Alecensa
Alecensa
Generic Name
Alecensa
Mechanism
- Irreversible covalent binding to the kinase domain (Cys 797) of EGFR, ALK, HER2, and KIT leading to persistent inhibition of downstream signaling pathways (PI3K/AKT, RAS/RAF/MEK/ERK).
- Blockade of ligand‑induced dimerization prevents receptor phosphorylation and reduces tumor cell proliferation, survival, and angiogenesis.
---
Pharmacokinetics
| Parameter | Data |
| Absorption | Oral bioavailability ~ 73 % with food; Tmax ≈ 5 h. |
| Distribution | Extensive tissue penetration; protein binding ~ 90 %. |
| Metabolism | Primarily hepatic via CYP3A4; notable metabolites with reduced activity. |
| Elimination | Bilateral hepatic and renal pathways; half‑life ~ 120 h (disposition half‑life). |
| Drug–Drug Interactions | Strong CYP3A4 inhibitors increase exposure → dose reduction or avoidance; strong CYP3A4 inducers decrease exposure. |
--
•
Indications
- First‑line therapy for EGFR‑mutated metastatic NSCLC (exon 19 del or L858R).
- May be used in patients with central nervous system (CNS) metastases owing to modest CNS penetration.
---
Contraindications
- Contraindicated in patients with known hypersensitivity to afatinib or any component.
- Severe hepatic impairment (Child‑Pugh C) or renal dysfunction (CrCl < 30 mL/min) not recommended.
- Cardiotoxicity warning: monitor for QT prolongation and heart failure, especially in those with pre‑existing cardiac disease.
- Fertility: teratogenic potential; contraceptive measures advised for both sexes.
---
Dosing
- Standard dose: 40 mg orally once daily; can be increased to 50 mg if tolerated.
- Starting dose in hepatic impairment: 30 mg daily.
- Administration: With or without food; take at the same time each day, preferably on an empty stomach to improve absorption.
- Treatment duration: Until disease progression or unacceptable toxicity.
---
Adverse Effects
Common (≥ 20 %)
• Diarrhea, asthenia, stomatitis, skin rash, dry mouth.
• Anorexia, nausea, constipation.
Serious (≤ 5 %)
• Severe diarrhea (≥ Grade 3).
• Cardiac events: arrhythmias, QT prolongation, heart failure.
• Hepatotoxicity (↑ ALT/AST ≥ 5× ULN).
• Interstitial lung disease (ILD)/pneumonitis.
> *Note*: Diarrhea is the most frequent adverse effect, often dose‑related and managed with loperamide and hydration.
---
Monitoring
- Baseline: CBC, CMP, ECG, echocardiogram (if cardiac history).
- During therapy:
- CBC, CMP every 4–6 weeks, then every 2–3 months.
- ECG at baseline and every 2–3 months or if symptoms of arrhythmia.
- Monitor for signs of ILD: dyspnea, cough.
- Dose adjustments: Based on toxicity severity (interruption → recovery → re‑initiation at reduced dose).
---
Clinical Pearls
- Early Supportive Care: Initiate anti‑diarrheal prophylaxis (loperamide) at the first sign of diarrhoea to avoid dose reductions.
- Caxinastro sign: A distinct tongue‑lingua pattern (posterior lingual erythema) often precedes severe stomatitis; pre‑emptive oral care can mitigate severity.
- Use in CNS metastases: Unlike first‑generation TKIs, afatinib has evidence of CNS activity; consider imaging after 8–12 weeks if neurological symptoms persist.
- Drug interactions: Avoid concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) and strong inducers (e.g., rifampin, carbamazepine); pause or dose‑adjust accordingly.
- Pregnancy: Registry data suggest potential teratogenicity; counsel patients on effective contraception for at least 3 months post‑therapy.
- Rechallenge: Limited data; some patients may tolerate afatinib upon retreatment after alternate therapies, but cautious dose management is warranted.
--
• Key Takeaway: For EGFR‑mutation positive NSCLC, _Alecensa_ provides durable disease control, but meticulous surveillance for diarrhoea, cardiac, and hepatic toxicities ensures optimal patient outcomes.