Repotrectinib

Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.

Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates.

Avoid concomitant use with P-gp inhibitors. Concomitant use of repotrectinib with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of repotrectinib.

Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of repotrectinib with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of repotrectinib.

The recommended dosage of repotrectinib has not been established in patients with severe renal impairment or kidney failure (eGFR-MDRD <30 mL/min) and patients on dialysis.

The recommended dosage of repotrectinib has not been established in patients with moderate (total bilirubin >1.5 to 3 times upper limit of normal [ULN] with any AST) or severe (total bilirubin >3 times ULN with any AST) hepatic impairment.

Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives.

Avoid concomitant use of repotrectinib with hormonal contraceptives. Advise females to use an effective nonhormonal contraceptive.

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, repotrectinib can cause fetal harm when administered to a pregnant woman. There are no available data on repotrectinib use in pregnant women. Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA (see Data). 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.

Data

Human Data

Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.

Animal Data

In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg [approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA]. No embryolethality was observed.

There are no data on the presence of repotrectinib in human milk or its effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children from repotrectinib, advise a lactating woman to discontinue breastfeeding during treatment with repotrectinib and for 10 days after the last dose.

Carcinogenicity studies with repotrectinib were not conducted.

Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.

Dedicated fertility studies were not conducted with repotrectinib. There were no effects on male and female reproductive organs observed in general repeat-dose toxicology studies of up to 3 months in duration in rats and monkeys at any dose level tested, which equated to exposures of up to approximately 3 times the human exposure at the 160 mg twice daily dose based on AUC.

• Central Nervous System Adverse Reactions
• Interstitial Lung Disease (ILD)/Pneumonitis
• Hepatotoxicity
• Myalgia with Creatine Phosphokinase Elevation
• Hyperuricemia
• Skeletal Fractures
• Embryo-Fetal Toxicity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates reported 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 repotrectinib as a single agent dosed at 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity in 351 patients with ROS1-positive NSCLC and other solid tumors in the TRIDENT-1 trial. Among 351 patients who received repotrectinib, 52% were exposed for 6 months or longer and 26% were exposed for greater than 1 year. In this pooled safety population, the most common (>20%) adverse reactions were dizziness (64%), dysgeusia (50%), peripheral neuropathy (47%), constipation (37%), dyspnea (30%), ataxia (29%), fatigue (29%), cognitive disorders (23%), and nausea (20%). The most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased gamma glutamyl transferase (13%), decreased lymphocytes (10%), increased urate (10%), decreased neutrophils (8%), decreased hemoglobin (7%), increased creatine phosphokinase (5.8%), decreased phosphate (4.9%), decreased leukocytes (3.8%), increased ALT (3.5%), decreased sodium (3.5%), increased AST (2.9%), increased magnesium (2.9%), increased alkaline phosphatase (2.6%), and increased glucose (2%).

TRIDENT-1

The safety of repotrectinib was evaluated in 264 patients with ROS1-positive NSCLC in TRIDENT-1. Eligible patients had an ECOG status of ≤1. Patients with a history of ILD, drug-related pneumonitis, significant, uncontrolled, active cardiovascular disease, or prolonged QTc interval were excluded from enrollment in this trial. Patients received repotrectinib at a dose of 160 mg orally once daily for the first 14 days, then increased to 160 mg orally twice daily until disease progression or unacceptable toxicity. Among patients who received repotrectinib, 52% were exposed for at least 6 months, and 27% were exposed for greater than 1 year.

The median age of patients who received repotrectinib was 56 years (range: 27 to 93); 62% female; 43% White, 49% Asian, 2.7% Black, 0.8% Native Hawaiian or Other Pacific Islander, 0.4% American Indian or Alaska Native, 3.4% race not reported, and 1.1% unknown.

Serious adverse reactions occurred in 33% of patients who received repotrectinib. Serious adverse reactions in ≥2% of patients included pneumonia (5.7%), dyspnea (3.8%), pleural effusion (3.4%), and hypoxia (3%). Fatal adverse reactions occurred in 4.2% of patients who received repotrectinib, including death, pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, sudden death, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.

Permanent discontinuation of repotrectinib was required in 8% of patients due to adverse reactions. The adverse reactions resulting in permanent discontinuation of repotrectinib in ≥1% of patients were dyspnea, pneumonitis, and muscular weakness.

Dosage interruptions of repotrectinib due to an adverse reaction occurred in 48% of patients. Adverse reactions that required dosage interruption in ≥5% of patients included CNS toxicity, dyspnea, and muscular weakness.

Dose reductions of repotrectinib due to an adverse reaction occurred in 35% of patients. Adverse reactions that required dosage reductions in ≥5% of patients included dizziness.

The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased hemoglobin, decreased lymphocytes, decreased leukocytes, increased alanine aminotransferase, decreased neutrophils, increased gamma glutamyl transferase, increased alkaline phosphatase, increased urate, increased magnesium, and decreased phosphate. Table 1 summarizes the adverse reactions in the TRIDENT-1 trial.

Table 1. Adverse Reactions (≥10%) in Patients with ROS1-positive NSCLC Who Received repotrectinib in TRIDENT-1:

¹ Based on NCI CTCAE v4.03
^a Includes terms dizziness, vertigo, dizziness postural, dizziness exertional, vertigo positional
^b Includes terms dysgeusia, ageusia, anosmia, hypogeusia
^c Includes terms neuralgia, neuropathy peripheral, peripheral sensory neuropathy, dysesthesia, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, hyperesthesia
^d Includes terms ataxia, gait disturbance, balance disorder, cerebellar ataxia
^e Includes terms memory impairment, disturbance in attention, cognitive disorder, confusional state, amnesia, attention deficit hyperactivity disorder, delirium, altered state of consciousness, aphasia, delusion, depressed level of consciousness, hallucination, mental status changes, neurological decompensation
^f Includes terms headache, migraine, tension headache
^g Includes terms dyspnea and dyspnea exertional
^h Includes terms productive cough, cough, and upper-airway cough syndrome
ⁱ Includes terms fatigue and asthenia
^j Includes terms generalized edema, periorbital edema, localized edema, face edema, edema peripheral, edema, eye edema, scrotal edema
^k Includes terms myalgia, myositis, musculoskeletal discomfort, musculoskeletal pain
^l Includes terms vision blurred, dry eye, visual impairment, visual field defect, cataract, conjunctivitis, eye pain, photophobia, photosensitivity reaction, visual acuity reduced, vitreous floaters, blepharospasm, color blindness, diplopia, eye hematoma, eye swelling, eyelid disorder, eyelid injury, eyelids pruritus, glaucoma, night blindness, ophthalmic herpes zoster

Clinically relevant adverse reactions in <10% of patients receiving repotrectinib were pyrexia (8%) and fall (2.7%).

Table 2 summarizes the laboratory abnormalities.

Table 2. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ROS1-positive NSCLC Who Received repotrectinib in TRIDENT-1:

Abbreviations: AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase; GGT: Gamma Glutamyl Transferase; aPTT: Activated Partial Thromboplastin Time; INR: Prothrombin International Normalized Ratio
¹ Based on NCI CTCAE v4.03
² The denominator used to calculate the rate varied from 163 to 261 based on the number of patients with a baseline value and at least one post-treatment value.