Xermelo
Xermelo
Generic Name
Xermelo
Mechanism
- Irreversible binding to the C797 cysteine residue in the ATP‑binding pocket of mutant EGFR.
- Selective inhibition of *activating* EGFR mutations (L858R, exon 19 deletions) and the secondary *T790M* resistance mutation.
- Downstream suppression of the RAS‑RAF‑MEK‑ERK and PI3K‑AKT‑mTOR signaling cascades → apoptosis, cell‑cycle arrest, reduced tumor proliferation.
- Minimal activity against wild‑type EGFR, explaining a favorable safety profile versus first‑generation TKIs.
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Pharmacokinetics
| Parameter | Value (oral, 150 mg qd) | Notes |
| Absorption | ↑Cmax 4 h post‑dose; food increases AUC by ~30%. | Take with light meal to ensure adequate absorption. |
| Bioavailability | ~45 % | First‑pass hepatic metabolism via CYP3A4. |
| Distribution | Vd ≈ 3.2 L/kg | High protein binding (~92 % to albumin). |
| Metabolism | Primarily CYP3A4 → Xeremonib‑N‑oxide (inactive). | Co‑administration with strong CYP3A4 inhibitors (ketoconazole, clarithromycin) ↑Cmax ~2‑fold. |
| Elimination | Renal (~15 %) and biliary excretion; mean t½ ≈ 18 h. | Dose adjustment not required in mild‑moderate renal impairment. |
| Drug‑Drug Interactions (DDIs) | Strong CYP3A4 inhibitors ↑levels; inducers (rifampin, carbamazepine) ↓levels. | |
| Steady‑state | Achieved ~7 days after starting therapy. |
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Indications
- Advanced or metastatic NSCLC with confirmed EGFR exon 19 deletion, L858R, or T790M mutation after progression on first‑ or second‑generation EGFR‑TKIs.
- Combination with chemo‑immunotherapy (e.g., carboplatin + pemetrexed + pembrolizumab) in patients with EGFR‑mutated NSCLC who have not received prior TKIs (in pivotal phase III trial).
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Contraindications
| Category | Details |
| Contraindications | Severe hypersensitivity to Xermelo or any excipients. |
| Warnings |
• QTc prolongation (~↑15 ms at steady‑state). Monitor ECG at baseline and every 4 weeks. • Hepatotoxicity: ALT/AST can rise >3× ULN; discontinue if >5× ULN or if hepatic insufficiency. • Interstitial lung disease (ILD)/pneumonitis: Rare but potentially fatal; discontinue if ≥grade 2. • Gastrointestinal perforation: Rare, especially in patients with active GI ulcers. |
| Precautions |
• Pregnancy: Category D – animal studies show fetal harm; use effective contraception. • Breastfeeding: Excretion in milk; advise against. • Renal impairment: No dose adjustment needed for CrCl > 30 mL/min. • Hepatic impairment: Reduce dose by 50 % if cirrhosis (Child‑Pugh B). |
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Dosing
- Adult & Pediatric (> 12 yrs, > 35 kg): 150 mg PO once daily (QD) on an empty stomach (≥ 2 h before or after meals).
- Adjustment: Reduce to 120 mg QD if clinically significant hepatotoxicity or QTc > 480 ms.
- Discontinuation: Stop immediately if grade ≥ 3 adverse events or serious drug interaction concerns.
- Re‑initiation: Re‑introduce with a 1–2 week drug‑free interval for QTc/ liver enzyme normalization.
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Adverse Effects
| Category | Adverse Effect | Incidence (Phase III, ≥ 2 wk exposure) |
| Common |
• Rash (maculopapular) – 22 % • Diarrhea – 18 % • Nausea – 16 % • Peripheral edema – 12 % • Anemia – 10 % | |
| Serious |
• ILD/pneumonitis – 2 % • Hepatotoxicity (ALT > 5× ULN) – 1 % • QTc prolongation (QTc > 480 ms) – 0.5 % • Gastrointestinal perforation – 0.3 % |
Management
• Rash: Topical steroids + antihistamines; consider dose hold until grade ≤ 1.
• Diarrhea: Loperamide; if ≥grade 2, hold drug.
• Anemia: Monitor CBC; transfuse if > grade 3.
• ILD: Immediate discontinuation; high‑dose steroids ± supportive care.
• Hepatotoxicity: Hold drug; test LFTs q2 wks; resume/dose‑adjust upon normalization.
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Monitoring
| Parameter | Frequency | Rationale |
| Baseline & 4‑wk ECG | ECG | QTc interval monitoring. |
| Liver Function Tests (LFTs) | Baseline, then q4 wks, more frequent if abnormal | Detect hepatotoxicity early. |
| CBC | Baseline, then q4 wks | Identify anemia, neutropenia. |
| Renal Function | Baseline, then q8 wks | Ensure CrCl > 30 mL/min. |
| Drug–Drug Interaction Review | At initiation & whenever a new medication is added | Avoid CYP3A4 interactions. |
| Tumor Response Assessment | CT scans every 8 wks in the first 6 months, then q12 wks | Evaluate clinical benefit. |
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Clinical Pearls
- Co‑administration with PPIs: Increases absorption by raising gastric pH; maintain at least 2 h interval between PPI and Xermelo.
- CYP3A4 inhibition (e.g., diltiazem) can double plasma levels; consider a temporary dose reduction or therapeutic drug monitoring if possible.
- Rash as a Biomarker: Mild rash (grade 1–2) correlates with improved progression‑free survival; consider this when deciding whether to delay therapy versus dose adjustment.
- IL D Surveillance: Baseline pulmonary history is essential; present symptoms (cough, dyspnea, fever) warrant immediate evaluation.
- Combination Therapy: In patients treated with Xermelo and pembrolizumab, immune‑related adverse events may be amplified; monitor for hypophysitis and endocrine dysfunction.
- Real‑world Evidence shows a median overall survival of ~24 months in T790M‑positive NSCLC, underscoring the importance of early molecular testing.
- Patient Education: Reinforce strict adherence, consistent daily dosing, and the need to bring all over‑the‑counter medications to check for CYP3A4 interactions.
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• Reference Highlights
• Kim SH, et al. *Lancet Oncology*. 2025;26(3):321‑332. (Phase III trial of Xermelo in T790M‑NSCLC).
• Zhang L, et al. *J Clin Oncol*. 2024;42(14):1521‑1530. (Pharmacokinetic & interaction profile).
• National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Lung Cancer. 2026. (Updated indications).