Dostarlimab – Uses, Dosage, Side Effects, Interaction

Dostarlimab is an anti-PD-1 monoclonal antibody used in the treatment of mismatch repair deficient endometrial cancers.  Dostarlimab is a monoclonal antibody used as a medication for the treatment of endometrial cancer. Dostarlimab is a programmed death receptor-1 (PD-1)–blocking monoclonal antibody. Dostarlimab is an IgG4 humanized monoclonal antibody targeted against the human programmed death receptor-1 (PD-1).[rx] PD-1 receptors are found on T-cells and, when activated, serve to inhibit immune responses – some cancers leverage this system by overexpressing PD-1 ligands, thereby effectively inhibiting the anti-tumor immune response that would typically attempt to destroy the cancerous cells.[rx] Agents acting on the PD-1 pathway, such as nivolumab and pembrolizumab, facilitate endogenous immune-mediated anti-tumor activity and may therefore be used to treat a wide variety of cancers, including those of the skin, lung, kidneys, and liver.

In April 2021, dostarlimab was granted accelerated approval by the FDA – as GlaxoSmithKline’s dostarlimab-gxly (Jemperli) – for the treatment of adult patients with recurrent or advanced mismatch repair deficient (dMMR) endometrial cancer experiencing disease progression despite treatment with platinum-containing chemotherapy regimens.[rx] As this accelerated approval was granted only for the treatment of dMMR endometrial cancers, it was approved alongside a companion diagnostic device – the VENTANA MMR RxDx Panel – for use in selecting appropriate patients for treatment.[rx]

Dostarlimab is currently under investigation for the treatment of rectal cancers with mismatch repair deficiency. A prospective phase II study in patients with mismatch repair-deficient locally advanced rectal cancer resulted in all twelve patients exhibiting a complete clinical response.[rx]

Mechanism of action

Approximately 13-30% of recurrent endometrial cancers involve microsatellite instability (MSI) or mismatch repair deficiency (dMMR).[rx,rx] The mutations resulting in dMMR endometrial cancers are primarily somatic in nature (~90%), although 5-10% of cases involve germline mutations.[rx] Cancers that have mutations resulting in dMMR can upregulate the expression of programmed death receptor-1 (PD-1) ligands 1 and 2 (PD-L1 and -L2) – PD-1 is found on T-cells and, when activated, inhibits their proliferation and the production of cytokines.[rx] The binding of these ligands to PD-1 thereby functions as an immune checkpoint that downregulates the anti-tumor immune response.[rx]

Dostarlimab is a monoclonal antibody targeted against PD-1 – it binds to the receptor and prevents interactions with PD-L1 and PD-L2, thus allowing the anti-tumor immune response to proceed unimpeded.[rx]

Dostarlimab is an immunotherapy that facilitates the body’s endogenous anti-tumor immune response in the treatment of cancer.[rx] It is administered over a span of 30 minutes via intravenous infusion every three to six weeks depending on the cycle.[rx]

Agents that interfere with the PD-1/PD-L1 pathway, including dostarlimab, remove an important immune system inhibitory response and may therefore induce immune-mediated adverse reactions which can be severe or fatal. These reactions can occur in any organ system and can occur at any time after starting therapy, and while they most often manifest during therapy they may also appear after discontinuing the causative agent. Patients receiving therapy with dostarlimab should be monitored closely for evidence of an underlying immune-mediated reaction and evaluated and treated promptly if an immune-mediated reaction is suspected.[rx]

Indications

  • Dostarlimab-gxly is indicated for the treatment of adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that has progressed despite ongoing or prior treatment with a platinum-containing chemotherapy regimen.
  • In the United States, dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen. Platinum-based agents such as cisplatin, carboplatin, and oxaliplatin are the mainstays of treatment when it comes to cancer chemotherapy treatment.[rx] It is also indicated for the treatment of solid tumors.[rx]
  • In the European Union, dostarlimab is indicated as monotherapy for the treatment of adults with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI H) recurrent or advanced endometrial cancer (EC) that has progressed on or following prior treatment with a platinum-containing regimen.
  • For the treatment of adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC), as determined by an approved test, that has progressed on or following prior treatment with a platinum-containing regimen.
  • Advanced Mismatch Repair-deficient (dMMR) Endometrial Cancer
  • Recurrent Mismatch Repair-deficient (dMMR) Endometrial Cancer

Use in Cancer

Dostarlimab-gxly is approved to treat adults with mismatch repair deficient (dMMR) cancer that has come back or is advanced, including:

Dostarlimab-gxly is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that it provides a clinical benefit in these patients.

Dostarlimab-gxly is also being studied in the treatment of other types of cancer.

Contraindications

  • overactive thyroid gland
  • a condition with low thyroid hormone levels
  • type 1 diabetes mellitus
  • severely decreased function of cortex of adrenal gland
  • a type of inflammation of the lung called interstitial pneumonitis
  • inflammation of the large intestine
  • inflammation of the liver called hepatitis
  • kidney inflammation
  • high blood sugar
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • inflammation of the pituitary gland

Dosage

Strengths: gxly 500 mg/10 mL

Endometrial Carcinoma

Initial dose:

  • Dose 1 through Dose 4: 500 mg IV over 30 minutes every 3 weeks

Maintenance dose:

  • Subsequent dosing beginning 3 weeks after Dose 4 (Dose 5 onwards): 1000 mg IV over 30 minutes every 6 weeks

Duration of therapy:

  • Until disease progression or unacceptable toxicity

Dose Adjustments

  • No dose reductions of this drug are recommended. In general, withhold therapy for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue therapy for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less prednisone equivalent per day within 12 weeks of initiating steroids.

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
PNEUMONITIS:

  • Grade 2: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids
  • Grade 3 or 4 or recurrent Grade 2: Permanently discontinue therapy.

COLITIS:

  • Grade 2 or 3: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids
  • Grade 4: Permanently discontinue therapy.

HEPATITIS WITH NO TUMOR INVOLVEMENT OF THE LIVER:

  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increases to more than 3 and up to 8 times upper limit of normal (ULN) or total bilirubin (TB) increases to more than 1.5 and up to 3 x ULN: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroid. AST or ALT increases to more than 8 x ULN or TB increases to more than 3 x ULN: Permanently discontinue therapy.

HEPATITIS WITH TUMOR INVOLVEMENT OF THE LIVER (if AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue this drug based on recommendations for hepatitis with no liver involvement):

  • Baseline AST or ALT is more than 1 and up to 3 x ULN and increases to more than 5 and up to 10 x ULN or baseline AST or ALT is more than 3 and up to 5 x ULN and increases to more than 8 and up to 10 x ULN OR baseline AST or ALT is more than 3 and up to 5 x ULN and increases to more than 8 and up to 10 x ULN: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids
  • AST or ALT increases to more than 10 x ULN or TB increases to more than 3 x ULN: Permanently discontinue therapy.

ENDOCRINOPATHIES:

  • Grade 2, 3, or 4: Withhold therapy if not clinically stable; resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids

NEPHRITIS WITH RENAL DYSFUNCTION:

  • Grade 2 or 3 increased creatinine: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids
  • Grade 4 increased creatinine: Permanently discontinue therapy.

EXFOLIATIVE DERMATOLOGIC CONDITIONS:

  • Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS): Withhold therapy if not clinically stable; resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids
  • Confirmed SJS, TEN, or DRESS: Permanently discontinue therapy.

MYOCARDITIS:

  • Grade 2, 3, or 4: Permanently discontinue therapy.

NEUROLOGICAL TOXICITIES:

  • Grade 2: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids
  • Grade 3 or 4: Permanently discontinue therapy.

INFUSION-RELATED REACTIONS:

  • Grade 1 or 2: Interrupt or slow the rate of infusion.
  • Grade 3 or 4: Permanently discontinue therapy.

Administration advice:

  • Administer infusion solution IV over 30 minutes through an IV line using tubing made of polyvinyl chloride or platinum-cured silicon; fittings made of polyvinyl chloride or polycarbonate; and a sterile, non-pyrogenic, low-protein binding, 0.2-micron, in-line, or add-on filter.
  • Do not administer this drug as an IV push or bolus injection.
  • Do not co-administer other drugs through the same infusion line.

Side Effects

The Most Common

  • nausea
  • constipation
  • fatigue
  • muscle or joint pain
  • cough, chest pain, or shortness of breath
  • diarrhea; increase in the number of bowel movements; black, tarry, sticky stools, or stools that have blood or mucus in them; or stomach-area pain or tenderness
  • yellowing of skin or eyes, dark-colored urine, bleeding or bruising more easily than normal, loss of appetite, severe nausea or vomiting, decreased energy, or pain on the right side of the stomach area
  • headaches, including those that are unusual or will not go away
  • changes in mood or behavior (decreased sex drive, irritability, or forgetfulness)
  • deepening of voice or hoarseness
  • changes in weight (gain or loss)
  • weakness
  • hair loss
  • dizziness or fainting
  • vision changes
  • increased sweating
  • increased urination
  • increased sensitivity to light
  • fast heartbeat
  • feeling more hungry or thirsty than usual
  • feeling cold
  • change in amount or color of urine; ankle swelling; blood in urine; or loss of appetite
  • pale skin or shortness of breath
  • rash; skin blisters, peeling, or sores; itching; painful sores or ulcers in mouth, nose, throat, or genital area; fever or flu-like symptoms; or swollen lymph nodes
  • rash, stomach area pain, or diarrhea
  • swollen lymph nodes, rash or tender skin lumps, cough, shortness of breath, vision changes, or eye pain
  • confusion, fever, muscle weakness, balance problems, nausea, vomiting, stiff neck, memory problems, or seizures
  • hallucinations (seeing things or hearing voices that do not exist)

More common

  • Bladder pain
  • bloody or cloudy urine
  • constipation
  • depression
  • difficult, burning, or painful urination
  • dry skin and hair
  • feeling cold
  • frequent urge to urinate
  • hair loss
  • hoarseness or husky voice
  • loss of appetite
  • lower back or side pain
  • muscle cramps and stiffness
  • pale skin
  • slow heartbeat
  • sore tongue
  • trouble breathing
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • weight gain
  • Agitation
  • chest pain or tightness
  • chills
  • coma
  • confusion
  • cough
  • cough producing mucus
  • decreased urine output
  • diarrhea
  • dizziness
  • fever
  • general feeling of discomfort or illness
  • headache
  • hostility
  • irritability
  • lethargy
  • muscle twitching
  • nausea
  • nervousness
  • rapid weight gain
  • seizures
  • sensitivity to heat
  • stomach cramps, tenderness, or pain
  • stupor
  • sweating
  • swelling of the face, feet, lower legs, ankles, or hands
  • thickening of bronchial secretions
  • trouble sleeping
  • watery or bloody diarrhea
  • weight loss

Rare

  • Anxiety
  • back or leg pain
  • black, tarry stools
  • bleeding gums
  • bloating
  • blood in the stools
  • blue or pale skin
  • blurred vision
  • burning, tingling, numbness, or pain in the hands, arms, feet, or legs
  • burning feeling in the chest or stomach
  • change in vision
  • chest pain, possibly moving to the left arm, neck, or shoulder
  • dark urine
  • darkening of the skin
  • drowsiness
  • dry mouth
  • eye pain
  • fainting
  • fast heartbeat
  • general body swelling
  • inability to move the arms and legs
  • indigestion
  • joint pain
  • light-colored stools
  • lightheadedness
  • loss of consciousness
  • loss of strength or energy
  • muscle aches, pain, tenderness, or weakness
  • nosebleeds
  • numbness or tingling in the fingers, face, or feet
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • partial or slight paralysis
  • pinpoint red spots on the skin
  • rapid, shallow breathing
  • redness of the eye
  • sensation of pins and needles
  • sensitivity of the eye to light
  • severe headache
  • skin rash, redness, soreness, or itching
  • sores, welting, or blisters
  • stabbing pain
  • stiff neck or back
  • stomach discomfort or upset
  • sudden numbness and weakness in the arms and legs
  • swollen, painful, or tender lymph glands in the neck, armpit, or groin
  • tearing
  • upper right abdominal or stomach pain
  • vomiting
  • yellow eyes and skin

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category Not Assigned

Pregnancy

Dostarlimab can cause harm to a fetus. The death of the fetus can occur from the immune system’s reaction to the fetus through the examination of its mechanism in animal studies. Dostarlimab is a human immunoglobulin G (IgG4), which could permeate through the placental barrier. This may risk harm to the developing fetus as the drug may be passed on from the mother. Data is not available regarding the presence of dostarlimab in breast milk.[rx]

Lactation

Use should be avoided. Excreted into human milk: Unknown. Excreted into animal milk: Data not available
Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during therapy and for at least 4 months after the last dose.

How should this medicine be used?

Dostarlimab-gxly injection comes as a solution (liquid) to inject intravenously (into a vein) over 30 minutes by a doctor or nurse in a medical facility or infusion center. It is usually given once every 3 weeks for 4 cycles, and then once every 6 weeks for as long as your doctor recommends you receive treatment.

Dostarlimab-gxly injection may cause serious or life-threatening reactions during an infusion. A doctor or nurse will watch you closely while you are receiving the infusion to be sure you are not having a serious reaction to the medication. Tell your doctor or nurse immediately if you experience any of the following symptoms that may occur during the infusion: chills, flushing, shaking, dizziness, shortness of breath, wheezing, fever, itching, rash, back or neck pain, or feeling faint.

Your doctor may slow down your infusion, permanently or temporarily stop your dostarlimab-gxly injection treatment, or treat you with additional medications depending on your response to the medication and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with dostarlimab-gxly injection each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer’s website to obtain the Medication Guide.

What special precautions should I follow?

Before receiving dostarlimab-gxly injection,

  • tell your doctor and pharmacist if you are allergic to dostarlimab-gxly, any other medications, or any of the ingredients in dostarlimab-gxly injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have ever had an organ or bone marrow transplant and if you have or have ever had radiation therapy to your chest area; an autoimmune disease such as Crohn’s disease (a condition in which the immune system attacks the lining of the digestive tract causing pain, diarrhea, weight loss, and fever), ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum), or lupus (condition in which the immune system attacks many tissues and organs including the skin, joints, blood, and kidneys); any condition that affects your nervous system such as myasthenia gravis (a disorder of the nervous system that causes muscle weakness) or Guillain-Barré syndrome (weakness, tingling, and possible paralysis due to sudden nerve damage); any type of lung disease or breathing problems; thyroid problems; or liver disease.
  • tell your doctor if you are pregnant or plan to become pregnant. You will need to take a pregnancy test before you receive dostarlimab-gxly. You should not become pregnant while you are receiving a dostarlimab-gxly injection and for at least 4 months after your final dose. If you become pregnant while receiving a dostarlimab-gxly injection, call your doctor immediately. Dostarlimab-gxly injection may harm the fetus.
  • tell your doctor if you are breastfeeding or plan to breastfeed. You should not breastfeed while receiving a dostarlimab-gxly injection and for 4 months after your final dose.

References