ALIENTRECTINIB Entrectinib Capsules

I. Basic Drug Information

Generic Name: Entrectinib

Brand Names: ALIENTRECTINIB / Rozlytrek

Dosage Form and Strength: 100 mg per capsule; 60 capsules per box

Manufacturer: Lao United Pharmaceutical Group Co., Ltd.

Lao National Drug Administration Approval No.: 11 L 1229/24

Storage Conditions: 20°C–25°C (excursions permitted between 15°C–30°C); protect from light and moisture; keep bottle cap tightly closed.

II. Indications

1. ROS1-Positive Non-Small Cell Lung Cancer (NSCLC)

Indicated for the treatment of adult patients with metastatic ROS1-positive NSCLC.

2. NTRK Gene Fusion-Positive Solid Tumors

Indicated for adult and pediatric patients aged ≥1 month who meet the following criteria:

Confirmed presence of an NTRK gene fusion via genetic testing (without a known acquired resistance mutation);

The tumor is metastatic, or surgical resection is likely to result in severe complications;

Disease progression following prior treatment, or no satisfactory alternative therapies are available.

Prior to administration, the presence of ROS1 rearrangements or NTRK gene fusions must be confirmed via genetic testing (there is currently no single FDA-approved diagnostic method).

III. Mechanism of Action

Entrectinib is an oral, multi-targeted tyrosine kinase inhibitor with central nervous system (CNS) penetrance:

Targets: Inhibits TRKA/B/C (encoded by NTRK1/2/3), ROS1, and ALK, with IC₅₀ values ranging from 0.1 to 2 nM;

Action: Blocks aberrant signaling pathways mediated by fusion proteins, thereby inhibiting tumor cell proliferation and survival;

Key Feature: Capable of penetrating the blood-brain barrier and is effective against brain metastases. IV. Dosage and Administration

1. Standard Dosing Regimen

| Patient Type                    | Recommended Dose                     | Duration of Treatment

| Adults (NSCLC/NTRK) | 600 mg orally, once daily | Continue until disease progression or intolerance

| Children (≥12 years, NTRK)| Adjusted based on Body Surface Area (BSA):| Same as adults

| - BSA 0.91–1.10 m² | 400 mg/day

| - BSA 1.11–1.50 m² | 500 mg/day

| - BSA >1.50 m² | 600 mg/day

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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

2. Administration Instructions

Method of Administration:

Swallow capsules whole; do not crush, chew, or dissolve them.

May be taken with or without food; however, avoid taking with grapefruit or grapefruit juice (as this affects CYP3A metabolism).

Management of Missed Doses/Vomiting:

Missed dose (more than 12 hours late): Take the missed dose immediately; otherwise, skip the dose.

Vomiting after administration: Take an additional dose. 3. Dosage Adjustment Guidelines

Table 1: Dosage Adjustments Based on Adverse Reactions

| Type of Adverse Reaction | Management Measures

| Congestive Heart Failure | Grade 2–3: Suspend → Reduce dose once recovered to ≤ Grade 1; Grade 4: Permanently discontinue |

| CNS Toxicity | Intolerable Grade 2 or 3: Suspend → Reduce dose once recovered; Grade 4: Permanently discontinue |

| Hepatotoxicity (Elevated ALT/AST) | Grade 3: Suspend → Reduce dose once recovered; Grade 4 or accompanied by elevated bilirubin: Permanently discontinue |

| QTc Prolongation > 500 ms | Suspend → Assess underlying cause once returned to baseline; If no clear cause, reduce dose; Life-threatening arrhythmia: Permanently discontinue |

| Visual Impairment ≥ Grade 2 | Suspend → Resume at original dose or reduced dose once improved |

Dosage Reduction Steps:

Adults: First reduction to 400 mg/day → Second reduction to 200 mg/day → Discontinue if still not tolerated.

Children: Reduce dose in steps based on BSA (e.g., if BSA > 1.5 m²: 600 mg → 400 mg → 200 mg).

V. Adverse Reactions

Common Adverse Reactions (Incidence ≥ 20%)

Systemic: Fatigue (54%), Fever (25%);

Gastrointestinal: Constipation (44%), Diarrhea (39%), Nausea (37%), Dysgeusia (36%);

Nervous System: Dizziness (33%), Paresthesia (29%), Cognitive Impairment (28.6%);

Other: Edema (35%), Weight Gain (28%), Arthralgia (26%), Blurred Vision (21%). **Severe Risk Warning (Requires Immediate Medical Attention)**

| Risk Type                 | Incidence Rate | Key Symptoms & Management

| Congestive Heart Failure  | 3.4%           | Dyspnea, lower extremity edema → Discontinue medication and assess cardiac function

| Fractures                 | Adults: 5%; Children: 23% | Non-traumatic fractures → Supplement with Calcium/Vitamin D; assess bone mineral density

| Hepatotoxicity            | ALT↑ 36%; AST↑ 42% | Jaundice, abdominal pain → Monitor liver enzymes every 2 weeks

| QT Interval Prolongation  | >500 ms (0.6%) | Dizziness, palpitations → ECG monitoring at baseline and during treatment

| Interstitial Lung Disease | 1.6%           | Dry cough, dyspnea → Permanently discontinue medication and initiate corticosteroid therapy

**VI. Contraindications and Precautions**

**1. Contraindications Regarding Drug Interactions:**

**Concomitant use prohibited:** Strong CYP3A4 inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin);

**Use with caution:** Drugs known to prolong the QTc interval (e.g., haloperidol), proton pump inhibitors (may reduce plasma drug concentrations).

**2. Contraindications for Special Populations:**

**Pregnant Women:** Teratogenic risk (fetal malformations); absolutely contraindicated; 

**Patients of Childbearing Potential:**

**Females:** Must use effective contraception during treatment and for ≥5 weeks after discontinuing the drug;

**Males:** Must use effective contraception during treatment and for ≥3 months after discontinuing the drug;

**Lactating Women:** Must suspend breastfeeding during treatment and for ≥7 days after discontinuing the drug.

**3. Key Monitoring Requirements:**

**Prior to Treatment:** ECG (QTc interval), liver function tests, uric acid levels;

**During Treatment:**

Monitor cardiac function (LVEF) monthly;

Monitor liver enzymes every 2 weeks for the first month, then monthly thereafter;

Perform periodic ophthalmologic examinations (to check for changes in visual acuity). VII. Clinical Efficacy Data

Table 2: Summary of Key Clinical Trial Results

| Indication | Study (N) | Overall Response Rate (ORR) | Median Duration of Response (DOR) |

| ROS1-positive NSCLC (Adults) | STARTRK-2 (51 patients) | 78% (CR 6%) | ≥12 months (55% of patients) |

| NTRK-fusion Solid Tumors (Adults) | ALKA (54 patients) | 57% (CR 7.4%) | ≥12 months (45% of patients) |

Note: Effective in patients with brain metastases; intracranial ORR reached 55%.

VIII. Storage

Storage: Keep sealed in original packaging; protect from light and moisture; store at a temperature ≤30°C.