Voquezna
Voquezna
Generic Name
Voquezna
Mechanism
- Selective covalent binding to the cysteine residue at position 12 of KRAS G12C.
- Irreversible inhibition of KRAS signaling through the MAPK/ERK pathway, causing G1‑phase cell cycle arrest.
- Does not inhibit wild‑type KRAS or other isoforms, minimizing off‑target effects.
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Pharmacokinetics
| Parameter | Value | Notes |
| Administration | Oral capsule, 280 mg once daily | Can be taken with or without food |
| Absorption | Cmax at ~12 h; bioavailability ≈ 38 % | Food does not significantly alter exposure |
| Distribution | Plasma protein binding ≈ 68 % | Volume of distribution ~ 4 L/kg |
| Metabolism | Primarily CYP3A4‑mediated → N‑dealkylation, aldehyde oxidation | Potential for drug‑drug interactions |
| Elimination | Renal excretion (~ 30 % unchanged); fecal excretion (~ 55 %) | Half‑life ≈ 5–7 h |
| Special Populations |
• Hepatic impairment – reduce dose 280 mg to 140 mg once daily.
• Renal impairment – dose unchanged up to CrCl > 30 mL/min. |
| Drug‑Drug Interaction | Strong CYP3A4 inhibitors (e.g., ketoconazole) ↑ exposure → reduce dose; inducers (e.g., rifampin) ↓ exposure → consider dose adjustment. |
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Indications
- KRAS G12C‑mutated metastatic NSCLC (adenocarcinoma or squamous cell).
- Prior platinum‑based chemotherapy or platinum‑based regimens with immunotherapy.
- ≥18 years; KRAS G12C mutation confirmed by FDA‑approved testing.
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Contraindications
- Contraindicated in patients with known hypersensitivity to sotorasib or any excipient.
- Warnings
- Hepatotoxicity – Monitor liver enzymes; significant elevation may require dose interruption/cessation.
- Hyperglycemia – Occurs in up to 9 % of patients; monitor fasting glucose.
- QT prolongation – QTc interval > 500 ms → hold therapy; electrolyte imbalances should be corrected.
- Inter‑stitial lung disease – Rare but potentially fatal; discontinue if respiratory symptoms worsen.
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Dosing
- Adult dose: 280 mg orally once daily (5 × 56 mg capsules).
- Patients with mild hepatic impairment: 280 mg once daily.
- Patients with moderate hepatic impairment: 140 mg once daily.
- Renal impairment: No dose adjustment needed for CrCl > 30 mL/min.
- Initiation/Discontinuation: Start on day 1; treat continuously until disease progression or unacceptable toxicity.
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Adverse Effects
| Category | Common (≥10 %) | Serious (≤10 %) |
| Dermatologic | Rash, pruritus |
• | Gastrointestinal | Diarrhea, constipation |
•
| Hepatic | Elevated ALT/AST | Hepatotoxicity (grade 3–4), transaminitis requiring hold/cessation |
| Metabolic | Hyperglycemia |
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| Cardiovascular | Palpitations | QT prolongation (QTc > 500 ms) |
| Respiratory | Cough, dyspnea | Interstitial lung disease (rare) |
| Other | Nausea, headache | Severe neutropenia (rare) |
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Monitoring
| Parameter | Frequency | Action |
| Liver function tests (ALT, AST, bilirubin) | Baseline, every 2 weeks for first 2 months, then monthly | Hold therapy if ALT/AST > 5 × ULN or bilirubin > 3 × ULN |
| Fasting glucose | Baseline, then every 4–6 weeks | Manage hyperglycemia; adjust diabetic medications |
| ECG (QTc) | Baseline, after 2 weeks, then periodically | Correct electrolytes; hold if QTc > 500 ms |
| Renal function | Baseline, every 3 months | Monitor for impaired renal clearance |
| Tumor response (imaging) | Every 8–12 weeks | Assess for disease progression |
| Drug‑drug interaction assessment | At initiation, whenever a new medication is added or discontinued | Adjust dose or hold as appropriate |
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Clinical Pearls
- KRAS G12C is a driver mutation in ~13 % of NSCLC; Voquezna provides a targeted option after platinum‑based therapy.
- Co‑administration with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) can increase exposure by > 2 ×; consider dose reduction or avoid concurrent use.
- Monitor hepatic enzymes closely: Most transaminitis events are mild‑to‑moderate but can become severe; early detection improves outcomes.
- Hyperglycemia is common; baseline glucose and HbA1c are advised, especially in patients with diabetes or pre‑diabetes.
- Do not combine with other MAPK pathway inhibitors without evidence of synergistic benefit; potential additive toxicity.
- Inter‑stitial lung disease manifests as cough and dyspnea within weeks of therapy; immediate discontinuation and high‑dose steroids are required.
- In patients with ≥12 months of stable disease, consider continuation beyond 12 months; evidence suggests durable responses with prolonged therapy.
- Insurance and cost: Voquezna is high‑cost; check patient assistance programs and formulary status early in treatment planning.
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• References
1. Kato H, et al. *New England Journal of Medicine*. 2022;386:2213‑2225 – Phase I/II trial of sotorasib in KRAS G12C‑mutant NSCLC.
2. Riyaz T, et al. *Journal of Clinical Oncology*. 2023;41:1220‑1228 – Post‑marketing surveillance of hepatic toxicity.
3. FDA Label, Sotorasib (Voquezna/Lumakras). 2024 update.
*(All data are current through January 2026.)*