Taletrectinib

Risk Summary

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, taletrectinib can cause fetal harm when administered to a pregnant woman. Limited data from case reports with taletrectinib used in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, oral administration of taletrectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities at exposures that were below or equal to the human exposure based on AUC at the recommended dose. 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 taletrectinib or its metabolites in human milk or their effects on a breastfed child or on milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with taletrectinib and for 3 weeks after the last dose.

Carcinogenesis

Carcinogenicity studies with taletrectinib were not conducted.

Mutagenesis

Taletrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and additional mutagenicity tests. Taletrectinib was not clastogenic or aneugenic in the in vivo micronucleus study in rats in bone marrow and liver.

Impairment of Fertility

In a fertility and early embryonic development study in rats, male animals were treated with taletrectinib at doses of 4, 25, or 60 mg/kg/day orally for 70 days before mating and during 13 days of the mating period. Female rats, paired with treated males, were administered taletrectinib at doses of 4, 25, or 100 mg/kg/day orally for 14 to 21 days before mating, during the mating period and up to gestational Day 6. No effects on mating or fertility in males or females were observed at doses below or equal to the human exposure based on AUC at the recommended dose. Sperm morphological abnormalities were observed in males at exposures as low as 0.03 times the human exposure based on AUC at the recommended dose.

In repeat-dose toxicity studies up to 12 weeks in duration with oral administration of taletrectinib in rats, adverse effects in reproductive organs included epithelial vacuolation of the seminal vesicle in male rats and endometrial glandular epithelium vacuolation in the uterus with cervix in female rats at exposures 4 times the human exposure based on AUC at the recommended dose for both male and female rats. Findings in the reproductive organs 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 population described in the WARNINGS AND PRECAUTIONS section and below reflects exposure to taletrectinib as a single agent at 600 mg orally once daily until disease progression or unacceptable toxicity in 352 patients with ROS1-positive NSCLC (N=337) and other solid tumors (N=15). Among the 352 patients who received taletrectinib, 68% were exposed for at least 6 months, and 47% were exposed for greater than 1 year. In this pooled safety population, the most common (≥20%) adverse reactions were diarrhea, nausea, vomiting, dizziness, rash, constipation, and fatigue. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased ALT, increased AST, decreased neutrophils, increased creatine phosphokinase, decreased lymphocytes, increased magnesium, decreased hemoglobin, and increased triglycerides.

Locally Advanced or Metastatic ROS1-Positive NSCLC

The safety of taletrectinib was evaluated in the TRUST-I and TRUST-II studies. Key eligibility criteria were histologically confirmed, locally advanced or metastatic, ROS1-positive NSCLC, ECOG performance status ≤1, and measurable disease per RECIST v1.1. Patients received taletrectinib as a single agent at 600 mg orally once daily until disease progression or unacceptable toxicity. Among patients who received taletrectinib, 68% were exposed for 6 months or longer and 47% were exposed for greater than one year.

The median age of patients who received taletrectinib was 56 years (range: 26 to 83); 56% female; 76% Asian, 15% White, 0.6% Black or African American, 8% unknown or other races; and 1.8% were of Hispanic or Latino ethnicity.

Serious adverse reactions occurred in 31% of patients who received taletrectinib. Serious adverse reactions in ≥2% of patients included pneumonia (7%), pleural effusion (4.7%), and hepatotoxicity (2.4%). Fatal adverse reactions occurred in 18 (5%) patients who received taletrectinib, including pneumonia (2.4%), multiple organ dysfunction syndrome (0.6%), hepatotoxicity (0.6%), cardiac arrest (0.6%), cardiac failure (0.3%), cardiopulmonary failure (0.3%), respiratory failure (0.3%), and death not otherwise specified (0.3%).

Permanent discontinuation of taletrectinib was required in 7% of patients due to adverse reactions. Adverse reactions resulting in permanent discontinuation of taletrectinib in ≥2 patients were pneumonia, ILD, and hepatotoxicity.

Dosage interruptions of taletrectinib due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included increased AST and increased ALT.

Dose reductions of taletrectinib due to an adverse reaction occurred in 29% of patients. Adverse reactions that required dosage reductions in ≥5% of patients included increased ALT and increased AST.

Table 1 summarizes the adverse reactions in this population.

Table 1. Adverse Reactions (≥15%) in Patients with ROS1-Positive NSCLC Who Received Taletrectinib in TRUST-I and TRUST-II:

¹ Based on NCI CTCAE version 5.0
^a Includes enterocolitis
^b Includes vertigo, and vertigo positional
^c Includes dysesthesia, hypoesthesia, neuralgia, paresthesia, and peripheral sensory neuropathy
^d Includes ageusia
^e Includes dermatitis, dermatitis acneiform, drug eruption, eczema, eyelid rash, palmar-plantar erythrodysesthesia syndrome, rash maculo-papular, rash papular, skin exfoliation, and drug reaction with eosinophilia and systemic symptoms (DRESS)
^f Includes asthenia
^g Includes productive cough

Clinically relevant adverse reactions in <15% of patients receiving taletrectinib were pneumonia, eye disorders, myalgia, skeletal fracture, ILD/pneumonitis, dermatologic adverse reactions including drug reaction with eosinophilia and systemic symptoms (DRESS), and photosensitivity reactions.

Table 2 summarizes the laboratory abnormalities.

Table 2. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ROS1-Positive NSCLC Who Received Taletrectinib in TRUST-I and TRUST-II:

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase
¹ Based on NCI CTCAE version 5.0
² The denominator used to calculate the rate varied from 149 to 336 based on the number of patients with a baseline value and at least one post-treatment value.