Generic Name

(Entrectinib)

Mechanism

Rybrevant selectively and potently blocks the ATP‑binding sites of the ALK, ROS1, and TRK tyrosine kinases, preventing downstream phosphorylation cascades that drive proliferation, survival, apoptosis evasion, and angiogenesis in ROS1‑positive tumor cells. It exhibits minimal activity against other kinases, limiting off‑target effects.

Pharmacokinetics

• Administration: Oral (tablet, 100 mg).
• Absorption: Rapid, Tmax ≈ 2 h; food increases exposure slightly but does not alter clinical effect.
• Distribution: Widely distributed, lipophilic, penetrates the central nervous system (CNS), achieving therapeutic concentrations in brain metastases.
• Metabolism: Primarily CYP3A4‑mediated (also CYP2D6, CYP1A2); extensive first‑pass effect.
• Elimination: Urinary (≈ 50 %) and fecal (≈ 25 %) excretion; terminal half‑life ≈ 42 h.
• Drug Interactions: Potentiating effect with strong CYP3A4 inhibitors (e.g., ketoconazole) and induction with strong CYP3A4 inducers (e.g., rifampin).

Indications

• Metastatic or unresectable ROS1‑positive NSCLC (post‑chemotherapy or as first‑line therapy when a ROS1‑positive mutation is confirmed).
• Intracranial metastases from ROS1‑positive NSCLC, given its CNS penetration.
• Off‑label use in ROS1‑positive solid tumors with intracranial disease (e.g., cholangiocarcinoma, sarcoma) on clinical trial or compassionate basis.

Contraindications

• Contraindicated in patients with severe hepatic impairment (Child‑Pugh C) due to increased exposure.
• Warnings:
• Hepatotoxicity (↑ ALT/AST, bilirubin); monitor baseline and periodic LFTs.
• QTc prolongation – use with caution in patients on other QT‑extending agents or with congenital long‑QT syndromes.
• Rash or interstitial lung disease have been reported; discontinue upon severe dermatologic reactions or persistent cough/shortness of breath.
• Precautions during pregnancy and lactation: Category X; avoid in pregnant women. Discuss contraception with male/female patients.

Dosing

• Standard dose: 600 mg orally once daily (2 × 300 mg tablets).
• Special populations:
• Impaired liver function: Reduce to 400 mg once daily if Child‑Pugh B; avoid in Child‑Pugh C.
• Pediatric: Not approved; use only in clinical trials.
• Administration with food: Preferable for maximizing absorption; no dose adjustment needed.
• Missed dose: If missed within 6 h, take immediately; beyond 6 h, skip and resume next scheduled dose. Do not double the next dose.

Adverse Effects

Common (≥ 10 %)
• Fatigue
• Diarrhea
• Nausea
• Dry mouth
• Rash (maculopapular)
• Hyperbilirubinemia (mild)

Serious (≥ 1 %)
• Hepatotoxicity: ALT/AST > 5 × ULN, or bilirubin > 3 × ULN → Discontinue.
• QTc prolongation (> 500 ms) → Monitor ECG; hold therapy.
• Interstitial lung disease (pulmonary infiltrates, cough, dyspnea) → Consider steroid therapy and drug discontinuation.
• Severe dermatologic reactions (Stevens–Johnson, TEN) → Immediate discontinuation and dermatology consult.

Monitoring

• Baseline: CBC, CMP (including LFTs and bilirubin), electrolytes, electrolytes/renal function, ECG (QTc).
• During therapy:
• LFTs every 2‑4 weeks for first 3 months, then every 3 months.
• ECG every 3 months or sooner if symptoms.
• CBC and renal panel monthly for the first 3 months, then every 3 months.
• Imaging: CT/MRI every 8–12 weeks to assess response, particularly for CNS lesions.
• Adverse symptom diary: Record rash, gastrointestinal symptoms, and any respiratory changes.

Clinical Pearls

• CNS efficacy: Because Rybrevant penetrates the blood–brain barrier, it should be the first‑line targeted agent for ROS1‑positive NSCLC with brain metastases, often achieving > 80 % intracranial response rates.
• Biomarker confirmation: ROS1 rearrangement must be confirmed with next‑generation sequencing (NGS) or fluorescence in situ hybridization (FISH) before initiating treatment.
• Drug–Drug Interaction watchlist:
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole) can double exposure → dose reduction or switch therapy.
• Strong CYP3A4 inducers (rifampin, carbamazepine) can halve exposure → avoid or monitor for lack of efficacy.
• Resistance mechanisms: Secondary ROS1 gatekeeper mutations (e.g., G2032R) are common; if progression occurs, consider second‑generation ROS1 inhibitors (e.g., entrectinib alternatives).
• Palliative benefit: Even after progression, patients may experience symptom stabilization due to anti‑angiogenic effects; consider continuing therapy in selected cases.

*References*: FDA Label (Rybrevant, Entrectinib), NCCN Clinical Practice Guidelines in Oncology (2025), J Thorac Oncol. 2020;15:e36-e37.