Durvalumab - Uses, Dosage, Drug Interactions, Side Effects, and Precautions

Overview:

Durvalumab, commercially available as IMFINZI, is immunotherapy approved for the treatment of extensive stage small cell lung cancer (ES-SCLC) and non-small cell lung (NSCLC) cancer in adults. Durvalumab is a monoclonal human immunoglobulin G1 kappa antibody that prevents the interaction between PD-1 and programmed cell death ligand 1. It is available as an injection (to be administered by a healthcare professional only). The U.S food and drugs administration approved this drug combination in May 2017 for the treatment of bladder cancer, and it received approval for the treatment of NSCLC in combination with Etoposide and Carboplatin or Cisplatin in March 2020.

How Does Durvalumab Work?

Durvalumab is a G1 kappa monoclonal antibody that acts by releasing the suppression of immune responses without causing antibody-dependent cell-mediated cytotoxicity by blocking the interaction of PD-L1 with PD-1 and CD80.

Uses:

• When the SCLC has progressed to the lungs or other parts of your body, Durvalumab is administered in combination with the chemotherapeutic drugs Etoposide and Carboplatin or Cisplatin as the initial treatment.

• Durvalumab may also be employed if the NSCLC has not migrated outside the chest, cannot be removed surgically, and has responded to or stabilized after receiving initial treatment with chemotherapy containing platinum, delivered with radiation therapy.

Dosage:

Durvalumab is available as an injection. The doctor or nurse will administer the drug on each cycle of chemotherapy as per dosing guidelines.

• A doctor or nurse will administer the liquid form of the Durvalumab injection for 60 minutes in a hospital or other healthcare setting.

• It is typically administered once every two or four weeks for the duration of your doctor's recommended course of treatment or up to one year for NSCLC.

• It is given once every three weeks for four cycles along with the other meds to treat ES-SCLC, and then once every four weeks on its own for however long your doctor advises you to continue treatment.

• The infusion may be delayed or discontinued if any side effects occur.

• The general dosing information of Durvalumab is as follows:

Warning:

1. Skin Infections: Symptoms may include itching, rash, skin blistering, or ulcers in the mouth.

2. Hypersensitivity Reactions: Symptoms include rash, itching, hives, and breathlessness.

3. Adrenal Insufficiency: Symptoms may include fast heart rate, hair loss, sudden alterations in weight, extreme tiredness, dizziness or fainting, feeling cold, persistent headaches, constipation, nausea, and vomiting;

4. Colitis: Symptoms may include diarrhea or increased bowel movements than usual, severe abdominal pain, tenderness, black stools or sticky with blood or mucus, and severe stomach pain or tenderness.

5. Lung Problems: Symptoms include cough, breathlessness, and chest pain.

6. Kidney Problems: Symptoms include decreased urine output.

7. Liver Problems: Symptoms include nausea, vomiting, yellowing of skin and eyes, and pale stools.

8. Infusion Reactions: Symptoms may include chills or shaking, flushing, wheezing, itching or rash, dizziness, or fever.

9. Diabetes: Symptoms include increased blood sugar, confusion, deep breathing, and metallic taste.

10. Low Platelet Count: Decreased platelet in blood, which may increase the chances of bleeding and bruising.

For Patients:

What Do You Need to Know About Lung Cancer?

Lung cancers are identified as the most common types of cancers affecting people worldwide. It is further classified into the following types:

• Lung Nodules: Formation of small tissue masses in the lungs. Often the larger nodules become cancerous.

• Small Cell Lung Cancer: This type of lung cancer occurs in cigarette smokers. The cancer growth and spread are rapid in this type.

• Non-Small Cell Lung Cancer: The spread is comparatively slower than small cell lung cancer. But spread to other parts of the body will require surgery.

• Mesothelioma: Cancer that occurs in the chest lining.

Of the above-mentioned types of cancers, Durvalumab is used to treat small cell and non-small cell cancers.

What Are the Causes of Lung Cancer?

The common causes of lung cancer include

• Cigarette Smoking: The number of cigarettes you smoke each day and the length of time you smoked both raise your risk of developing lung cancer.

• Secondhand Smoking: Even if you do not smoke, being around secondhand smoke raises your risk of developing lung cancer.

• Exposure to Pollutants Like Asbestos: The chance of developing lung cancer can increase if the work environment contains substances like asbestos and carcinogens like nickel, chromium, and arsenic especially if you smoke.

• Family History: Lung cancer risk is higher in people with a parent, sibling, or child with the disease.

Symptoms of Lung Cancer:

The symptoms include

• Unresolved cough.

• Shortness of breath.

• Headache.

• Hoarseness.

• Bone pain.

• Unexplained weight loss.

Bladder Cancer:

Durvalumab was initially approved for the treatment of bladder cancer. It is the type of cancer that starts in the cells of the urinary bladder. The highest risk factor for bladder cancer is smoking. This is due to the compounds in tobacco, which are known as carcinogens. If you smoke for a long time, your kidneys filter these toxins into urine before they enter your bloodstream. Symptoms include blood in urine, dark urine, and increased urination.

Learn More About Durvalumab:

Before Starting Durvalumab:

When and Why to Take Durvalumab?

Durvalumab is a drug that requires medical supervision for its administration. It is generally prescribed for NSCLC and ES SCLC and has also been approved for the treatment of bladder cancer. It is immunotherapy and acts by inhibiting the immune responses without causing cell toxicity.

How Effective Is Durvalumab?

Twenty-four months of treatment with Durvalumab showed a 66.3 % survival rate compared to the control group in stage III non-small cell lung cancer. It showed overall survival and longer-progression-free survival as compared with the placebo group.

Things to Inform Your Doctor Before They Prescribe You Durvalumab:

Inform your doctor if you have any of the below-mentioned conditions:

• Previous history of allergy or hypersensitivity reactions to drugs.

• Have immune system conditions such as Crohn's disease, lupus, or ulcerative colitis.

• Have undergone or scheduled for a stem cell transplant using donor stem cells.

• Have you undergone radiation therapy for your chest area.

• Have a neurological disorder, such as myasthenia gravis or Guillain-Barré syndrome

• If expecting or intends to get pregnant, Durvalumab may harm the unborn child.

• Either currently breastfeeds or want to do so. Whether Durvalumab enters breast milk is unknown. Avoid breastfeeding while receiving Durvalumab therapy and for at least three months following the final dosage.

• All medications you use, including prescription and over-the-counter medications, vitamins, and herbal supplements, should be mentioned to your healthcare professional.

Starting Durvalumab:

How Is Durvalumab Given?

Durvalumab will be given in a hospital or clinic under the supervision of an experienced doctor.

• The recommended dose of Durvalumab is 10 mg per kg of the body weight every two weeks or 1500 mg every three or four weeks.

• Your doctor will give the medication through an infusion or drip into your vein for about one hour.

• Your doctor will decide on the number of cycles needed for the treatment.

Things to Do After You Start Taking Durvalumab:

• Once the therapy begins, watch for any changes in symptoms.

• Inform your doctor if unwanted symptoms arise or if you experience any adverse side effects so they can advise you on what to do.

• The doctor will not be able to assess how well the medication functions unless the effects of the medication are monitored and communicated clearly.

Look Out for Side Effects:

Negative side effects or adverse effects are common with chemotherapy treatment. Immediately report to the doctor if any of these side effects appear. The list of side effects is as follows:

Very Common Symptoms:

• Cough.

• Diarrhea.

• Fever.

• Upper respiratory tract infections.

• An underactive thyroid gland can result in fatigue or weight gain.

• Abdominal pain.

• Itching or a skin rash.

• Joint aches (arthralgia).

Common Symptoms:

• Severe respiratory infections (pneumonia), oral fungus, and soft tissue infections of the teeth and mouth.

• Muscle aches (myalgia).

• Flu-like conditions.

• An overactive thyroid gland can lead to weight loss or a rapid heartbeat.

• Lung inflammatory disease (pneumonitis).

• A raspy voice (dysphonia).

• Sweaty nights.

• Increased liver tests (aspartate aminotransferase increased; alanine aminotransferase increased).

• Alterations in kidney function testing (blood creatinine increased).

• Painful urination.

• Swelling in the leg.

• A response to a medication infusion that may result in fever or flushing.

Uncommon and Rare Symptoms:

• Inflammation of thyroid gland, kidneys, gut, and muscle.

• Scarring of lung tissue.

• Decrease in the amount of urine.

• Loss of appetite.

• Increased blood sugar levels.

• Myasthenia gravis (a condition where muscles become weak accompanied by extreme fatigue).

• Bladder inflammation.

• Meningitis.

When used in combination with other chemotherapeutic agents, the following side effects have also been observed:

• Hair loss.

• Cough.

• Decrease in blood counts.

• Diarrhea.

• Skin rashes.

• Muscle ache.

• Joint pain.

• Abdominal pain.

Dietary Alterations:

Alcohol should be strictly avoided while taking this drug as it may worsen the side effects.No other special nutritional changes are necessary when using Durvalumab. If your doctor does not ask you to make any dietary modifications, keep taking your regular diet. Be sure to eat a balanced diet full of the vitamins and minerals your body needs to function correctly.

What Should Be Done When You Miss a Dose?

Reschedule your appointment immediately by calling your doctor, as the drug must be administered at the scheduled time. Ask your doctor if you have any more queries concerning the care.

What Should Be Done to Treat Durvalumab Overdose?

Chances of overdosing are minimal since Durvalumab is administered in a clinical setting. However, contact your doctor or seek immediate medical attention if you experience side effects like hives, itching of the lip, tongue, or facial swelling during or after receiving a Durvalumab infusion.

How to Store Durvalumab?

Durvalumab is administered in a hospital or clinic, and a medical specialist is in charge of keeping it stored. These are the storage specifics:

• Keep the medication vial out of reach of children.

• After medication use after its expiration date, which will be noted on the carton and vial labels.

• Keep in a cold place (two to eight degrees Celsius).

• Avoid freezing.

• To protect against light, keep it in the original container.

• Do not use it if the medication is foggy, discolored, or visible particles.

• The infusion solution should not be kept in storage for future use. any trash or leftover medication

For Doctors:

Indication:

• Non-Small Cell Lung Cancer: Adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose illness has not advanced after concurrent platinum-based chemotherapy and radiation therapy.

• Small Cell Lung Cancer: First-line therapy in adult patients with extensive-stage small cell lung cancer (ES-SCLC), used in combination with Etoposide and Cisplatin/Carboplatin.

Pharmacology:

Mechanism of Action:

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that binds to the programmed cell death ligand-1 (PD-L1) and allows an immune response without inducing antibody-dependent cell-mediated cytotoxicity by blocking the interaction of PD-L1 with PD-1 and CD80 (B7.1).

In the tumor microenvironment, the expression of programmed cell death ligand-1(PD-L1) can be triggered by inflammatory signals (such as IFN-gamma). PD-L1 is present on both tumor cells and tumor-associated immune cells. PD-L1 interacts with PD-1 and CD80 to inhibit T-cell function and activation. (B7.1). PD-L1 decreases cytotoxic T-cell activity, proliferation, and cytokine production via attaching to its receptors.

Pharmacodynamics:

When patients receive 1500 mg every four weeks, their steady-state AUC, Ctrough, and Cmax are, respectively, 6 %, 19 %, and 55 % greater than when patients receive 10 mg/kg every two weeks.

No significant exposure associations for safety based on modeling of pharmacokinetic data predicted clinically significant variations in safety and effectiveness for the 1500 mg every four as compared to 10 mg/kg every two weeks in patients with NSCLC who weigh more than 30 kg.

Active Ingredients:

The active ingredient present in the medication is Durvalumab.

Inactive Ingredients:

The inactive ingredients present in Durvalumab are:

• Histidine.

• Trehalose Dihydrate.

• Histidine Hydrochloride Monohydrate.

• Polysorbate 80.

• Water for injections.

Pharmacokinetics:

Patients who received doses ranging from 0.1 mg/kg (0.01 times the approved or recommended dose) to 20 mg/kg (2 times the approved or recommended dose) were provided once every two, three, or four weeks to study the pharmacokinetics of durvalumab as a single agent. At doses 3 mg/kg (0.3 times the authorized therapeutic dosage) and doses 3 mg/kg every two weeks, PK exposure increased more than dose-proportionally. A steady condition was attained after around 16 weeks. Durvalumab's pharmacokinetics are comparable when it is evaluated as a single agent and used in conjunction with chemotherapy.

Distribution:

The geometric mean steady-state volume of distribution (Vss) was 5.6 (18 %) L.

Elimination:

Based on the baseline clearance, Durvalumab had a total body clearance of 8.2 mL/hr. The elimination half-life of Durvalumab is 18 days.

Toxicity:

Inhibition of PD-L1/PD-1 signaling exacerbated some infections' severity and inflammatory responses in animal models. Compared to wild-type controls, the survival of PD-1 knockout mice infected with M. tuberculosis is significantly reduced, which is correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 mutant mice likewise displayed lower survival after infection with the lymphocytic choriomeningitis virus.

In Humans:

• Toxicity:

A toxic dose for Durvalumab has not been established.

• Therapeutic Dose:

Adult: Dose varies with indication and patient's body weight.

Children: The safety and effectiveness of Durvalumab have not been established in pediatric patients. The toxicity is anticipated to have adverse effects on the drug, which include,

15 % Or Greater in Patients With Urothelial Carcinoma: Fatigue, musculoskeletal pain, constipation, decreased appetite, peripheral edema, nausea, and urinary tract infections.

20 % Or Greater of Patients With Unresectable Stage III NSLC: Cough, pneumonitis or radiation pneumonitis, fatigue, upper respiratory tract infections, rash, and dyspnea.

Common Laboratory Abnormalities:

• Effects: Hypocalcemia, elevated liver enzymes, hyponatremia, hyperkalemia, lymphopenia, hypothyroidism, and hyperthyroidism.

• Rare: In clinical trials, immune-related adverse reactions, including aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, nephritis, and ocular inflammatory toxicity (uveitis, keratitis) developed in less than one percent of patients receiving Durvalumab.

Warning and Precaution:

• Endocrine: Immune-mediated adrenal insufficiency (primary or secondary) may have been reported; monitoring is recommended, and treatment, interruption of therapy, or permanent discontinuation may be necessary.

• Dermatologic: Immune-mediated rash and dermatitis have been reported. Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported with programmed death-receptor 1 (PD-1)/PD-ligand 1 blocking antibodies. Monitoring is recommended; treatment, therapy interruption, or permanent discontinuation may be necessary.

• Metabolic: Immune-mediated thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis, have been reported; monitoring is recommended, and treatment, interruption of therapy, or permanent discontinuation may be necessary.

• Hepatic: Immune-mediated hepatitis, including fatalities, has been reported; monitoring is recommended, and treatment, interruption of therapy, or permanent discontinuation may be necessary.

• Renal: Immune-mediated nephritis with renal dysfunction has been reported; monitoring is recommended, and treatment, interruption of therapy, or permanent discontinuation may be necessary.

• Reproductive: May cause fetal harm; advice using effective contraception in women of reproductive potential during therapy and for at least three months after discontinuation.

• Respiratory: Immune-mediated pneumonitis, including fatalities, has been reported; increased risk in patients who have received prior thoracic radiation. Monitoring is recommended; treatment, therapy interruption, or permanent discontinuation may be necessary.

Dosage and Forms:

Durvalumab is administered as an injection. 50 mg of Durvalumab are present in each mL of concentrate for solution for infusion.

Administration of the Drug:

• Withdraw the desired volume from the vial and dilute in either NS of D5W to a final concentration of one to 15 mg/mL.

• Gently invert to mix; do not shake.

• Discard unused portions of the vial.

• Do not freeze.

• If the infusion solution is stored at room temperature (up to 25 degrees C or 77 degrees F), administer within 8 hours, including preparation and infusion time; if stored under refrigeration (2 to 8 degrees C or 36 to 46 degrees F), administer within 24 hours.

• Infuse solution over one hour via a sterile, low protein-binding 0.2 or 0.22 in-line filter.

• Do not infuse other drugs via the same IV line.

Considerations for Administration:

Monitoring is required for the following parameters:

• Immune-Mediated Adverse Reactions: Like pneumonitis, colitis, endocrinopathies, exfoliative dermatologic conditions, myocarditis, and neurological toxicities may occur. Monitoring is required.

• Liver Enzymes: At baseline and periodically during treatment.

• Creatinine: At baseline and periodically during treatment.

• Thyroid Function: Check at baseline and periodically during therapy.

• Hyperglycemia: Or any other signs and symptoms of diabetes.

• Transplant-Related Complications: In patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with Durvalumab.

• Signs and symptoms of infusion-related reactions.

Contraindications:

Durvalumab has not been reported with any specific contraindications.

Clinical Studies for Durvalumab:

1. Non-Small Cell Lung Cancer (NSCLC):

The PACIFIC study, a randomized, multicenter, double-blinded, placebo-controlled trial, assessed the effectiveness of Durvalumab in patients with unresectable Stage III NSCLC who had finished at least two cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days before the study drug was started and had a WHO performance status of zero or one. Patients who had advanced after concomitant chemoradiation, those with active or previously documented autoimmune disease within two years of the research's start date, and those with illnesses requiring systemic immunosuppression were not included in the study.

Results From Clinical Trials:

• In comparison to the placebo group, the Durvalumab-treated group showed a statistically significant improvement in progression-free survival (PFS).

• In comparison to the placebo group, the Durvalumab-treated group showed a statistically significant improvement in overall survival (OS).

• With a median follow-up of 34.2 months throughout the five-year analysis, Durvalumab showed improved OS and PFS compared to placebo. The primary study and the follow-up analysis's OS and PFS findings.

• All predefined subgroups studied, including ethnicity, age, gender, smoking history, EGFR mutation status, and histology, consistently showed increases in PFS and OS in favor of individuals receiving Durvalumab compared to those receiving placebo.

2. Small Cell Lung Cancer (SCLC):

In CASPIAN, a randomized, active-controlled, multicenter, open-label trial, the effectiveness of Durvalumab in combination with Etoposide and Carboplatin or Cisplatin in previously untreated ES-SCLC was studied. Patients qualified for receiving a platinum-based chemotherapy regimen as the first line of treatment for SCLC if they had a WHO Performance Status of zero or one. Eligible patients had either undiagnosed or treated brain metastases.

Results From Clinical Trials:

• The trial showed a statistically significant increase in OS with Durvalumab + Etoposide + Platinum vs. Etoposide + Platinum alone at a scheduled interim (primary) analysis. Durvalumab plus Etoposide plus Platinum showed an improvement in PFS compared to Etoposide plus Platinum alone, while not having been formally tested for significance.

• Durvalumab + Etoposide + Platinum vs. Etoposide + Platinum continued to show improved OS in the anticipated follow-up analysis (median: 25.1 months).

Drug Interactions:

Drug interactions refer to the interaction of drugs with other drugs, food, supplements, or beverages. These can result in unwanted side effects.

The drug interactions of Durvalumab are as follows:

With Other Drugs:

• Adalimumab.

• Betamethasone.

• Budesonide.

• Cortisone.

• Dexamethasone.

• Deflazacort.

• Etanercept.

• Prednisone.

With Alcohol: Taking alcohol can worsen the side effects of the medication and can result in liver damage. Hence, not preferred during therapy.

With Diseases:

• Diabetes.

• Colitis.

• Thyroid disorders.

• Renal disease.

• Liver disease.

• Infections.

• Adrenal insufficiency.

• Pneumonitis.

Other Specifications:

• Durvalumab in Pregnant and Lactating Women:

Although the effects of this medication on pregnant women have not yet been thoroughly investigated, there is a chance that the medication could harm the unborn child. Nursing moms are not advised to feed while taking the drug.

• Durvalumab in Pediatric Patients:

The use, safety, and efficacy of Durvalumab are not yet established in children below 18 years of age. Therefore, it is not indicated in pediatrics.

• Durvalumab in Geriatric Patients:

No specific recommendations are suggested for use in geriatrics. No clinically important effect on the clearance of Durvalumab has been observed.

• Durvalumab in Renal Impairment Patients:

No specific dose adjustment is indicated in patients with renal impairment.