Introduction:
Trastuzumab deruxtecan is an antibody-drug conjugate comprising the humanized monoclonal antibody Trastuzumab covalently linked to the topoisomerase 1 inhibitor deruxtecan. The drug has been indicated for treating breast cancer, gastric cancer, or gastroesophageal adenocarcinoma. Trastuzumab deruxtecan is a revolutionary drug in managing HER 2-positive breast cancer because removal of the ovaries and chemotherapy was the sole treatment options for breast cancer earlier. However, new clinical trials have opened doors for more effective metastatic breast cancer treatments. The main criteria for the development of Trastuzumab deruxtecan was the protein named HER2. It is a tyrosine kinase growth promoter protein expressed on the tumor surface, including breast, lung, gastric, and colorectal cancer. HER2 is one of the biomarkers of breast cancer because the presence or absence of HER2 determines whether the person is positive or negative for cancer. Trastuzumab deruxtecan binds and blocks the HER2 receptors as the cancer cells rely on them for their growth. As a result, the tumor cells fail to grow, and the person lives a long life.
Drug Developmental History and Approval Timeline:
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Trastuzumab deruxtecan was developed by AstraZeneca and Daiichi Sankyo for the treatment of metastatic or unresectable HER2-positive breast cancer in adult patients who received an anti-HER2-based regimen in the metastatic, adjuvant, or neoadjuvant settings.
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In December 2019, the US Food and Drug Administration (FDA) granted accelerated approval to the drug for patients with HER2-positive breast cancer after a trial was done to evaluate the efficacy of the drug.
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In January 2021, the US FDA granted accelerated approval to Trastuzumab deruxtecan for the management of locally advanced or metastatic HER2-positive or gastric esophageal adenocarcinoma.
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Finally, the drug was approved by the FDA on 4th May 2022 for adult patients suffering from HER2-positive breast cancer who have developed disease recurrence during or within six months of completing the HER2-based therapy.
General Information About Trastuzumab Deruxtecan:
How Does Trastuzumab Deruxtecan Work to Treat HER2-Positive Breast Cancer?
Breast cancer is the most prevalent cancer that affects women worldwide. Trastuzumab deruxtecan is a specifically engineered HER2-directed antibody-drug conjugate given by infusion into the veins. It consists of a monoclonal antibody and topoisomerase 1 that delivers payload directly to the tumor cells that produce HER2. When the drug is synthesized into the body in its active form, the membrane-permeable payload results in DNA (deoxyribonucleic acid) damage and cell death, causing the destruction of HER2+ tumor cells and the surrounding cells. This phenomenon is known as the bystander antitumor effect. In simple terms, the drug binds to the HER2 receptors on the tumor cells and cleaves or breaks them, resulting in cell death due to DNA damage.
What Information Is Available Related to the Safety and Efficacy of Trastuzumab Deruxtecan?
The safety and efficacy of Trastuzumab deruxtecan were evaluated in a multicenter, open-label, and randomized trial known as DESTINY-Breast03. This trial was done on 524 patients with HER2-positive unresectable or metastatic cancer. These patients received Trastuzumab and taxane therapy for metastatic disease or developed disease recurrence within six months of completing the neoadjuvant or adjuvant therapy. In the trial results, it was observed that people who received Trastuzumab deruxtecan lived twice longer than the ones who received the placebo. In addition, 4.3% of the women showed a complete response to the drug, whereas 56% of the females showed a partial response to the drug. These patients did not exhibit any further growth or progression in their breast cancer. Hence, the drug was declared safe, effective, and approved for market use. Furthermore, the incidence of adverse reactions was seen in less than 30% of patients.
How Is Trastuzumab Deruxtecan Different From Chemotherapy Drugs Used for Breast Cancer?
Trastuzumab deruxtecan is not a chemotherapeutic agent. However, it is a type of chemotherapy drug known as a topoisomerase 1 inhibitor. The other active content is Trastuzumab deruxtecan which is a HER2 antibody. Its structure is similar to HER2, which is overexpressed by breast cancer cells. In simple terms, the drug works as a combination to treat breast cancer, making it unique from other chemotherapy drugs. As the drug contains the HER2 antibody, it allows the drug to directly target the HER2 receptors. Once Trastuzumab deruxtecan reaches HER2 cancer cells, it damages the DNA of the cells resulting in cell death and tumor shrinkage.
What Are the Uses of Trastuzumab Deruxtecan?
FDA has approved Trastuzumab deruxtecan specifically to treat HER2-positive breast cancer. It may be used off-label to treat other medical conditions.
It is used to treat:
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HER2-positive breast cancer that has spread throughout the body and cannot be removed by surgery.
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The patient has already received anti-HER2 breast cancer treatment for metastatic disease, or the breast cancer has recurred during or within six months of completion of the treatment.
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Gastric cancer or gastroesophageal adenocarcinoma spreads to the nearby areas of the stomach or other parts of the body, and the patient has already received the Trastuzumab therapy.
Dosage and Administration:
Patient Selection for Locally Advanced or Metastatic Cancer:
Patients with locally advanced or metastatic cancer must be selected based on the HER2 protein overexpression of HER2 gene amplification. In addition, the patient’s HER2 protein status must be reassessed to obtain a new tumor specimen after prior Trastuzumab-based therapy and before administering Trastuzumab deruxtecan.
Recommended Dosage and Schedules:
Do not use Trastuzumab or Ado-Trastuzumab emtansine in place of Trastuzumab deruxtecan.
The drug infusion details are given below:
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First Infusion - The first infusion must be administered over 90 minutes.
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Subsequent Infusions - The subsequent infusions must be administered over 30 minutes if the patient could not tolerate the prior infusions. Interrupt the infusion of the drug if the patient develops severe infusion-related symptoms. Permanently discontinue the drug if the patient develops severe infusion-related reactions.
Recommended Dosage for Metastatic HER2-Positive Breast Cancer:
The recommended dosage of Trastuzumab deruxtecan is 5.4 mg per kg. The drug is given as an intravenous infusion once every three weeks until the disease progresses.
Recommended Dosage for Advanced or Metastatic Gastric Cancer:
The recommended dosage of Trastuzumab deruxtecan is 6.4 mg per kg. The drug is given as an intravenous infusion once every three weeks until the disease progresses.
Dosage Modifications:
The adverse reactions related to Trastuzumab deruxtecan might require temporary interruption, treatment discontinuation, and drug dose reduction. Do not re-escalate the drug if a dose reduction has been recommended. If the planned dose of the drug has been missed or delayed, the drug must be taken as soon as possible. The patient must not wait until the next planned cycle. The drug administration schedule must be adjusted so that a three-week interval exists between the doses. The doctor must administer the drug at an infusion rate well tolerated by the patient.
The dose reduction schedule is listed in the table below:
Dosage Modifications for Adverse Reactions:
Information About HER2-Positive Breast for Patients:
What Is HER2-Positive Breast Cancer?
HER2-positive breast cancer is a condition in which the patient tests positive for a protein named HER2. The main work of this protein is to promote the growth of tumor or cancer cells. Breast cancer cells with more than normal levels of HER2 are known as HER2-positive. The main problem with HER2-positive breast cancer is that these cells tend to grow faster than the cells that are HER2-negative. However, the drugs or other treatment measures targeting HER2 are very effective. Therefore, the prognosis of HER2-positive breast cancer is better than that of HER2-negative. Some chemotherapeutic agents can also be used to treat HER2-positive breast cancer, but they are ineffective.
What Are the Signs and Symptoms of HER2-Positive Breast Cancer?
The patient usually feels a lump in his breast that might feel different from the area surrounding it.
Some of the other symptoms of HER2-positive breast cancer are listed below:
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Swelling in the breasts.
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Change in the shape of the breasts.
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Skin irritation.
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Pain in the breast or nipple.
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Discharge from the nipple.
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Thickness or redness of the breast skin or the nipple.
For Patients
Trastuzumab deruxtecan is a prescription medication approved by the FDA to treat HER2-positive breast cancer in men and women. It can also be used for people who have undergone two previous treatments for metastatic breast cancer. The drug can specifically treat breast cancer that is metastatic or unresectable. Although Trastuzumab deruxtecan has been approved for use in males and females, the drug has still not been studied in males. The drug is used as a combination because it contains the active drug Trastuzumab deruxtecan, which is a HER2 antibody. The second drug is a topoisomerase 1 inhibitor. The HER2 antibody allows the chemotherapy drug to target the HER2 cells. These drugs damage the cancer cells resulting in their death. The drug comes as a powder mixed with a liquid to form a solution and is given as an intravenous infusion. Trastuzumab deruxtecan can also treat gastric cancer or gastroesophageal junction adenocarcinoma that has spread to other body areas.
What Should the Patient Inform the Doctor Before Taking Trastuzumab Deruxtecan?
Before taking Trastuzumab deruxtecan, the patient must inform the doctor if he or she is:
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Having pulmonary disorders or breathing difficulties.
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Having signs or symptoms of any infection.
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Has a previous history of cardiac diseases.
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Develops allergy to Trastuzumab deruxtecan and some of its other ingredients. The patient must be aware of the exact composition of the drug before taking it to prevent drug-induced allergic reactions.
How Should the Patient Take Trastuzumab Deruxtecan?
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The patient will receive Trastuzumab deruxtecan into his veins through an intravenous line. The drug is usually given once every three weeks (a 21-day treatment cycle).
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The doctor will decide the number of treatments required.
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The doctor might slow down or temporarily stop the treatment of the infusion of Trastuzumab deruxtecan if the patient depicts infusion-related reactions.
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The doctor might permanently discontinue the drug if he develops severe infusion reactions.
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If the patient misses a planned dose of Trastuzumab deruxtecan, he must consult his doctor immediately and must not wait until the next treatment cycle.
What Are the Possible Side Effects of Trastuzumab Deruxtecan?
Trastuzumab deruxtecan can cause serious side effects, including the following:
1. Lung Problems - The patient might develop severe and life-threatening lung problems leading to the death of a person. If the patient develops lung problems, the doctor might administer corticosteroids to treat the condition.
The following are the signs and symptoms of lung problems:
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Cough.
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Respiratory difficulties.
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Fever.
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Tightness of the chest.
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Wheezing.
2. Neutropenia - It is a condition in which the white blood cell count becomes low. It has been noted that low white blood cell count problems are common with Trastuzumab deruxtecan. The doctor will check the white blood cell count before administering the drug.
3. Heart Problems - Sometimes, the patient develops heart problems making it difficult for the heart to pump blood.
The patient must inform the doctor if he observes the following signs and symptoms:
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Worsening shortness of breath.
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Cough.
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Tiredness.
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Swelling of the legs and ankles.
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Irregular heartbeat.
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Weight gain.
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Dizziness.
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Lightheadedness.
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Loss of consciousness.
4. Harm to the Unborn Baby - The patient must inform the doctor if she is pregnant or planning to conceive.
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The doctor might do a pregnancy test before starting the treatment with Trastuzumab deruxtecan.
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Females planning to conceive must use effective barrier contraceptive methods during and seven months after the last dose of the drug.
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Males who have had female partners that are planning to conceive must use effective birth control measures during and four months after the last dose of the drug.
Some of the other common side effects that can occur due to Trastuzumab deruxtecan are listed below:
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Nausea.
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Low red blood cell count.
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Vomiting.
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Hair loss.
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Low platelets count.
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Increased liver function test.
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Low blood potassium levels.
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Loss of appetite.
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Diarrhea.
Some General Information About the Safety and Efficacy of Trastuzumab deruxtecan:
Sometimes, the doctor might recommend the drug for uses other than those listed in the patient information leaflet. However, the patient must avoid using Trastuzumab deruxtecan for the condition it was not prescribed. Avoid administering the drug to other people even if they have symptoms similar to the ones the patient is suffering from because the drug might be harmful to them.
For Doctors
Description:
Trastuzumab deruxtecan is a conjugate of HER2-directed antibody and topoisomerase 1. It is a combination drug that mainly comprises three main components:
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Humanized anti-HER2 immunoglobulin G1 monoclonal antibody.
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Topoisomerase inhibitor.
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Tetrapeptide-based cleavable linker.
Trastuzumab mainly comprises a protease-cleavable maleimide tetrapeptide linker and the topoisomerase inhibitor, DXd, which is an exatecan derivative. The antibody is usually produced in the Chinese hamster ovary cells by using recombinant DNA technology. The topoisomerase inhibitor and linker are usually produced by chemical synthesis. Trastuzumab deruxtecan is a sterile, white to yellowish white, and preservative-free lyophilized powder that comes in a single dose vial. Each vial delivers around 100 mg of Trastuzumab deruxtecan-nxki, L-histidine (4.45 mg), L-histidine hydrochloride monohydrate (20.2 mg), polysorbate 80 (1.5 mg), and sucrose (450 mg). After the drug is reconstituted with 5 mL of sterile water for injection, the resulting concentration of Trastuzumab deruxtecan-nxki is 20 mg/mL with a pH of 5.5.
Indications and Usage:
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Metastatic Breast Cancer:
Trastuzumab deruxtecan is mainly indicated for managing adult patients with metastatic or unresectable HER2-positive breast cancer who have received two or more anti-HER2-based therapy before.
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Locally Advanced or Metastatic Gastric Cancer:
Trastuzumab is also indicated for the management of adult patients with metastatic or locally advanced HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.
Clinical Pharmacology:
Mechanism of Action:
Trastuzumab is a HER2-directed antibody-drug conjugate and is a humanized IgG1. It consists of a small molecule named Dxd, a topoisomerase 1 inhibitor. It is attached to the antibody by a cleavable linker. After the drug binds to HER2 on tumor cells, Trastuzumab deruxtecan undergoes internalization and intercellular linker cleavage by the lysosomal enzymes. When the drug is released into the body, the membrane permeable Dxd causes apoptotic cell death and damage to the DNA.
Composition of the Drug:
Active Ingredient - Fam-Trastuzumab deruxtecan-nxki.
Inactive Ingredients - L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, and sucrose.
Pharmacodynamics:
Cardiac Electrophysiology:
When multiple doses of Trastuzumab deruxtecan 6.4 mg per kg were administered every three weeks, the patients did not present with a clinically significant effect on the QTc interval in an open-label study on 51 patients with metastatic HER2-positive breast cancer.
Pharmacokinetics:
Trastuzumab deruxtecan and its pharmacokinetics were evaluated in patients with HER2-positive breast cancer. After a single dose exposure to the drug, the topoisomerase 1 levels increased proportionally over a dose range of 3.2 to 8 mg per kg.
Metastatic HER2-Positive Breast Cancer:
When the recommended dosage of Trastuzumab deruxtecan was administered to the patients with HER2-positive breast cancer, the variations in the geometric mean levels were around 122 micrograms per mL and 4.4 ng per mL. The accumulation of Trastuzumab deruxtecan was noted to be approximately 35 % at a steady state.
Distribution:
Studies reported the volume of distribution of the drug as 2.78 L based on the population pharmacokinetic analysis. The plasma protein binding of the drug is approximately 97 %, and the blood-to-plasma ratio is 0.6.
Elimination:
The median elimination half-life of the drug in patients with HER2-positive breast cancer and gastric cancer was approximately 5.7 to 5.8 days. The systemic clearance of the drug based on the population pharmacokinetic analysis was 0.42 L per day. Therefore, the median elimination half-life of the topoisomerase in patients with HER2-positive breast cancer is 5.5 to 5.8 days.
Specific Population:
No clinically significant differences were noted in the pharmacokinetics of Trastuzumab deruxtecan or topoisomerase in young patients, underweight or overweight individuals, people with hepatic impairment, or moderate renal impairment. These results were based on the population pharmacokinetic analysis.
Drug Interactions With Trastuzumab Deruxtecan:
The following drugs must not be administered with Trastuzumab deruxtecan:
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Acetaminophen.
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Clonazepam.
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Cyclobenzaprine.
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Dexamethasone.
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Fludrocortisone.
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Pantoprazole.
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Rosuvastatin.
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Potassium chloride.
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Tramadol.
Nonclinical Toxicology:
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
No studies have been conducted to know about the carcinogenic potential of Trastuzumab deruxtecan. However, during the animal studies, it was observed that the topoisomerase was clastogenic but not mutagenic. Furthermore, nothing has been known related to the impairment of fertility in humans.
Dosage Forms and Strength:
For Injection - 100 mg of Trastuzumab deruxtecan as a white to yellowish white lyophilized powder is present in a single dose vial for reconstitution and further dilution.
Drug Warnings and Precautions:
1. Interstitial Lung Disease (ILD) Or Pneumonitis - It has been noted that severe life-threatening and fatal interstitial lung disease, including pneumonitis, can occur in patients treated with Trastuzumab deruxtecan. The patient must immediately consult the doctor if he experiences cough, fever, dyspnea, or other symptoms. Patients suspected of having ILD must be investigated radiographically. Corticosteroids, including Prednisolone, must be administered in patients with grade 1 or grade 2 ILD. the drug must be permanently discontinued in patients with symptomatic grade 2 or grade 3 ILD.
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Metastatic HER2-Positive Breast Cancer - A clinical study was conducted on 234 patients with metastatic or unresectable HER2-positive breast cancer. After the study, it was observed that ILD occurred in 9 % of the patients, and fatal outcomes due to ILD or pneumonitis were reported in 2.6 % of the patient
2. Neutropenia - Severe or febrile neutropenia can occur in patients treated with Trastuzumab deruxtecan. The doctor must monitor the complete blood count before initiating the treatment with Trastuzumab deruxtecan. The drug might need to be interrupted or discontinued based on the severity of the condition.
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Metastatic HER2-Positive Breast Cancer - During a clinical study, 62 % of the patients reported a decrease in neutrophil count, whereas 60 % of them had a grade 3 to grade 4 decrease in the neutrophil count.
3. Left Ventricular Dysfunction - Patients receiving Trastuzumab deruxtecan are at a higher risk of developing left ventricular dysfunction. A decrease in the left ventricular ejection fraction (LVEF) was noted with anti-HER2 therapy. Out of the 234 patients who received Trastuzumab deruxtecan, two patients were reported to show an asymptomatic decrease in the LVEF. During the DESTINY-Gastric01 trial, no clinically significant events of heart failure were reported. So, the patients with cardiac disorders must be evaluated for LVEF, and the drug must be interrupted or discontinued depending on the patient’s severity.
4. Embryo-Fetal Toxicity - Depending upon its mechanism of action, Trastuzumab deruxtecan can cause fetal harm if given to a pregnant female. In the postmarketing reports, oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death were noted. The topoisomerase inhibitor of Trastuzumab deruxtecan might also cause embryo-fetal harm because of its genotoxic nature. The doctor must verify the pregnancy status of the females before initiating treatment with Trastuzumab deruxtecan. The females planning to conceive must use effective contraceptive methods during and after the treatment with the drug.
What Are the Adverse Reactions of Trastuzumab Deruxtecan?
The following clinically significant adverse reactions were noted in patients who received Trastuzumab deruxtecan:
1. Gastrointestinal Disorders:
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Nausea.
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Vomiting.
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Constipation.
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Diarrhea.
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Abdominal pain.
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Stomatitis.
2. General Disorders:
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Fatigue.
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Pyrexia.
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Peripheral edema.
3. Metabolism and Nutrition Disorders:
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Decreased appetite.
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Dehydration.
4. Skin and Subcutaneous Tissue Disorders:
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Alopecia.
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Rashes.
5. Respiratory and Thoracic Disorders:
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Cough.
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Dyspnea.
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Epistaxis.
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Interstitial lung disease.
6. Neurological Disorders:
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Headache.
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Dizziness.
7. Infections and Infestations:
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Upper respiratory tract infections.
8. Eye Disorders:
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Dryness of the eyes.
The following laboratory abnormalities were noted in patients receiving Trastuzumab deruxtecan:
1. Hematology - The following levels decreased:
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Hemoglobin.
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White blood cells.
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Neutrophil count.
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Lymphocyte count.
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Platelet count.
2. Chemistry - The following levels increased:
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Aspartate aminotransferase.
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Blood alkaline phosphatase.
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Alkaline aminotransferase.
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Potassium.
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Blood bilirubin.
3. Immunogenicity - There is a potential for immunogenicity when the therapeutic proteins are administered. The sensitivity and specificity of the assay influence the detection of antibodies.
The following factors influence the antibody positivity in an assay:
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Assay methodology.
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Sample handling.
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Timing of sample collection.
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Concomitant medications.
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Underlying diseases.
Treatment-induced antibodies were noted in 1.7 % of the patients. However, no conclusions can be drawn because not a significant number of patients demonstrated antibody formation.
Preparation for Administration:
The patient must check the vial labels before taking the drug to ensure that he is taking the correct taking and there are no errors. Reconstitute and dilute Trastuzumab deruxtecan before giving intravenous infusion. Use an aseptic technique while handling the drug.
The reconstitution, dilution, and administration of the drug are done in the following ways:
Reconstitution:
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Reconstitute the drug immediately before dilution.
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Calculate the dose, the total volume of the reconstituted drug solution required, and the number of vials required. If the full dose of the drug is to be administered, more than one vial might be required.
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Reconstitute the 100 mg vial by using a sterile syringe and slowly inject sterile water for injection into the vial to obtain a concentration of 20 mg per mL.
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Swirl the vial gently, but do not shake it.
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Inspect the parenteral drug products carefully for any particulate matter or discoloration. The solution should be clear or colorless to light yellow and free of visible particles.
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If the solution is not to be used immediately, store it in a refrigerator at 2 to 8 degrees Celsius for up to 24 hours from the time of reconstitution.
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The vial must be kept away from direct sunlight.
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As the drug is commonly used without a preservative, it must be discarded if unused 24 hours after refrigeration.
Dilution:
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Dilute the calculated volume of the drug in an IV infusion bag containing 100 mL of 5 % dextrose injection. Avoid using sodium chloride injection. Trastuzumab deruxtecan is compatible with an infusion bag made of polyvinyl chloride or polyolefin.
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Invert the infusion bag so that the solution mixes properly, but avoid shaking it.
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Cover the infusion bag to protect it from sunlight.
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If the solution is not used immediately, the drug must be stored at room temperatures for four hours or in a refrigerator for up to 24 hours.
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Discard the unused portion left in the vial.
Administration:
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If the prepared solution was refrigerated, allow it to return to room temperature before administration.
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Administer Trastuzumab deruxtecan as an intravenous infusion with an infusion set made of polyolefin and 0.2 microns polyethersulfone filter.
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Do not administer the drug as an intravenous push or bolus.
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Do not mix Trastuzumab deruxtecan with other drugs.
Some More Information About Trastuzumab Deruxtecan:
Use in Specific Populations:
Pregnancy:
Trastuzumab deruxtecan can cause fetal harm when administered to a pregnant female. However, no studies have been conducted on pregnant females, but the post-marketing reports have indicated that neonatal death, skeletal abnormalities, and pulmonary hypoplasia were seen in pregnant females. In addition, clinically significant adverse reactions like miscarriage, birth defects, and other outcomes were seen when the females became pregnant seven months after taking the drug.
Lactation:
No data is available regarding the presence of Trastuzumab deruxtecan in human milk, effects on the breastfed child, or milk production. However, the females should refrain from breastfeeding during treatment with Trastuzumab deruxtecan as it can cause serious adverse reactions in the child.
Pediatric Age Group:
Not much information is available related to the safety and efficacy of the drug in children.
Geriatric Use:
Of the 234 patients with HER2-positive cancer treated with Trastuzumab deruxtecan 5.4 mg per kg, 26 % were above 65 years, and 5 % were 75 years or younger. No significant differences were noted in the safety and efficacy of the drug in patients above 65 years of age. However, there was a higher incidence of grades 3 and 4 adverse reactions in 65 years old patients.
Renal Impairment:
The dosage of the drug must be adjusted accordingly in patients with mild or moderate renal impairment. However, no clinically significant data is available regarding severe renal impairment.
Hepatic Impairment:
The dosage of the drug need not be adjusted in patients with mild or moderate hepatic impairment. However, patients with severe hepatic impairment must be carefully monitored for increased toxicities related to the drug.
Clinical Trial:
Metastatic Breast Cancer:
The safety and efficacy of Trastuzumab deruxtecan was evaluated in a clinical trial named DESTINY-Breast01. It is a multicenter and a single-arm trial that included 184 female patients suffering from HER2-positive breast cancer. The cancer was unresectable or metastatic, and these patients had previously received two or more anti-HER therapies. The patients suffering from ILD, cardiac diseases, and active brain metastases were excluded from the trial. The trial participants received Trastuzumab deruxtecan 5.4 mg per kg by intravenous infusion every three weeks. In addition, the tumor imaging of the patients was done every six weeks.
Trial Results:
The efficacy results are listed in the table below:
