ENTREDX Entrectinib Capsules

[Product Name] Entrectinib Capsules

[Specification] 200 mg × 45 Capsules/Box

[Manufacturer] Bigbear Pharmaceutical Laos

[Overview]

Entrectinib is a specific tyrosine kinase inhibitor designed to target NTRK and ROS1 gene fusions, indicated for the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumors.

[Indications]

1. Adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive.

2. Adult and pediatric patients aged 12 years and older with solid tumors that:

① Harbor a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation;

② Are metastatic or where surgical resection is likely to result in severe complications; 

③ Have progressed following prior treatment or for which there is no satisfactory alternative therapy.

[Storage]

Store in a dry place at 20°C to 25°C. Excursions are permitted between 15°C and 30°C (59°F and 86°F).

[Dosage and Administration]

1. Recommended Dosage for ROS1-Positive Non-Small Cell Lung Cancer: 600 mg orally once daily.

2. Recommended Dosage for NTRK Gene Fusion-Positive Solid Tumors:

① Adults: 600 mg orally once daily.

② Pediatric patients aged 12 years and older: The recommended dosage is based on Body Surface Area (BSA), as follows:

• BSA > 1.50 m²: 600 mg orally once daily;

• BSA 1.11 to 1.50 m²: 500 mg orally once daily;

• BSA 0.91 to 1.10 m²: 400 mg orally once daily. Pediatric Patient BSA Dosage Calculator

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Body Surface Area (BSA) | Recommended Dose | Dosing Frequency

BSA ≥ 1.5 m² | 600 mg | Once daily

1.2 m² ≤ BSA < 1.5 m² | 500 mg | Once daily

1.0 m² ≤ BSA < 1.2 m² | 400 mg | Once daily

[Adverse Reactions]

1. Common:

1) Abdominal or stomach pain or tenderness; blurred vision; burning sensation; crawling sensation on the skin.

2) Itching; numbness; tingling; "pins and needles" sensation; changes in color vision.

3) Clay-colored stools; confusion; dark urine; decreased appetite; impairment in (intellect, short-term memory, learning ability, and attention).

4) Difficulty seeing at night; dizziness; fever; headache; increased sensitivity of the eyes to sunlight.

5) Rash; joint (pain, stiffness, or swelling); loss of appetite; lower back pain; flank pain.

6) Nausea and vomiting; balance problems; drowsiness or unusual sleepiness; swelling of the feet or lower legs.

7) Difficulty sleeping; unusual tiredness or weakness; yellowing of the eyes or skin.

2. Uncommon:

1) Chest pain; decreased urine output; distended neck veins; double vision.

2) Extreme fatigue; fainting; irregular breathing; recurrent irregular heartbeat.

3) Amnesia; memory problems; speech difficulties; (seeing, hearing, or feeling things that do not exist); swelling of the (face, fingers, feet, or lower legs).

4) Chest tightness; difficulty remembering; difficulty breathing; weight gain.

[Precautions]

1. Congestive Heart Failure: Among the 355 patients enrolled in clinical trials for entrectinib, the incidence of congestive heart failure (CHF) was 3.4%, including Grade 3 events (2.3%). 2. Central Nervous System Effects: Patients treated with entrectinib experienced a wide range of central nervous system (CNS) adverse reactions, including cognitive impairment, mood disorders, dizziness, and sleep disorders.

3. Fractures: Entrectinib increases the risk of fractures. In an expanded safety trial involving 338 adult patients and 30 pediatric patients treated with entrectinib, fractures occurred in 5% of adult patients and 23% of pediatric patients.

4. Hepatotoxicity: Among 355 patients treated with entrectinib, 42% experienced AST elevations of varying grades, and 36% experienced ALT elevations of varying grades. Grade 3 or 4 AST or ALT elevations occurred in 2.5% and 2.8% of patients, respectively; however, as 4.5% of patients did not undergo post-treatment liver function testing, the actual incidence may be underestimated.

5. Hyperuricemia: Among 355 patients enrolled in clinical trials of entrectinib, 32 patients (9%) developed hyperuricemia, accompanied by symptoms and elevated uric acid levels.

6. QT Interval Prolongation: Among 355 patients treated with entrectinib, 3.1% experienced a QTcF interval prolongation of >60 ms from baseline on at least one post-baseline ECG assessment, and 0.6% experienced a QTcF interval of >500 ms.

7. Vision Disorders: Among 355 patients in clinical trials of entrectinib, 21% experienced vision changes, including Grade 1 (82%), Grade 2 (14%), and Grade 3 (0.8%) events.

8. Embryo-fetal Toxicity: Based on published literature regarding human congenital mutations that alter TRK signaling, findings from animal studies, and its mechanism of action, entrectinib can cause fetal harm when administered to pregnant women. [Mechanism of Action]

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK)—specifically TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes *NTRK1*, *NTRK2*, and *NTRK3*, respectively)—as well as the proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and anaplastic lymphoma kinase (ALK), with IC50 values ranging from 0.1 to 2 nM. Entrectinib also inhibits JAK2 and TNK2, with IC50 values > 5 nM. Entrectinib’s major active metabolite, M5, demonstrates similar *in vitro* activity against TRK, ROS1, and ALK.

[Safety and Efficacy]

1. ROS1-Positive Non-Small Cell Lung Cancer

The efficacy of entrectinib was evaluated in a pooled subgroup of patients with ROS1-positive metastatic NSCLC. These patients received entrectinib at various doses and schedules (90% received 600 mg orally once daily) and were enrolled in one of three multicenter, single-arm, open-label clinical trials: ALKA, STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267).

Efficacy was evaluated in 51 patients with ROS1-positive NSCLC. The overall response rate was 78%, comprising 6% complete responses and 73% partial responses; the proportions of patients with a duration of response (DOR) of ≥ 9 months, ≥ 12 months, and ≥ 18 months were 70%, 55%, and 30%, respectively.

2. NTRK Gene Fusion-Positive Solid Tumors

The efficacy of entrectinib was evaluated in a pooled subgroup of adult patients with unresectable or metastatic solid tumors harboring NTRK gene fusions. These patients were enrolled in three multicenter, single-arm, open-label clinical trials: ALKA, STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267). Efficacy was evaluated in 54 adult patients with solid tumors harboring *NTRK* gene fusions. The overall response rate was 57%, comprising a complete response rate of 7.4% and a partial response rate of 50%; the proportions of patients with a duration of response (DOR) of ≥ 6 months, ≥ 9 months, and ≥ 12 months were 68%, 61%, and 45%, respectively.