Dostarlimab-gxly - Uses, Dosage, Precautions, and Side Effects

What Is Dostarlimab-gxly?

Dostarlimab-gxly is a monoclonal antibody drug developed primarily by a biotech company in Massachusetts, formerly known as Tessaro.

Is Dostarlimab-gxly FDA-approved?

Dostarlimab-gxly received approval from the U.S. Food and Drug Administration (FDA) on 17th August 2021, for the treatment of mismatch repair-deficient recurrent and advanced solid tumors.

Dostarlimab-gxly Administration

Dostarlimab-gxly is an injectable drug, so it has to be administered carefully. The drug is given intravenously over 30 minutes utilizing an intravenous line. Dostarlimab-gxly should not be administered as an intravenous push or bolus injection. Ensure no other drugs are administered with Dostarlimab-gxly through the same infusion line.

Dosage:

• Four doses of 500 mg each are administered every three weeks.

• The subsequent dose of Dostarlimab-gxly is given 3 weeks after the fourth dose, and 1000 mg of the drug is administered every 6 weeks.

• Dostarlimab-gxly is administered intravenously over 30 minutes.

Mechanism of Action of Dostarlimab-Gxly

• PD-1 receptors on T cells normally bind to PD-L1 and PD-L2 ligands, which suppress T-cell activity by reducing cytokine production and cell proliferation.

• Some tumors use this pathway to weaken T-cell function, preventing the immune system from recognizing and attacking cancer cells.

• Dostarlimab-gxly is a humanized IgG4 monoclonal antibody that binds to PD-1 receptors and blocks their interaction with PD-L1 and PD-L2.

• It is a humanized monoclonal antibody of the immunoglobulin G4 isotype that binds to PD-1 receptors and blocks their interaction with PD-L1 and PD-L2.

• By inhibiting PD-1 signaling it restores T-cell activity and enhances the immune system’s ability to target tumor cells.

How Does Dostarlimab-gxly Work to Treat Cancer?

Dostarlimab-gxly harnesses the immune system's power. It belongs to the class of monoclonal antibodies and is a programmed death receptor-1 (PD-1). The cancer cells express PD-L1 (programmed death-ligand 1) on their surfaces, which binds to PD-1 on the T cells (natural immune cells of the human body).

This reduces the immune cells' ability to recognize and kill cancer cells. Dostarlimab-gxly binds to PD-1 receptors on the T cells and blocks the interaction of PD-L1 with the body’s immune cells. As a result, the body's immune system identifies the cancer cells and inhibits tumor growth. Dostarlimab-gxly helps restore the cytotoxic properties of the body's immune cells.

What Are the Uses of Dostarlimab-gxly?

Dostarlimab-gxly is specifically used to treat adult patients who have a specific type of endometrial cancer and solid tumors that have a genetic biomarker called mismatch repair-deficient recurrent (dMMR) or microsatellite instability-high (MSI–H).

The uses of Dostarlimab-gxly are listed below:

• Advanced Endometrial Cancer - When cancer originates from the uterus lining, it is known as endometrial cancer. It is also known as uterine cancer because it initiates in the cells forming the uterus lining. Dostarlimab-gxly is indicated when cancer has progressed, and patients have received a platinum-containing regimen, but that has failed.

• Solid Tumors - A solid tumor is an abnormal mass of tissue that might be benign or malignant. According to the FDA-approved test, Dostarlimab-gxly is indicated for patients with solid tumors that have progressed after prior therapy. Also, the patient has no alternative treatment options and has not shown satisfactory results from the prior treatments.

Drug Warning:

• This can cause immune-related side effects, which may be serious or even life-threatening.

• These side effects can affect any organ in the body.

• Doctors should check for symptoms and perform routine blood tests, including liver function tests, thyroid function tests, and creatinine levels, to ensure the body is functioning properly.

Use the drug carefully under the following conditions:

• Immune-mediated pneumonitis.

• Immune-mediated colitis.

• Immune-mediated endocrinopathies: Adrenal insufficiency, hypophysitis, thyroid disorders, and type 1 diabetes mellitus.

• Immune-mediated nephritis.

• Immune-mediated dermatologic reactions.

• Infusion-related reactions.

Dosage Modifications for Adverse Drug Reactions:

The table given below summarizes the drug modification for adverse drug reactions:

For Patients:

Is Dostarlimab-gxly Indicated for All Types of Cancer?

Dostarlimab-gxly is a prescription drug used to treat adults suffering from cancer whose laboratory specimens have shown mismatch repair-deficient (dMMR) or solid tumors. This drug is mainly indicated when cancer has recurred, has spread, is in the advanced stage, and cannot be removed surgically.

Is the Drug Really Effective Against Cancer?

A clinical trial was done recently in 18 patients with rectal cancer who were kept on follow-up for six months. The trial results were miraculous, as 14 patients showed an excellent clinical response to phase 2 advanced rectal cancer. In addition, no evidence of cancer was found on the biopsy, digital rectal examination, magnetic resonance imaging (MRI), and positron emission tomography (PET) scan.

What Things Must the Patient Inform the Doctor Before Taking Dostarlimab-gxly?

Before taking Dostarlimab-gxly, the patient must inform the doctor if he or she:

• Has problems related to the immune system, like Crohn’s disease, lupus, and ulcerative colitis.

• Is allergic to Dostarlimab-gxly or its ingredients.

• Is taking over-the-counter drugs, vitamins, nutritional supplements, or other herbal products because the dose of these drugs might need to be altered. The doctor might also monitor the side effects and the drug interactions.

• Has undergone an organ transplant previously.

• Has or is likely to receive a stem cell transplant that requires donor cells (allogeneic transplant).

• Has undergone radiation therapy in the chest region.

• Has nervous disorders like myasthenia gravis or Guillain-Barré syndrome.

• Is pregnant or planning to become pregnant because Dostarlimab-gxly can harm the baby in the womb.

Guidelines For Pregnant Females:

• The doctor will do a pregnancy test before starting the drug.

• The pregnant female must use effective birth control methods during the treatment and for four months after the last dose of Dostarlimab-gxly. Consult the doctor to know about the birth control methods to be used during the treatment.

• The patient must inform the doctor immediately if she thinks she might become pregnant during the treatment.

• Lactating mothers or those planning to breastfeed the baby must inform the doctor because the drug might pass into the baby through the milk.

• Avoid breastfeeding during the treatment and for four months after the last dose of Dostarlimab-gxly.

When Should the Patient Contact the Doctor After Taking the Drug?

The patient must contact his doctor immediately if he develops any new signs and symptoms in addition to the ones listed below:

• Cough.

• Shortness of breath.

• Chest pain.

Intestinal Problems:

• Diarrhea or accelerated bowel movements.

• Black, sticky, or tarry stools containing blood and mucus.

• Severe abdominal pain and tenderness.

Liver Problems:

The skin or the whites of the eyes might appear yellowish.

• Dark or tea-colored urine.

• Nausea and vomiting.

• Pain on the right side of the abdomen.

• Bleeding or bruising might occur more than usual.

Problems Related to the Hormones and Glands:

• Unusual headaches that do not subside immediately.

• The eyes become sensitive to light.

• Eye problems.

• Irregular or rapid heartbeat.

• Increased perspiration or sweating.

• Extreme fatigue or tiredness.

• Weight changes (weight gain or loss).

• Feeling hungrier or thirstier than usual.

• Urinary frequency (urinating more than normal).

• Hair loss.

• Feeling cold.

• Constipation.

• Changes in the voice, such as it becoming deeper.

• Dizziness.

• Fainting.

• Behavioral changes like forgetfulness, reduced sex drive, and irritability.

Kidney Problems:

• Change in the urine output and color.

• Blood in the urine.

• Swollen ankles.

• Loss of appetite.

Skin Problems:

• Skin itching and rashes.

• Blistering and peeling of the skin.

• Painful sores or ulcers in the mouth, nose, throat, and genital areas.

• Fever or flu-like symptoms.

• Swelling in the lymph nodes.

In addition to the above side effects, the patient might present with problems in the other tissues and organs, including the immune system.

Call the doctor immediately if any of the following problems are noted:

• Respiratory difficulties.

• Chest pain.

• Mental confusion and memory problems.

• Mood changes and sleepiness.

• Stiff neck.

• Hallucinations.

• Problems related to body balance.

• Numbness or tingling sensation in the arms or legs.

• Vision-related problems such as double vision, blurred vision, light sensitivity, eye pain, or changes in eyesight.

• Severe muscle pain, cramps, or weakness.

• Bruising more than usual.

• Low red blood cell count.

Infusion Problems

The infusion reaction might be severe or life-threatening. The signs and symptoms of infusion reactions are listed below:

• Chills and shaking.

• Skin rash or itching.

• Flushing.

• Wheezing.

• Shortness of breath.

• Dizziness.

• The patient might feel giddy and faint.

• Fever.

• Pain in the neck and back.

Reactions Related to the Transplanted Organ

The doctor will inform the patient about the signs and symptoms he will develop after taking Dostarlimab-gxly. The symptoms depend on the type of organ transplant the patient had. Studies have reported that people who received a bone marrow or stem cell transplant from the donor cells (allogeneic transplant) are more likely to develop complications, including graft-versus-host disease. These complications are serious and might turn fatal. They can occur in patients who underwent organ transplantation before or after receiving Dostarlimab-gxly.

What Should Be Done to Avoid Serious Complications Due to Dostarlimab-gxly?

To stay safe and avoid serious problems, these steps are important:

• Doctors need to keep checking for side effects during treatment.

• If you feel worse or notice new symptoms, tell the doctor right away.

• Go to all your doctor appointments.

• During the IV treatment, if you feel feverish or get chills, tell the nurse right away.

• Do not take medicines from the store unless the doctor says so.

• Do not get live vaccines during treatment.

• Take rest breaks because feeling tired is common.

• Wash your hands often to stay clean.

• Try to avoid crowded places.

What Are Some of the Other Possible Side Effects of Dostarlimab-gxly?

The common side effects of Dostarlimab-gxly in patients with deficient mismatch repair (dMMR) solid tumors include the following:

• Lethargy and weakness.

• Anemia (reduced hemoglobin concentration).

• Nausea and diarrhea.

• Reduced white blood cell count.

• Decreased albumin concentration in blood.

• Elevated liver blood tests.

• Reduced sodium concentration in the blood.

Information for Doctors:

Clinical Pharmacology of Dostarlimab-gxly:

Pharmacodynamics:

The pharmacodynamics and exposure-response relationship for the safety of the drug have not been fully explained. However, Dostarlimab-gxly directly binds to PD-1 receptors on T cells, demonstrating sustained target engagement and interleukin-2 (IL-2) production throughout the dosing interval.

Drug Distribution:

The total volume of distribution of Dostarlimab-gxly at a steady rate is approximately 5.3 L (14 %).

Drug Elimination:

The elimination half-life of Dostarlimab-gxly in the steady state is 23.5 days, and the mean clearance of the drug at a constant state is 0.007 L/h (30 %).

Drug Metabolism:

Dostarlimab-gxly might get metabolized via the catabolic pathway into small peptides and amino acids.

Non-clinical Toxicology:

No studies have been conducted to evaluate the potential carcinogenicity, mutagenicity, or impairment of fertility of Dostarlimab-gxly. In animal studies evaluating the effects of Dostarlimab-gxly, no significant changes in fertility were observed.

Storage of the Infusion Solution:

Make sure to store the drug in the original carton until preparation to protect it from sunlight.

The infusion solution can be stored in the following ways:

• The drug must be stored at room temperature for no more than 6 hours, from the time of preparation until infusion.

• The drug can also be refrigerated at temperatures between 2 and 8 degrees Celsius. However, make sure the drug returns to the normal temperature before infusion.

• Discard the drug after 6 hours at room temperature and after 24 hours under refrigeration.

Drug Storage and Handling:

• Dostarlimab-gxly injection is a clear or opalescent, colorless, or slightly yellowish solution supplied in a single-dose vial.

• The drug is supplied in a carton containing a 500 mg/10 mL single-dose vial.

• The vial must be stored in a refrigerator at 2-8 °C.

• Store the vial in the original carton and keep it away from sunlight.

• Do not freeze or shake the vial, as this may alter the drug's properties.

Warnings and Precautions:

• Severe and Fatal Immune-Mediated Reactions - Dostarlimab-gxly can cause severe and life-threatening immune reactions. Avoid the drug in patients presenting with the following immune-mediated adverse reactions, such as immune-mediated pneumonitis, immune-mediated hepatitis, etc.

• Infusion-Related Reactions - Life-threatening infusion reactions have been reported with Dostarlimab-gxly. Monitor patients closely during infusion. If a severe reaction occurs, slow the infusion or stop the drug permanently.

• Complications of Hematopoietic Stem Cell Transplant (HSCT) - Dostarlimab-gxly may cause serious complications in patients who have had a stem cell transplant. These include hyperacute graft-versus-host disease (GVHD), chronic GVHD, hepatic veno-occlusive disease, and steroid-requiring febrile syndrome. Monitor these patients closely and use the drug only after carefully weighing the risks and benefits.

• Embryo-Fetal Toxicity - Dostarlimab-gxly can harm the fetus if used during pregnancy due to PD-1/PD-L1 inhibition, which may cause fetal loss. Pregnant patients should be informed of this risk, and females of reproductive potential should use effective contraception during treatment and for four months after.

What Adverse Reactions Were Seen in the Patients After Taking Dostarlimab-gxly?

The following adverse reactions were reported in less than 10 % of the patients who received Dostarlimab-gxly:

• Endocrine Disorders - Hypothyroidism, hyperthyroidism, autoimmune thyroiditis, and adrenal insufficiency.

• Optic Disorders - Iridocyclitis, uveitis.

• General Disorders - Pyrexia, chills.

• Gastrointestinal Disorders - Acute pancreatitis, colitis, and enterocolitis hemorrhage.

• Urinary Tract Disorders - Nephritis, tubulointerstitial nephritis.

• Respiratory and Mediastinal Disorders - Pneumonitis.

• Skin and Subcutaneous Diseases - Rash, pemphigoid, and erythema.

• Procedural Complications - Infusion-related reactions.

• Hepatic Disorders - Hepatocellular injuries.

• Musculoskeletal Disorders - Myalgia.

Adverse Reactions in a Clinical Trial:

The safety of Dostarlimab-gxly was evaluated during the GARNET trial in 104 patients having advanced or recurrent dMMR endometrial cancer. Patients were administered four doses of Dostarlimab-gxly 500 mg followed by 1000 mg every six weeks until disease progression or unacceptable toxicity. The following severe adverse reactions were seen.

• Sepsis.

• Acute kidney injury.

• Urinary tract infections.

• Acute kidney injury.

• Abdominal pain.

• Pyrexia.

• Fatigue.

• Asthenia.

• Nausea.

• Diarrhea.

• Constipation.

• Anemia.

The common grade 3 and grade 4 abnormalities that were seen in the laboratory specimens are listed below:

• Decreased lymphocyte count.

• Reduced sodium concentration.

• Decreased leukocyte count.

• Increased creatinine levels.

• Decreased albumin concentration.

• Increased alkaline phosphatase levels.

• Elevated alanine aminotransferase levels.

Immunogenicity:

Immunogenicity can occur with any of the therapeutic proteins. The presence or absence of antibodies in the assay depends upon their sensitivity and specificity. However, the immunogenicity was determined during the GARNET trial.

During this trial, 384 patients received the drug, and 2.1% developed treatment-emergent anti-drug antibodies. In contrast, neutralizing antibodies were found in 1% of the patients. Only a small number of patients experienced adverse drug reactions, so nothing could be concluded about the relationship between immunogenicity and the drug's safety and efficacy.

Clinical Trial:

Mismatch Repair-Deficient Recurrent or Advanced Endometrial Cancer:

The efficacy of Dostarlimab-gxly was studied during the GARNET (genomic and randomized trials network) trial. It is a multicohort, multicenter, and open-label trial conducted in patients with advanced-stage tumors. The trial was conducted on 71 patients with mismatch repair-deficient recurrent and advanced endometrial cancer, which progressed even after treatment with the platinum-containing regimen.

The trial participants received four doses of Dostarlimab-gxly 500 mg intravenously for three weeks, followed by 1000 mg for six weeks. 66% of the trial patients had stage 4 disease, 90% were undergoing anticancer surgery, and 79% received anticancer radiotherapy. After the trial, the confirmed overall response rate was 42.3%, and the partial response rate was 29.6%.

Use of Dostarlimab-gxly in Specific Populations:

Pregnancy: Dostarlimab-gxly must not be injected into a pregnant female because it can be lethal for the fetus.

Lactation: Lactating mothers are advised not to breastfeed the child during the treatment and for four months after the last dose of Dostarlimab-gxly.

Females and Males of Reproductive Age: Females planning to conceive during or before the treatment must get a pregnancy test done to confirm their pregnancy status. In addition, they should use effective contraceptive methods during the treatment and for four months after the last dose.

Pediatric Population: No data are available on the safety and efficacy of Dostarlimab-gxly in children.

Geriatric Population: No significant differences were observed in the drug's effects, safety, or efficacy.