Durvalumab

Introduction Overview

Generic Name

durvalumab

Brand Name

Imfinzi

Dosage Form

injection (500 mg/10 mL, 120 mg/2.4 mL)

Drug Class

Anti-PD-1 and PD-L1 monoclonal antibodies (immune checkpoint inhibitors)

Pharmacokinetics

Absorption:
Durvalumab is administered intravenously, thus bypassing gastrointestinal absorption, which ensures complete bioavailability. Following administration, durvalumab is distributed rapidly and directly into systemic circulation without first-pass metabolism. The intravenous route enables precise control of plasma concentration, which is critical for monoclonal antibodies whose therapeutic activity depends on maintaining adequate systemic levels for immune modulation.

Distribution:
Durvalumab exhibits a volume of distribution that approximates serum volume, reflecting its confinement largely to the vascular and interstitial spaces. As an IgG1 monoclonal antibody, it binds with high specificity to the PD-L1 protein expressed on tumor cells and immune cells within the tumor microenvironment. Protein binding is selective to PD-L1, limiting nonspecific interactions. Distribution is influenced by factors such as tumor burden and PD-L1 expression, which can act as a sink. Limited tissue penetration is typical of monoclonal antibodies due to their size and hydrophilic nature, but durvalumab has shown adequate tumor tissue penetration sufficient for therapeutic effect.

Metabolism:
Durvalumab, like other monoclonal antibodies, is catabolized through proteolytic degradation into small peptides and amino acids by ubiquitous proteases in the reticuloendothelial system and endothelial cells. This degradation is non-specific and does not involve hepatic cytochrome P450 enzymes, thus minimizing drug-drug interactions related to metabolism. The Fc region of durvalumab may engage with the neonatal Fc receptor (FcRn), which protects it from lysosomal degradation, extending its half-life. The metabolic pathway and rate may vary with changes in immune status and presence of anti-drug antibodies.

Elimination:
Elimination of durvalumab occurs predominantly via proteolytic catabolism rather than renal or hepatic excretion. Clearance is mediated by cellular uptake and degradation primarily in the reticuloendothelial system. The half-life of durvalumab ranges approximately between 14 to 31 days, which supports dosing intervals every 2 to 4 weeks depending on clinical indication. Clearance can be influenced by factors such as body weight, immunogenicity, and tumor burden. No dose adjustments have been firmly established based on renal or hepatic impairment due to its catabolic elimination pathway. Clinical studies confirm predictable elimination consistent with other immune checkpoint inhibitor monoclonal antibodies.

Dosage Forms

Available Dosage Forms:
- Solution for intravenous injection provided as single-dose vials:
- 500 mg/10 mL (50 mg/mL)
- 120 mg/2.4 mL (50 mg/mL)

Dosages for Adults and Adolescents:
- Dosing varies by indication and body weight; commonly administered intravenously every 2, 3, or 4 weeks.
- For extensive-stage small cell lung cancer (ES-SCLC):
- Patients >30 kg: 1500 mg IV every 3 weeks for 4 cycles with chemotherapy, followed by 1500 mg IV every 4 weeks as single agent until progression or toxicity.
- Patients ≤30 kg: 20 mg/kg every 3 weeks for 4 cycles, followed by 10 mg/kg every 4 weeks as single agent.
- For biliary tract cancer (BTC):
- Patients >30 kg: 1500 mg IV every 3 weeks for up to 8 cycles with chemotherapy, then 1500 mg IV every 4 weeks as single agent.
- Patients ≤30 kg: 20 mg/kg every 3 weeks for up to 8 cycles, then 20 mg/kg every 4 weeks.
- For unresectable hepatocellular carcinoma:
- Patients ≥30 kg: 1500 mg IV in combination with tremelimumab, then 1500 mg every 4 weeks as single agent.
- Patients <30 kg: 20 mg/kg in combination with tremelimumab, followed by 20 mg/kg every 4 weeks.
- For dMMR endometrial cancer:
- Patients >30 kg: 1120 mg IV in combination with carboplatin and paclitaxel every 3 weeks for 6 cycles, followed by 1500 mg IV every 4 weeks.
- Patients ≤30 kg: 15 mg/kg in combination for 6 cycles, then 20 mg/kg every 4 weeks.

Specific Patient Populations:
- Pediatric dosing has not been established; current approvals are for adult patients.
- Dose adjustments for renal or hepatic impairment are not clearly defined due to elimination by proteolytic catabolism.
- Patients with body weight ≤30 kg receive weight-based dosing; those above receive fixed dosing.
- Dosing regimens are also tailored depending on whether durvalumab is used as monotherapy or in combination with chemotherapy or other immunotherapies.
- Treatment duration continues until disease progression, unacceptable toxicity, or clinical decision.

Clinical Guidelines:
- Imfinzi must be administered intravenously over approximately 1 hour.
- When used in combination regimens, Imfinzi is typically administered prior to chemotherapy on the same day.
- Treatment monitoring includes immune-mediated adverse effect surveillance and laboratory assessments.
- Dosing requires careful adherence to approved regimens per indication to maximize efficacy and minimize toxicity.

Mechanism Of Action

Durvalumab, marketed as Imfinzi, is a fully human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that specifically targets programmed death-ligand 1 (PD-L1), a transmembrane protein expressed on tumor cells and tumor-infiltrating immune cells. The primary molecular mechanism by which durvalumab exerts its therapeutic effect is by binding to PD-L1, thereby blocking its interaction with the programmed cell death protein-1 (PD-1) receptor and CD80 on T cells. Under physiological conditions, the interaction of PD-L1 with PD-1 acts as an immune checkpoint pathway that downregulates T-cell activation, promoting immune tolerance and preventing autoimmune responses. Tumors exploit this pathway by overexpressing PD-L1, which allows them to evade immune surveillance.

By interrupting PD-L1 binding to PD-1 and CD80, durvalumab removes the inhibitory signaling that restrains cytotoxic T-cell responses, effectively reactivating exhausted T cells and restoring their ability to recognize and kill tumor cells. This reactivation enhances anti-tumor immune responses within the tumor microenvironment, facilitating tumor regression and preventing further tumor spread. This immune checkpoint inhibition is a hallmark of current immunotherapy strategies targeting cancer.

Durvalumab’s IgG1 backbone lacks antibody-dependent cellular cytotoxicity (ADCC) activity, designed to minimize depletion of PD-L1-expressing immune cells, thus preserving immune competence. This pharmacologic specificity differentiates it from other monoclonal antibodies that may have differing effector functions. Clinical studies have shown the blockade of PD-L1 by durvalumab results in increased infiltration of activated CD8+ T cells into tumors and improved survival outcomes across several cancer types.

Comparatively, durvalumab differs from PD-1 inhibitors such as nivolumab or pembrolizumab that bind PD-1 itself; by targeting PD-L1, durvalumab selectively inhibits interaction with PD-1 and CD80, offering a distinct immunologic modulation. Additionally, combined regimens with other agents like tremelimumab, a CTLA-4 inhibitor, exploit complementary pathways to achieve synergistic activation of anti-cancer immunity. Emerging research highlights the importance of tumor PD-L1 expression levels and biomarkers in predicting responsiveness to durvalumab therapy, underscoring the drug’s role in personalized oncology treatments.

Pharmacological Actions

Selective blockade of PD-L1, preventing its interaction with PD-1 and CD80, thereby relieving T-cell inhibition.
Activation and proliferation of tumor-infiltrating cytotoxic T lymphocytes (CTLs) enhancing anti-tumor immunity.
Modulation of the tumor microenvironment to promote immune recognition and destruction of cancer cells.
Reduction of tumor immune evasion mechanisms characteristic of PD-L1-expressing malignancies.
Synergistic enhancement of anti-tumor immune responses when combined with chemotherapy or other immunotherapies.
Lack of Fc-mediated cytotoxicity, thereby preserving PD-L1-expressing immune cells and reducing off-target immune depletion.
Inhibition of cancer progression by promoting immune-mediated tumor cell apoptosis.
Potential restoration of immune function in exhausted T-cell populations within solid tumors.
Improvement in overall survival and progression-free survival in various cancer indications.
Facilitation of neoadjuvant and adjuvant treatment strategies by enhancing immune surveillance post-surgery.

Therapeutic Or Clinical Uses

Treatment of unresectable Stage III non-small cell lung cancer (NSCLC) in patients with no disease progression after chemoradiotherapy.
First-line treatment of extensive-stage small cell lung cancer (ES-SCLC) in combination with etoposide and carboplatin or cisplatin.
Combination therapy with platinum-based chemotherapy for metastatic NSCLC lacking sensitizing EGFR or ALK mutations/rearrangements.
Treatment of locally advanced or metastatic biliary tract cancers including bile duct and gallbladder cancer, in combination with gemcitabine and cisplatin.
Management of unresectable hepatocellular carcinoma in combination with tremelimumab.
Treatment of mismatch repair deficient (dMMR) advanced or recurrent endometrial cancer in combination with carboplatin and paclitaxel, followed by monotherapy.
Neoadjuvant and adjuvant treatment in muscle invasive bladder cancer (MIBC) combined with gemcitabine and cisplatin chemotherapy.
Use as an immune checkpoint inhibitor to enhance anti-tumor immunity in PD-L1 expressing tumors.
Potential to increase overall survival, reduce tumor progression, and shrink tumor size across approved indications.
Adjuvant therapy to maintain remission following initial treatment in select cancer types.
Treatment option for patients intolerant or refractory to other standard chemotherapeutic regimens.
Component of combination regimens exploiting synergistic anti-cancer effects with chemotherapy and CTLA-4 inhibitors.

Side Or Adverse Effects

Common: Fatigue and tiredness affecting quality of life and functional status.
Respiratory: Dyspnea (shortness of breath), cough, and pneumonitis occurring especially in monotherapy for Stage III NSCLC.
Infections: Upper respiratory tract infections resembling common cold symptoms.
Gastrointestinal: Nausea, constipation, abdominal pain, vomiting, diarrhea, and potential colitis in severe cases.
Dermatologic: Rash, itching, and other skin reactions including severe skin blistering or rash in rare cases.
Musculoskeletal: Bone and muscle pain contributing to discomfort.
Neurologic: Peripheral neuropathy characterized by numbness, tingling, burning, or weakness.
Laboratory abnormalities: Elevated liver transaminases (ALT, AST), decreased magnesium levels indicating hepatic or metabolic effects.
Immune-mediated hypothyroidism occurring in up to 14% of patients, requiring endocrine therapy.
Serious allergic or infusion-related reactions including hives, swelling, difficulty breathing, and flushing.
Potential immune-related adverse events affecting lungs, liver, pancreas, kidneys, intestines, thyroid, pituitary, or adrenal glands.
Symptoms suggestive of organ inflammation including chest pain, severe abdominal pain, diarrhea with blood, skin blistering, fever, vision problems, or neurologic changes.
Risk of transplant rejection in patients with allogeneic hematopoietic stem cell transplantation.
Hair loss, fever, painful urination, and constitutional symptoms occurring with combination therapies.
Delayed or permanent discontinuation of therapy may be required if toxicities become life-threatening.

Precautions

Screen and monitor patients for pre-existing autoimmune diseases as exacerbations can occur.
Caution in patients with history of organ or stem cell transplantation due to risk of immune rejection.
Evaluate for active infections prior to initiating therapy as immune modulation may worsen infections.
Close hepatic and renal monitoring given potential immune-mediated organ inflammation.
Pregnancy Category: contraindicated or advised with caution due to embryo-fetal toxicity risks.
Use contraception during treatment and for at least 3 months following last dose to prevent fetal harm.
Avoid breastfeeding during treatment and for at least 3 months post-therapy due to unknown risks to infant.
Careful assessment of respiratory status is advised due to risk of pneumonitis and pulmonary toxicity.
Monitor for infusion-related reactions; readiness to intervene with supportive measures is necessary.
Surveillance for thyroid function and endocrinopathies; initiate hormone replacement as indicated.
Use cautiously in patients receiving radiation therapy to chest given potential additive toxicities.
Patient education on recognizing signs of immune-related adverse events for prompt reporting.
Dose modifications or discontinuations may be necessary based on severity of adverse reactions.
Immunosuppressive treatment may be required to manage severe immune-mediated toxicities.
Avoid concomitant immunosuppressants unless necessary; balance immunotherapy efficacy and safety.

Warnings

Risk of immune-mediated inflammation affecting lungs (pneumonitis), liver (hepatitis), pancreas (pancreatitis), kidneys (nephritis), intestines (colitis), thyroid, pituitary, and adrenal glands.
Potential for severe or life-threatening infusion-related allergic reactions requiring immediate medical intervention.
Monitor for signs of new or worsening symptoms such as fatigue, mood changes, headaches, vision changes, skin rash, or respiratory difficulties.
Immune system activation may cause transplant rejection in patients who have undergone allogeneic hematopoietic stem cell transplantation.
Embryo-fetal toxicity: can cause fetal harm; ensure effective contraception during and after treatment.
Infusion should be administered slowly over approximately 1 hour to reduce incidence of infusion reactions.
Treatment may need to be delayed or permanently discontinued in case of severe immune-related adverse effects.
Patients should be warned about symptoms indicative of endocrinopathies, including unusual headaches, fatigue, weight changes, or temperature sensitivity.
Close monitoring is mandatory for patients with pre-existing respiratory or autoimmune conditions.
Risk of severe skin reactions including rash with blistering and peeling requires prompt evaluation and treatment.
Patients should be monitored for gastrointestinal toxicities, particularly severe diarrhea or bloody stools.
Be vigilant for potential mood or cognitive changes that could indicate neurologic involvement.
Concurrent use with other immunomodulatory agents requires careful consideration due to additive risks.
Report all adverse events promptly to healthcare providers and regulatory authorities as appropriate.
Emergency medical help is required if symptoms of severe allergic reaction or organ toxicity occur.

Contraindication

Known hypersensitivity to durvalumab or any of the inactive ingredients in the formulation.
Use in patients with active, severe autoimmune diseases where immunotherapy may exacerbate disease.
Patients who have experienced severe infusion-related reactions to prior anti-PD-L1 therapies.
Pregnancy, due to demonstrated embryo-fetal toxicity risks; unless benefits outweigh risks and no alternatives.
Patients undergoing recent or planned allogeneic hematopoietic stem cell transplantation due to high risk of fatal complications.
Use with caution or avoid in individuals with uncontrolled infections requiring systemic antimicrobial therapy.
Concurrent use with immunosuppressive drugs that may negate therapeutic immune activation of durvalumab.
Severe hepatic impairment due to potential exacerbation of immune-mediated hepatic toxicity.
Severe pulmonary or respiratory diseases where risk of pneumonitis may be elevated.
Patients with known hypersensitivity to any monoclonal antibodies if cross-reactivity is suspected.
Avoid use in combination with agents contraindicated with immune checkpoint inhibitors unless under clinical supervision.
Infants and pediatric patients as safety and efficacy have not been established.
Patients with conditions that could be significantly worsened by immune activation, e.g., myasthenia gravis.
Individuals with active graft-versus-host disease post-transplant.
Patients with uncontrolled or unstable cardiovascular conditions due to potential exacerbations with immune therapy.

Drug Interactions

Concurrent administration with chemotherapy agents such as etoposide, carboplatin, cisplatin, gemcitabine, paclitaxel as part of combination regimens; dosing and timing require careful scheduling.
Potential alteration of immune response when used with other immunomodulatory agents or checkpoint inhibitors (e.g., tremelimumab).
No known cytochrome P450 enzyme interactions owing to non-metabolic clearance but monitor for additive toxicities with other drugs.
Possible increased risk of immune-related adverse events when combined with other immune checkpoint inhibitors or immunotherapies.
Use with systemic corticosteroids or immunosuppressants may attenuate therapeutic efficacy by suppressing immune activation.
Concomitant use with live vaccines is not recommended due to potential impaired vaccine response or increased risk of infection.
No established interactions with common over-the-counter vitamins or herbal supplements, but patients should inform their physician of all agents used.
Monitoring advised when used with drugs affecting the immune system or bone marrow function to assess combined toxicity.
Drug interactions may affect the pharmacodynamics of durvalumab by either increasing toxicity or reducing efficacy.
Combination with radiation therapy may enhance immunotherapeutic effects but increases risk of tissue inflammation.
Potential interaction with agents causing hepatotoxicity that may exacerbate immune-mediated liver injury.
Therapeutic antibodies may interfere with laboratory measurements or imaging studies, necessitating awareness of clinical context.
No significant known impact on renal or hepatic clearance mechanisms that typically mediate drug interactions.
Interaction risks increase with polypharmacy common in oncology patients, requiring multidisciplinary management.
Careful documentation and communication among healthcare providers to avoid adverse interaction consequences.

Preparations Of The Drug

Durvalumab (Imfinzi) is supplied as a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution for intravenous infusion.
Available in single-dose vials at concentrations of 120 mg/2.4 mL (50 mg/mL) and 500 mg/10 mL (50 mg/mL).
Contains inactive ingredients including L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, polysorbate 80, and Water for Injection, USP.
Formulated to maintain stability and efficacy under recommended storage conditions (2°C to 8°C, protected from light).
Vial presentations facilitate flexibility for weight-based dosing and fixed dosing regimens depending on patient's body weight and treatment plan.
Prepared for intravenous infusion after dilution with appropriate infusion fluids per prescribing guidance.
Manufactured by AstraZeneca UK Limited and distributed through AstraZeneca Pharmaceuticals LP.
Supplied under NDC codes 0310-4611-50 for the 500 mg/10 mL vial and 0310-4500-12 for the 120 mg/2.4 mL vial.
Storage conditions require refrigeration and avoidance of freezing or agitation to maintain protein integrity.
Discard any unused portion due to single-use vial formulation to prevent contamination and infection risk.
Packaging includes detailed prescribing information and handling instructions for healthcare professionals.
Preparation for administration mandates aseptic technique and infusion over approximately one hour.
No preservative present; strict adherence to sterile handling is critical to patient safety.
Formulation maintained to minimize immunogenicity and infusion reaction predisposition.
Accompanied by J-code J9173 for accurate insurance billing in clinical settings.