Dostarlimab is a PD-1 blocking antibody that is indicated as a single agent for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other dMMR solid tumors that progressed on or following prior treatment. It is also indicated in combination with carboplatin and paclitaxel for the treatment of adults with dMMR or microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer. Immune-mediated adverse reactions including colitis, pneumonitis, hepatitis, nephritis, and endocrinopathies have been reported with dostarlimab use; treatment with high-dose corticosteroids may be necessary for patients who develop immune-mediated toxicity.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Dostarlimab (50 mg/mL vial) is available as a single-dose vial containing a clear to slightly opalescent, colorless to yellow solution.
-Do not shake the vial.
Dilution:
-Use a disposable sterile syringe made of polypropylene to withdraw the dostarlimab dose.
-Dostarlimab is compatible with infusion bags made of polyolefin, ethylene vinyl acetate, or polyvinyl chloride with di (2-ethylhexyl) phthalate (DEHP).
-For the 500-mg dose, withdraw 10 mL from the dostarlimab vial and dilute in an infusion bag containing 0.9% Sodium chloride injection or 5% Dextrose injection to a final concentration between 2 and 10 mg/mL (maximum total volume, 250 mL).
-For the 1,000-mg dose, withdraw a total of 20 mL from 2 dostarlimab vials and dilute in an infusion bag containing 0.9% Sodium chloride injection or 5% Dextrose injection to a final concentration between 4 and 10 mg/mL (maximum total volume, 250 mL).
-Mix the diluted solution by gentle inversion; do not shake.
-Discard any unused drug left in the vial.
-Storage following dilution: Store at room temperature for up to 6 hours or refrigerated (2 to 8 degrees C; 36 to 46 degrees F) for up to 24 hours from the time of dilution (includes infusion time).
Intravenous (IV) Infusion:
-If refrigerated, allow the diluted solution to warm to room temperature prior to administration.
-Administer the diluted solution IV over 30 minutes using a line with tubing made of polyvinyl chloride or platinum cured silicon and tubing fittings made of polyvinyl chloride or polycarbonate.
-Use a sterile, non-pyrogenic, low-protein binding, 0.2-micron, in-line or add-on filter.
-Do not give as an IV push or bolus injection.
-Do not administer other drugs through the same infusion line.
Immune-mediated pneumonitis was reported in 2.3% (grade 3 or 4, 1%) of patients with advanced or recurrent solid tumors who received dostarlimab (n = 605) in a multicohort clinical study. Systemic corticosteroids were required in 79% of patients with pneumonitis; pneumonitis resolved in 11 of 14 patients. Of 5 patients who resumed dostarlimab therapy after resolution, pneumonitis recurred in 2. Monitor patients for signs and symptoms of pneumonitis. If confirmed, dostarlimab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary. Additionally, cough occurred in 13% to 15% of patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in 2 cohorts of a multicenter, nonrandomized study; pneumonitis and/or interstitial lung disease were reported in less than 10% of dostarlimab patients in these cohorts.
Immune-mediated colitis occurred in 1.3% (grade 3, 0.7%) of patients with advanced or recurrent solid tumors who received dostarlimab (n = 605) in a multicohort clinical study. Systemic corticosteroids were administered to 6 of the 8 patients who developed colitis; colitis resolved in 5 patients. Of 4 patients who resumed dostarlimab therapy after resolution, colitis recurred in 1. Additionally, cytomegalovirus (CMV) or CMV reactivation has been reported in patients who received PD-1/PD-L1 blocking therapy and had steroid-refractory immune-mediated colitis. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Dostarlimab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating an infectious workup to exclude alternative etiologies. Gastrointestinal adverse events including nausea (30% to 32%; grade 3 or 4, 0.7% or less), diarrhea (26% to 29%; grade 3 or 4, 1.9% to 2.7%), constipation (16% to 23%; grade 3 or 4, 0.4% to 0.7%), vomiting (17% to 23%; grade 3 or 4, 0.7% to 1.5%), decreased appetite/anorexia (12% to 15%; grade 3 or 4, 0.4% or less) occurred in patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in clinical trials; severe cases of abdominal pain occurred in 2.7% to 3.7% of patients. Colitis, enterocolitis, and hemorrhagic enterocolitis were reported in less than 10% of dostarlimab patients in these cohorts.
Grade 3 immune-mediated hepatitis was reported in 3 patients (0.5%) with advanced or recurrent solid tumors who received dostarlimab (n = 605) in a multicohort, clinical study. Two patients were treated with systemic corticosteroids; hepatitis resolved in 2 patients and led to discontinuation of therapy in 1 patient. Monitor hepatic function at baseline and periodically during treatment. Dostarlimab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary. Elevated hepatic enzymes including increases from baseline in AST and ALT occurred in 12% to 31% (grade 3 or 4, 1.5% to 4.7%) occurred in cohorts of patients with dMMR recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in a multicenter, single-arm trial; increases from baseline in alkaline phosphatase (26% to 31%; grade 3 or 4, 2.7% to 3.4%) and decreases from baseline in albumin (hypoalbuminemia) were also reported in 26% to 36% (grade 3 or 4, 2.2% to 27%) of these patients. Increases from baseline in total bilirubin (hyperbilirubinemia) occurred in 7% (grade 3 or 4, 1.5%) and hepatocellular injury in less than 10% of patients in the cohort of patients with solid tumors other than endometrial cancer.
Immune-mediated adrenocortical insufficiency (1.2%; grade 3, 0.7%) occurred in patients with advanced or recurrent solid tumors who received dostarlimab (n = 605) in a multicohort clinical study. Systemic corticosteroids were required in 5 of the 7 patients who developed adrenocortical insufficiency; resolution occurred in 4 of the 7 patients. Grade 2 immune-mediated hypophysitis occurred in 1 patient (0.2%); the event did not resolve after treatment with systemic corticosteroids. Hypophysitis may present with acute symptoms associated with mass effect (e.g., visual field cuts, photophobia, headache) and can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Withhold or permanently discontinue therapy depending on the severity of the reaction.
Immune-mediated thyroid disorders including hypothyroidism (7.6%), hyperthyroidism (2.3%; grade 3, 0.2%), and thyroiditis (0.5%) occurred in patients with advanced or recurrent solid tumors who received dostarlimab (n = 605) in a multicohort clinical study. Treatment with systemic corticosteroids was not required in patients who experienced hypothyroidism or hyperthyroidism; hormone replacement therapy was necessary in 45 of 46 patients with hypothyroidism and in 10 of 14 patients with hyperthyroidism. One of 3 patients who developed thyroiditis required treatment with systemic corticosteroids and 2 of 3 required hormone replacement therapy; none of the thyroiditis cases resolved. Additionally, immune-mediated hypoparathyroidism was reported in less than 1% of patients who received dostarlimab in the clinical study or with the use of other PD-1/PD-L1 blocking antibodies. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Dostarlimab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Grade 2 immune-mediated nephritis including tubulo-interstitial nephritis occurred in 3 patients (0.5%) with advanced or recurrent solid tumors who received dostarlimab (n = 605) in a multicohort clinical study. Dostarlimab may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary. Increased serum creatinine level that worsened from baseline (21% to 33%; grade 3 or 4, 1.1% to 3.4%) and acute kidney injury (grade 3 or 4, 2.2% to 2.7%) occurred in patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab.
Grade 3 infusion-related reactions were reported in 1 patient (0.2%) with advanced or recurrent solid tumors who received dostarlimab (n = 605) in a multicohort, clinical study. Monitor patients for signs and symptoms of infusion. Interrupt or slow the rate of infusion for mild or moderate infusion related reactions (grade 1 or 2); stop the infusion and permanently discontinue dostarlimab for severe or life-threatening infusion-related reactions (grade 3 or 4).
Immune-mediated musculoskeletal adverse reactions that were reported in less than 1% of patients who received dostarlimab (n = 605) in a multicohort clinical study or that occurred with the use of other PD-1/PD-L1 blocking antibodies include myositis, rhabdomyolysis and associated sequelae including renal failure (unspecified), arthritis, and polymyalgia rheumatica; cases may be severe or fatal. Dostarlimab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids may be necessary. Myalgia occurred in 10% or fewer patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in clinical trials.
Immune-mediated gastrointestinal adverse reactions that were reported in less than 1% of patients who received dostarlimab (n = 605) in a multicohort clinical study or that occurred with the use of other PD-1/PD-L1 blocking antibodies include pancreatitis, including increases in serum amylase (hyperamylasemia) and lipase levels, gastritis, and duodenitis; cases may be severe or fatal. Dostarlimab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids may be necessary. Acute pancreatitis and gastritis were each reported in less than 10% of patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in clinical trials.
Immune-mediated cardiovascular adverse reactions that were reported in less than 1% of patients who received dostarlimab (n = 605) in a multicohort, clinical study or that occurred with the use of other PD-1/PD-L1 blocking antibodies include myocarditis, pericarditis, and vasculitis; cases may be severe or fatal. Dostarlimab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids may be necessary. Permanently discontinue dostarlimab in patients who develop grade 2 or higher myocarditis.
Immune-mediated neurologic adverse reactions that were reported in less than 1% of patients who received dostarlimab (n = 605) in a multicohort clinical study or that occurred with the use of other PD-1/PD-L1 blocking antibodies include meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome, nerve paresis, and autoimmune neuropathy; cases may be severe or fatal. Dostarlimab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids may be necessary.
Immune-mediated ocular adverse reactions that were reported in less than 1% of patients who received dostarlimab (n = 605) in a multicohort clinical study or that occurred with the use of other PD-1/PD-L1 blocking antibodies include uveitis, iritis, and other ocular inflammation toxicity; some cases were associated with retinal detachment. Visual impairment including blindness has also occurred. Consider a diagnosis of Vogt-Koyanagi-Harada syndrome if uveitis occurs in combination with other immune-mediated adverse reactions; systemic corticosteroids may be required to reduce the risk of permanent vision loss. Iridocyclitis and uveitis were reported in less than 10% of patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in clinical studies.
Immune-mediated adverse reactions that were reported in less than 1% of patients who received dostarlimab (n = 605) in a multi-cohort clinical study or that occurred with the use of other PD-1/PD-L1 blocking antibodies include hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, and other transplant rejection including corneal graft rejection; cases may be severe or fatal. Dostarlimab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids may be necessary.
Fatigue including asthenia occurred in 42% to 49% (grade 3 or 4, 3.3% to 3.4%) of patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in a clinical study.
Anemia occurred in 30% to 35% (grade 3 or 4, 11% to 18%) of patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab 2 cohorts of a multicenter, nonrandomized study. The term anemia included decreased hemoglobin level, iron deficiency, and iron deficiency anemia. Decreases from baseline in lymphocytes (lymphopenia) (33% to 46%; grade 3 or 4, 7% to 15%), leukocytes (leukopenia) (18% to 21%; grade 3 or 4, 1.1% to 2%), and neutrophils (neutropenia) (12% to 17%; grade 3 or 4, 1.5% to 2.7%) were also reported in these cohorts. Immune-mediated autoimmune hemolytic anemia and aplastic anemia were each reported in less than 1% of patients who received dostarlimab (n = 605) in a multicohort, clinical study or with the use of other PD-1/PD-L1 blocking antibodies.
Urinary tract infection (19%; grade 3 or 4, 4%) occurred in 1 cohort of patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer who received dostarlimab in a clinical trial; sepsis occurred in 2.6% to 3.3% of patients with dMMR recurrent or advanced endometrial cancer or other solid tumors in this trial.
Rash (14% to 21%; grade 3 or 4, 0.4% or less) and pruritus (15% to 19%; grade 3 or 4, 0.4% to 1.3%) occurred in patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in a clinical trial; the term "rash" included maculopapular rash, erythematous rash, toxic skin eruption, and pemphigoid.
Electrolyte abnormalities have been reported with dostarlimab therapy including hyponatremia, hypomagnesemia, hypokalemia, hyperkalemia, hypercalcemia, hypermagnesemia, and hypocalcemia. Decreases from baseline in sodium (21% to 29%; grade 3 or 4, 4.9% to 5%), magnesium (16% to 28%; grade 3 or 4, 1.1% to 2%), and potassium (14% to 22%; grade 3 or 4, 1.1% to 2%), as well as an increase from baseline in calcium (6% to 8%; grade 3 or 4, 1.1% to 2%) occurred in patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in clinical trial. Additionally, increases from baseline in potassium (14%; grade 3 or 4, 1.1%) and magnesium (4.1%; grade 3 or 4, 1.5%) and a decrease from baseline in calcium (2.6%; grade 3 or 4, 1.5%) were reported in 1 cohort of this trial.
Antibody formation was reported in 2.1% of patients who received dostarlimab at the recommended dosage (n = 384); 1% of patients developed neutralizing antibodies. The impact of antibody formation on the efficacy or safety of dostarlimab is unknown.
Fatal and serious adverse events occurred in patients who received an allogeneic hematopoietic stem-cell transplant (HSCT) prior to and after treatment with a PD-1/PD-L1 blocking antibody, such as dostarlimab. Monitor patients closely for evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause); treat adverse events promptly. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.
Fever (12% to 13%) and chills (less than 10%) were reported in patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer or other solid tumors who received dostarlimab in a clinical trial.
Grade 3 type 1 diabetes mellitus occurred in 0.2% of patients with advanced or recurrent solid tumors treated with dostarlimab in a multicohort clinical trial (n = 605). Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Dostarlimab therapy may need to be interrupted or discontinued depending on the severity of hyperglycemia; administer insulin as clinically indicated.
Immune-mediated reactions, which may be severe or fatal, can occur in patients treated with drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), thus removing inhibition of the immune response, such as dostarlimab. Use dostarlimab with caution in patients who have autoimmune disease. Immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system simultaneously. Although usually occurring during treatment with PD-1/PD-L1 inhibitors, immune-mediated reactions can occur at any time after starting therapy including after discontinuation of therapy. Because early identification and management is critical to safe usage of PD-1/PD-L1 inhibitors, closely monitor patients for signs and symptoms that may be clinical manifestations of underlying immune-mediated reactions. Initiate an appropriate workup to exclude alternative etiologies including infection in cases of suspected immune-mediated reaction. Begin medical management promptly, including specialty consultation as appropriate. An interruption or discontinuation of dostarlimab therapy may be necessary, depending on the severity of the reaction. In general, if an interruption or discontinuation of therapy is necessary, administer systemic corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent); upon improvement to grade 1 or less, begin a steroid taper over at least 1 month. Consider additional systemic immunosuppression in patients whose symptoms are not controlled with corticosteroid therapy.
Immune-mediated pneumonitis has been reported with dostarlimab therapy. The incidence of pneumonitis with other PD-1/PD-L1 inhibitors is higher in patients who have received prior thoracic radiation therapy. Use dostarlimab with caution in patients with pre-existing pulmonary disease. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, dostarlimab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary.
Immune-mediated colitis has been reported with dostarlimab therapy. Additionally, cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Dostarlimab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
Immune-mediated hepatitis has been reported with dostarlimab therapy. Monitor hepatic function at baseline and periodically during treatment. Dostarlimab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary.
Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with dostarlimab. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Hold dostarlimab if the patient is not clinically stable; administer appropriate treatment (e.g., hormone replacement therapy).
Dostarlimab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Hold dostarlimab if the patient is not clinically stable; administer appropriate treatment.
Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, has been reported in 1 patient treated with dostarlimab and has also occurred with PD-1/PD-L1 inhibitors. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Dostarlimab therapy may need to be interrupted or discontinued depending on the severity of hyperglycemia; administer insulin as clinically indicated.
Immune-mediated interstitial nephritis has been reported with dostarlimab therapy; renal failure may occur. Monitor renal function at baseline and periodically during treatment. Dostarlimab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.
Immune-mediated serious rash, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with PD-1/PD-L1 inhibitors. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-bullous/exfoliative rashes. Dostarlimab therapy may need to be interrupted or discontinued depending on the rash severity; treatment with systemic corticosteroids may also be necessary.
Severe infusion-related reactions have occurred with dostarlimab. Monitor patients for signs and symptoms of infusion reactions including fever, chills, wheezing, pruritus, rash, and flushing. Interrupt or slow the rate of infusion for mild or moderate infusion related reactions (grade 1 or 2); stop the infusion and permanently discontinue dostarlimab for severe or life-threatening infusion-related reactions (grade 3 or 4).
Immune-mediated neurotoxicity has been reported with dostarlimab or other PD-1/PD-L1 inhibitors. Dostarlimab may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.
Fatal and other serious complications including hyperacute, acute, and chronic graft-versus-host-disease, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and a steroid-requiring febrile syndrome (without an identified infectious cause) have been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Therefore, perform a risk/benefit analysis prior to starting treatment with a PD-1/PD-L1 blocking antibody, such as dostarlimab, in patients who may receive or who have a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic SCT.
Based on its mechanism of action, dostarlimab may cause fetal harm if administered during pregnancy by increasing the risk of immune-mediated rejection of the developing fetus; increasing the risk of developing immune-related disorders or altering the normal immune response in the fetus is also possible. Human IgG4 immunoglobulins are known to cross the placenta; therefore, there may be drug exposure to the developing fetus. If dostarlimab is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. The programmed death receptor-1 (PD-1)/PD-1 ligand (PDL-1) pathway helps to preserve pregnancy by maintaining maternal tolerance to the fetus. Inhibiting PD-1/PDL-1 binding and signaling led to an increase in fetal loss in murine models. Potential risks for blocking the PD-1/PDL-1 pathway include an increased incidence of abortion or stillbirths.
Counsel patients about the reproductive risk and contraception requirements during dostarlimab therapy. Pregnancy testing should be performed prior to starting dostarlimab in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 4 months after dostarlimab therapy. Women who become pregnant while receiving dostarlimab should be apprised of the potential hazard to the fetus.
Because of the potential for adverse reactions in nursing children from dostarlimab, women should avoid breast-feeding during dostarlimab therapy and for 4 months after the last dose. Maternal IgG is known to be present in human milk. It is not known if dostarlimab is secreted in human milk or if it has effects on the breast-fed child or on milk production. The effects of any local gastrointestinal exposure and limited systemic exposure to dostarlimab in breast-fed children are unknown.
For the treatment of mismatch repair deficient (dMMR) endometrial cancer:
NOTE: Select patients for treatment based on the presence of dMMR in the tumor specimen. Information on FDA-approved tests for the detection of dMMR status is available at www.fda.gov/companiondiagnostics.
-for the treatment of dMMR recurrent or advanced endometrial cancer that progressed on or following treatment with a platinum-containing regimen in any setting, in patients who are not candidates for curative surgery or radiation:
Intravenous dosage:
Adults: 500 mg IV every 3 weeks for 4 doses; starting 3 weeks after the fourth dose, give 1,000 mg IV every 6 weeks until disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. In an interim efficacy analysis, the overall response rate was 45.4% (complete response, 15.6%) in 141 patients with dMMR recurrent or advanced endometrial cancer with disease progression during or after treatment with a platinum-containing chemotherapy regimen who received dostarlimab in a multicenter, multicohort, phase 1 study (the GARNET trial). At a median follow-up of 27.9 months, the median duration of response had not been reached; 85.9% of patients had a response duration of at least 12 months, and 54.7% of patients had a response duration of at least 24 months.
-for the treatment of dMMR or microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer, in combination with carboplatin and paclitaxel following by single agent therapy:
NOTE: Select patients for treatment based on the presence of dMMR/MSI-H in the tumor specimen. There is currently not an FDA-approved test for the detection of MSI-H.
Intravenous dosage:
Adults: 500 mg IV every 3 weeks in combination with carboplatin (AUC of 5 on day 1) and paclitaxel (175 mg/m2 on day 1) for 6 doses; administer dostarlimab prior to chemotherapy on day 1 of each cycle. Starting 3 weeks after the sixth dose, give single-agent dostarlimab 1,000 mg IV every 6 weeks until disease progression or for up to 3 years. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. At a median follow-up time of approximately 25 months in a randomized, double-blind, phase 3 (RUBY) trial, the 24-month investigator-assessed progression-free survival rates were significantly higher in the dostarlimab plus carboplatin and paclitaxel arm compared with the placebo plus carboplatin and paclitaxel arm in patients with primary advanced or recurrent endometrial cancer in the overall study population (n = 494; 36.1% vs. 18.1%; hazard ratio (HR) = 0.64; 95% CI, 0.51 to 0.8) and in a subpopulation of 118 patients with dMMR/MSI-H tumors (61.4% vs. 15.7%; HR = 0.28; 95% CI, 0.16 to 0.5). At the time of this interim analysis, the 24-month overall survival rates were also significantly improved in patients who received dostarlimab compared with placebo in the overall (71.3% vs. 56%; HR = 0.64; 95% CI, 0.46 to 0.87) and dMMR/MSI-H tumor subgroup (83.3% vs. 58.7%; HR = 0.3; 95% CI, 0.13 to 0.7) populations. In the overall population, 54.7% of patients had endometrioid carcinoma-type endometrial cancer, 47.8% of patients had recurrent disease, and 82.6% had not received external pelvic radiation.
For the treatment of mismatch repair deficient solid tumors:
-for the treatment of mismatch repair deficient (dMMR) solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options:
NOTE: Select patients for treatment based on the presence of dMMR in the tumor specimen. Information on FDA-approved tests for the detection of dMMR status is available at www.fda.gov/companiondiagnostics.
Intravenous dosage:
Adults: 500 mg IV every 3 weeks for 4 doses; starting 3 weeks after the fourth dose, give 1,000 mg IV every 6 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. The overall response rate to dostarlimab was 41.6% (complete response, 9.1%) in patients with progressive, advanced, dMMR solid tumors and no satisfactory alternative treatment options in a multicenter, nonrandomized, multicohort trial (GARNET). The median duration of response was 34.7 months, with 95.4% of patients sustaining a response for at least 6 months.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Immune-Mediated Reactions
NOTE: Corticosteroid therapy consists of prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less. Consider starting other systemic immunosuppressants if toxicity is not controlled by corticosteroids. Permanently discontinue dostarlimab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Colitis
Grade 2 or 3 toxicity: Hold dostarlimab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 4 toxicity: Permanently discontinue dostarlimab and administer corticosteroids.
Endocrinopathies (including Type 1 diabetes, Hypophysitis, Hypothyroidism, Hyperthyroidism, and Adrenal Insufficiency)
Grade 2, 3, or 4 toxicity: Hold dostarlimab therapy; administer appropriate treatment (e.g., hormone replacement therapy, corticosteroids, insulin). Resume therapy or permanently discontinue treatment when the patient is clinically stable, depending on the severity of the reaction.
Exfoliative Skin Reactions
Suspected Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS): Hold dostarlimab and administer corticosteroids as applicable.
Confirmed SJS, TEN, or DRESS: Permanently discontinue dostarlimab and administer corticosteroids.
Infusion-Related Reactions
Grade 1 or 2 toxicity: Hold dostarlimab or slow the infusion rate.
Grade 3 or 4 toxicity: Permanently discontinue dostarlimab.
Myocarditis
Grade 2, 3, or 4 toxicity: Permanently discontinue dostarlimab and administer corticosteroids.
Neurologic Toxicity
Grade 2 toxicity: Hold dostarlimab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 3 or 4 toxicity: Permanently discontinue dostarlimab and administer corticosteroids.
Pneumonitis
Grade 2 toxicity: Hold dostarlimab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. If grade 2 toxicity recurs, permanently discontinue dostarlimab.
Grade 3 or 4 toxicity: Permanently discontinue dostarlimab and administer corticosteroids.
Other Immune-Mediated Adverse Reactions
Grade 3 toxicity: Hold dostarlimab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Recurrent grade 3 toxicity that requires treatment with systemic immunosuppressants: Permanently discontinue dostarlimab.
Grade 4 toxicity: Permanently discontinue dostarlimab and administer corticosteroids.
Maximum Dosage Limits:
-Adults
500 mg IV every 3 weeks OR 1,000 mg IV every 6 weeks.
-Geriatric
500 mg IV every 3 weeks OR 1,000 mg IV every 6 weeks.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Treatment-Related Immune-Mediated Hepatitis
No Tumor Involvement of the Liver
AST or ALT level of more than 3 to 8 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold dostarlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue dostarlimab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
AST or ALT level more than 8 times the ULN or a total bilirubin level more than 3 times the ULN: Permanently discontinue dostarlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
Tumor Involvement of the Liver
Baseline AST or ALT level at the ULN or less: Hold or permanently discontinue dostarlimab based on recommendations for hepatitis with no tumor involvement of the liver.
Baseline AST or ALT level of more than 1 to 3 times the ULN
AST or ALT level of more than 5 to 10 times the ULN: Hold dostarlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue dostarlimab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Baseline AST or ALT level of more than 3 to 5 times the ULN
AST or ALT level of more than 8 to 10 times the ULN: Hold dostarlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue dostarlimab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Any Baseline AST or ALT level
AST or ALT level more than 10 times the ULN or a total bilirubin level to more than 3 times the ULN: Permanently discontinue dostarlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
Patients with Renal Impairment Dosing
Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction
Grade 2 or 3 increased serum creatinine (SCr) level: Hold dostarlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue dostarlimab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Grade 4 increased SCr level: Permanently discontinue dostarlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Dostarlimab is a recombinant humanized immunoglobulin G4 monoclonal antibody that binds to the programmed death receptor-1 (PD-1) found on T-cells and blocks the interaction of PD ligand-1 (PD-L1) and PD-L2 with PD-1 on the tumor cell. Blocking the PD-1/PD-L1 pathway improves the anti-tumor immune response by reducing the immunosuppressive signals between immune cells and tumor cells that cause inhibition of T-cell proliferation and cytokine production. In mice models, dostarlimab inhibited PD-1 activity resulting in decreased tumor growth. Additionally, mismatch repair deficient (dMMR) endometrial tumors may have higher response rates with immunotherapy, including PD-1 inhibitors such as dostarlimab.
Dostarlimab is administered intravenously. It has a mean volume of distribution at steady state of approximately 5.8 L (coefficient of variation (CV), 15%). The steady-state clearance of dostarlimab was 0.007 L/hour (CV, 30%) and the mean terminal elimination half-life was 23.5 days in patients with various solid tumors, including 546 patients with endometrial cancer. Dostarlimab is metabolized via catabolic pathways into small peptides and amino acids.
-Route-Specific Pharmacokinetics
Intravenous Route
The pharmacokinetics of dostarlimab increase proportionally over the dose range of 1 to 10 mg/kg IV. When given as a single-agent, the mean cycle 1 Cmax and AUC(0-tau) values were 171 mcg/mL (coefficient of variation (CV), 20%) and 35,730 mcg X hour/mL (CV, 20%), respectively, following dostarlimab 500 mg IV given once every 3 weeks and 309 mcg/mL (CV, 31%) and 95,820 mcg X hour/mL (CV, 29%), respectively, following dostarlimab 1,000 mg IV given once every 6 weeks. Exposures were similar to single agent dostarlimab when it was given in combination with carboplatin and paclitaxel.
-Special Populations
Hepatic Impairment
Mild (total bilirubin level more than 1 to 1.5 times the ULN or AST level more than the ULN) or moderate (total bilirubin level more than 1.5 to 3 times the ULN and any AST level) hepatic impairment has no clinically significant impact on the pharmacokinetic parameters of dostarlimab.
Renal Impairment
Renal impairment has no clinically significant impact on the pharmacokinetic parameters of dostarlimab.
Geriatric
Age (range, 24 to 86 years) has no clinically significant impact on the pharmacokinetic parameters of dostarlimab.
Gender Differences
Gender has no clinically significant impact on the pharmacokinetic parameters of dostarlimab.
Ethnic Differences
Race/ethnicity (White [75%], Asian [2%], and African American [5%] patients) has no clinically significant impact on the pharmacokinetic parameters of dostarlimab.
Other
Tumor Type
The type of cancer has no clinically significant impact on the pharmacokinetic parameters of dostarlimab.