Entrectinib

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, entrectinib can cause fetal harm when administered to a pregnant woman. There are no available data on entrectinib use in pregnant women. Administration of entrectinib to pregnant rats during the period of organogenesis resulted in malformations at maternal exposures approximately 2.7 times the human exposure at the 600 mg dose (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

Entrectinib administration to pregnant rats during the period of organogenesis at a dose of 200 mg/kg [resulting in exposures up to 2.7 times the human exposure (AUC) at the 600 mg dose] resulted in maternal toxicity and fetal malformations including body closure defects (omphalocele and gastroschisis) and malformations of the vertebrae, ribs, and limbs (micromelia and adactyly), but not embryolethality. Lower fetal weights and reduced skeletal ossification occurred at doses ≥12.5 and 50 mg/kg [approximately 0.2 and 0.9 times the human exposure (AUC) at the 600 mg dose], respectively.

Risk Summary

There are no data on the presence of entrectinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential adverse reactions in breastfed children from entrectinib, advise a lactating woman to discontinue breastfeeding during treatment with entrectinib and for 7 days after the final dose.

Carcinogenicity studies were not conducted with entrectinib. Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay; however, an in vitro assay in cultured human peripheral blood lymphocytes did demonstrate a potential for abnormal chromosome segregation (aneugenicity). Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.

Dedicated fertility studies were not conducted with entrectinib. With the exception of dose-dependent decreases in prostate weight in male dogs, there were no effects on male and female reproductive organs observed in general toxicology studies conducted in rats and dogs at doses resulting in exposures of up to approximately 3.2 fold the human exposure (AUC) at the 600 mg dose.

• Congestive Heart Failure
• Central Nervous System Effects
• Skeletal Fractures
• Hepatotoxicity
• Hyperuricemia
• QT Interval Prolongation
• Vision Disorders

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.

Data in WARNINGS AND PRECAUTIONS and below reflect exposure to entrectinib in 355 patients, including 172 (48%) patients exposed for 6 months or longer and 84 (24%) patients exposed for 1 year or longer. Entrectinib was studied in one dose-finding trial in adults [ALKA (n=57)], one dose-finding and activity-estimating trial in adults [STARTRK-1 (n=76)], one dose-finding and activity-estimating trial in pediatric and adult patients [STARTRK-NG (n=16)], and one single arm, activity-estimating trial in adults [STARTRK-2 (n=206)].

The population characteristics were: median age 55 years (range: 4 to 86 years); 5% (n=17) were less than 18 years of age; 55% were female; and 66% were White, 23% were Asian, and 5% were Black; 3% were Hispanic/Latino. The most common tumors (≥5%) were lung (56%), sarcoma (8%), and colon (5%). ROS1 gene fusions were present in 42% and NTRK gene fusions were present in 20%. Most adults (75%) received entrectinib 600 mg orally once daily. The doses ranged from 100 mg/m² to 1600 mg/m² once daily in adults and 250 mg/m² to 750 mg/m² once daily in pediatric patients. entrectinib is not indicated for pediatric patients less than 12 years of age.

Serious adverse reactions occurred in 39% of patients. The most frequent serious adverse reactions (≥2%) were pneumonia (3.9%), dyspnea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2.3%), respiratory failure (2%), and pyrexia (2%). Grade 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2.5%). Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumor lysis syndrome (0.3%). One patient developed Grade 4 myocarditis after one dose of entrectinib which resolved after discontinuation of entrectinib and administration of high-dose corticosteroids.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received entrectinib. The most frequent adverse reactions (< 1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnea, and fatigue.

Dose interruptions due to adverse reactions occurred in 46% of patients. The most frequent adverse reactions (≥2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%).

Dose reductions due to adverse reactions occurred in 29% of patients who received entrectinib. The most frequent adverse reactions resulting in dose reductions (≥1%) were dizziness (3.9%), increased blood creatinine (3.1%), fatigue (2.3%), anemia (1.7%), and increased weight (1.4%).

The most common adverse reactions (≥20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia and vision disorders.

Table 1 summarizes the adverse reactions observed in these 355 patients.

Table 1. Adverse Reactions (≥10%) in Patients Receiving Entrectinib in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG:

* Grades 3–5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea.
^† Includes fatigue, asthenia‡Includes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling
^§ Includes abdominal pain upper, abdominal pain, lower abdominal discomfort, abdominal tenderness
^¶ Includes dizziness, vertigo, dizziness postural
^# Includes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoesthesia, palmar-plantar erythrodysesthesia, oral paresthesia, genital hypoesthesia
^Þ Includes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes
^ß Includes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy
^à Includes ataxia, balance disorder, gait disturbances
^è Includes hypersomnia, insomnia, sleep disorder, somnolence
^ð Includes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation
^ø Includes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain
^ý Includes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters
^£ Includes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection
^¥ Includes hypotension, orthostatic hypotension
^ΠIncludes rash, rash maculopapular, rash pruritic, rash erythematous, rash papular

Clinically relevant adverse reactions occurring in ≤10% of patients include dysphagia (10%), fall (8%), pleural effusion (8%), fractures (6%), hypoxia (4.2%), pulmonary embolism (3.9%), syncope (3.9%), congestive heart failure (3.4%), and QT prolongation (3.1%).

Table 2 summarizes the laboratory abnormalities.

Table 2. Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Receiving Entrectinib in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG:

AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase
* Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 111 to 34 6 patients.
^† Based on NCI CTCAE v5.0
^‡ NE = Not evaluable. Grade 1 and 2 could not be determined per NCI CTCAE v5.0, as fasting glucose values were not collected.