnormalities in ARROS-1.

Table 2. Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ROS1-Positive NSCLC Who Received Zidesamtinib in ARROS-1:

¹ Based on NCI CTCAE v5.0
² The denominator used to calculate the rate varied from 37 to 429 based on the number of patients with a baseline value and at least one post-baseline treatment value.