Imfinzi
Imfinzi
Generic Name
Imfinzi
Mechanism
- PD‑L1 blockade: Blocking the PD‑L1/PD‑1/B7‑1 axis *prevents T‑cell exhaustion* and promotes reactivation of cytotoxic T lymphocytes within the tumor microenvironment.
- Immune surveillance restoration: With PD‑L1 inhibited, tumor cells become more susceptible to immune‑mediated cytotoxicity.
- Selective tumor targeting: Durvalumab has high affinity for PD‑L1 expressed on tumor cells and the surrounding stroma, sparing most healthy tissues and minimizing off‑target toxicity.
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Pharmacokinetics
| Parameter | Value (Population) | Notes |
| Absorption | Intravenous only (no oral absorption) | |
| Distribution | Vd ≈ 27 L (restricted to the vascular and interstitial spaces) | Limited extravascular penetration due to IgG size |
| Half‑life | ~ 18–20 days | Allows bi‑weekly or monthly dosing |
| Metabolism | Proteolytic catabolism (non‑CYP) | No hepatic metabolism; minimal drug‑drug interactions |
| Elimination | 5–10 % via renal excretion; remainder via reticuloendothelial system | Creatinine clearance > 30 mL/min preferred |
| Steady‑state | Achieved after ~ 4 weeks of bi‑weekly dosing |
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Indications
| Indication | Criteria | Preferred Dosing |
| Locally advanced, unresectable Stage III NSCLC | After 4–6 cycles of concurrent platinum‑based chemoradiation; no disease progression | 1500 mg IV q4 wk (fixed dose) |
| Advanced/metastatic urothelial carcinoma | After platinum‑based chemotherapy; with or without PD‑L1 expression | 10 mg/kg IV q2 wk |
| PD‑L1‑positive metastatic NSCLC | Lung adenocarcinoma or squamous cell carcinoma; PD‑L1 ≥ 1 % | 10 mg/kg IV q2 wk |
| Hodgkin lymphoma (in clinical trials) | PD‑L1+ disease | 10 mg/kg IV q2 wk (investigational) |
| Other solid tumors under investigation | e.g., melanoma, head‑and‑neck cancer | 10 mg/kg IV q2 wk (study) |
*(Dosing regimens are based on pivotal trials: PACIFIC for NSCLC, KEYNOTE‑045 for urothelial carcinoma, and RECIST‑based phase III data.)*
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Contraindications
- Contraindications:
- Known hypersensitivity to durvalumab or any of its excipients.
- Warnings:
- Immune‑related adverse events (irAEs): colitis, hepatitis, endocrinopathies, nephritis, pneumonitis, and others. Treat promptly with corticosteroids or immunosuppressants.
- Active autoimmune disease: Use with caution; consider risk–benefit.
- Pregnancy & lactation: Animal studies show potential fetal harm; not recommended.
- Immunosuppression: Reduces efficacy; avoid concurrent cytotoxic immunosuppressives if possible.
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Dosing
| Population | Dose | Schedule | Administration Notes |
| Adults & pediatric patients ≥ 30 kg | 10 mg/kg IV (weight‑based) or 1500 mg fixed dose (NSCLC) | Every 2 weeks (fixed dose) or every 4 weeks (NSCLC) | Infuse over 30 min; pre‑medicate only if patient has history of infusion reactions. |
| Adults < 30 kg | 10 mg/kg IV | Every 2 weeks | Adjust dose based on weight. |
| Special populations (renal/hepatic impairment) | No major dose adjustment | Monitor closely | Renal: avoid if creatinine clearance < 30 mL/min for NSCLC; for other indications use caution. Hepatic: reduce dose if Child‑Pugh C. |
| Post‑infusion monitoring | Vital signs, immediate reaction screening | Observe for 60 min after infusion | Use of epinephrine for severe reactions. |
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Adverse Effects
| Class | Incidence | Examples |
| Infusion reactions | 2–5 % | Fever, chills, rash, bronchospasm |
| GI | 20–30 % | Nausea, vomiting, diarrhea, abdominal pain |
| Dermatologic | 15–20 % | Pruritus, rash, vitiligo |
| Hepatotoxicity | 5–10 % | Elevation of ALT/AST, jaundice |
| Endocrinopathies | 10–15 % | Hypophysitis, thyroiditis, adrenal insufficiency |
| Pulmonary | 8–12 % | Pneumonitis, cough |
| Renal | Key Take‑away: Monitor liver enzymes and thyroid function at baseline and every 6–8 weeks; adjust steroids based on severity.
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Monitoring
| Parameter | Frequency | Rationale |
| Baseline labs | Prior to first infusion | CBC, CMP, LDH, bilirubin, ALP, serum creatinine, thyroid panel |
| Lab monitoring | Every 6–8 weeks (or per protocol) | Detect subclinical irAEs early |
| Immunogenicity | During treatment | Anti‑drugg antibodies may reduce efficacy |
| Imaging | Every 8–12 weeks | Evaluate tumor response per RECIST v1.1 |
| Quality‑of‑life surveys | Every cycle | Assess fatigue, pruritus, anorexia |
| Serum creatinine & eGFR | Every cycle | Avoid accumulation in renal impairment |
| Thyroid‑stimulating hormone (TSH) | Every 6–12 weeks | Endocrine irAEs |
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Clinical Pearls
- PD‑L1 testing is optional for NSCLC – In the PACIFIC trial, 1500 mg was given regardless of PD‑L1 expression; still, molecular profiling helps select patients for first‑line monotherapy.
- Crossover dosing – If a patient switches from weight‑based to fixed dosing (e.g., from 1500 mg to 10 mg/kg), ensure a washout period of at least 2 weeks to avoid double exposure.
- Infusion reaction mitigation – Use pre‑medication (diphenhydramine, lorazepam) only for patients with prior mild reactions; most patients tolerate first‑time infusions uneventfully.
- Timing of irAE onset – 80 % of immune‑related toxicities begin within the first 6–12 weeks; maintain vigilance thereafter, especially in patients receiving combination therapy.
- Gut‑related toxicity – Early treatment with high‑dose steroids (prednisone 1 mg/kg) improves outcomes; avoid antibiotics unless absolutely necessary, as gut dysbiosis may synergize with irAEs.
- Endocrine management – Screen for cortisol, FT4, FT3, TSH before therapy. Newly diagnosed hypophysitis often needs lifelong hormone replacement; ongoing monitoring of pituitary function is essential.
- Pneumonitis first sign – Use low‑dose CT chest if cough or dyspnea develops; early immunosuppression (corticosteroids and/or infliximab) can reverse progression.
- Combination therapy – When used with platinum chemotherapy or radiotherapy, the safety profile remains manageable but requires concurrent monitoring for overlapping toxicities such as nephrotoxicity and pneumonitis.
- Export of data – Document any infusion time and reaction; this data aids pharmacovigilance and future dosing decisions.
- Regimen flexibility – The 1500 mg q4‑week dose simplifies clinic visits for NSCLC; however, for many solid tumors, bi‑weekly 10 mg/kg remains the standard, ensuring steady blockade of PD‑L1.
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• References (selected)
1. FDA label: Durvalumab (Imfinzi) 2024.
2. NCCN Guidelines: Non‑Small Cell Lung Cancer 2024.
3. KEYNOTE‑045: Pembrolizumab vs. chemotherapy in urothelial carcinoma (J Clin Oncol 2018).
4. PACIFIC Trial: Durvalumab after chemoradiation in Stage III NSCLC (NEJM 2018).
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