Dostarlimab-gxly (Monograph)

Brand name: Jemperli
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on May 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody.

Uses for Dostarlimab-gxly

Endometrial Cancer

Single agent: Treatment of adults with mismatch repair deficiency (dMMR) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen in any setting and are not candidates for curative surgery or radiation.

Combination therapy: Used with carboplatin and paclitaxel, followed by dostarlimab-gxly as a single agent, for the treatment of adults with primary advanced or recurrent endometrial cancer that is dMMR or microsatellite instability-high (MSI-H). FDA-approved test for detection of MSI-H is not currently available.

Solid Tumors

Treatment of adults with dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment and for which there are no satisfactory alternative treatment options.

Accelerated approval based on tumor response rate and durability of response. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Rectal Cancer

Based on current evidence, dostarlimab-gxly as neoadjuvant therapy for adult patients with locally advanced, dMMR/MSI-H rectal cancer^{† [off-label]} has Level 2 (moderate strength/quality) evidence supporting its use and is a reasonable choice (accepted, with possible conditions) in this setting. Currently available data show a complete clinical response to dostarlimab-gxly therapy in 100% of patients, with none requiring chemoradiotherapy or surgery and no grade 3 or 4 adverse events observed. However, the number of patients enrolled in the only prospective, single-center, phase 2 study is small (n=23) and data on survival and the duration of complete response are not available to date.

Dostarlimab-gxly Dosage and Administration

General

Pretreatment Screening

Prior to initiating therapy as a single agent, confirm deficient mismatch repair (dMMR) tumor status with an FDA-approved diagnostic test.
Prior to initiating combination therapy with carboplatin and paclitaxel, confirm presence of dMMR/microsatellite instability-high (MSI-H) in tumor specimens.
Confirm pregnancy status of females of reproductive potential prior to initiation of therapy.
Evaluate liver function tests, serum creatinine concentrations, and thyroid function tests at baseline.

Patient Monitoring

Monitor patients closely for manifestations of underlying immune-mediated adverse effects.
Evaluate and monitor liver enzymes, serum creatinine concentrations, and thyroid function tests periodically during treatment.
Monitor patients for signs and symptoms of infusion-related reactions.
Monitor patients for hyperglycemia or other manifestations of diabetes mellitus.

Administration

IV Administration

Administer by IV infusion after dilution. Do not administer as rapid (bolus) injection.

Do not co-administer with other drugs through the same infusion line.

Dilution

Must dilute injection concentrate prior to administration. Visually inspect vials for discoloration or particulates prior to dilution. Undiluted solutions should be clear to slightly opalescent, and colorless to yellow; do not use if visible particles are observed.

To prepare a 500-mg dose: Withdraw 10 mL of dostarlimab-gxly solution from a vial using a polypropylene sterile syringe; dilute in an IV infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection to a final concentration of 2–10 mg/mL (maximum 250 mL).

To prepare a 1000-mg dose: Withdraw 10 mL of dostarlimab-gxly solution from each of 2 vials (20 mL total) using a polypropylene sterile syringe; dilute in an IV infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection to a final concentration of 4–10 mg/mL (maximum 250 mL).

Dostarlimab is compatible with an infusion bag made of polyolefin, ethylene vinyl acetate, or polyvinyl chloride with di(2-ethylhexyl) phthalate (DEHP).

Do not shake diluted solution; mix by gentle inversion. Discard any unused portion of vial.

Rate of Administration

Administer by IV infusion over 30 minutes.

Dosage

Adults

Endometrial Cancer

IV infusion

Monotherapy: 500 mg every 3 weeks for the first 4 doses, followed by 1000 mg every 6 weeks (starting 3 weeks after fourth dose).

Continue therapy until disease progression or unacceptable toxicity occurs.

Combination therapy: 500 mg every 3 weeks for 6 doses followed by 1000 mg as monotherapy every 6 weeks. Initial 6 doses are given in combination with carboplatin and paclitaxel. Administer prior to carboplatin and paclitaxel when administered on the same day. Continue therapy until disease progression, unacceptable toxicity occurs, or for up to 3 years.

Solid Tumors

IV infusion

500 mg every 3 weeks for the first 4 doses, followed by 1000 mg every 6 weeks (starting 3 weeks after fourth dose).

Continue therapy until disease progression or unacceptable toxicity occurs.

Rectal Cancer

IV Infusion

When used as neoadjuvant therapy for adult patients with dMMR/MSI-H locally advanced rectal cancer^{† [off-label]}, administer 500 mg every 3 weeks for 6 months (9 cycles).

Dosage Modification for Toxicity

Some adverse effects require temporary interruption or discontinuance of therapy (see Table 1).

Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce corticosteroid dosage to <10 mg of prednisone daily (or equivalent) within 12 weeks of initiating steroids.

If AST and ALT ≤ ULN at baseline in patients with liver involvement, withhold or permanently discontinue based on recommendations for hepatitis with no liver involvement.

Table 1. Recommended Dosage Modifications for Dostarlimab-gxly Toxicity1
Adverse Reaction	Dosage Modification
Pneumonitis	Grade 2: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid taper Grade 3 or 4 or recurrent grade 2: Permanently discontinue therapy
Colitis	Grade 2 or 3: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid taper Grade 4: Permanently discontinue therapy
Hepatitis with no tumor involvement of the liver	AST or ALT elevations >3 times but ≤8 times the upper limit of normal (ULN) or total bilirubin concentrations >1.5 but ≤3 times the ULN: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid taper AST or ALT elevations >8 times the ULN or total bilirubin concentrations >3 times the ULN: Permanently discontinue therapy
Hepatitis with tumor involvement of the liver	Baseline AST or ALT >1 but ≤ 3 times the ULN and increases to >5 but ≤ 10 times the ULN or baseline AST or ALT >3 but ≤5 times the ULN and increases to >8 but ≤10 times the ULN: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid taper AST or ALT elevations >10 times the ULN or total bilirubin concentrations >3 times the ULN: Permanently discontinue therapy
Endocrinopathies	Grade 2, 3, or 4: Withhold therapy until clinically stable or permanently discontinue, depending on severity; may resume after recovery to grade 0 to 1 and completion of corticosteroid taper
Nephritis with renal dysfunction	Grade 2 or 3 increased serum creatinine concentrations: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid taper Grade 4 increased serum creatinine concentrations: Permanently discontinue therapy
Exfoliative dermatologic conditions	Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS): Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid taper Confirmed SJS, TEN, or DRESS: Permanently discontinue therapy
Myocarditis	Grade 2, 3, or 4: Permanently discontinue therapy
Neurologic toxicities	Grade 2: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid taper 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

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.

Renal Impairment

Manufacturer makes no specific dosage recommendations.

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

Cautions for Dostarlimab-gxly

Contraindications

None.

Warnings/Precautions

Immune-mediated Adverse Reactions

Severe and fatal immune-mediated adverse reactions can occur at any time in any organ system or tissue. Early identification and management essential to ensure safe use.

If an immune-mediated adverse effect is suspected, evaluate patient to exclude alternative etiologies including infection.

Withhold or permanently discontinue treatment depending on severity and promptly initiate appropriate management. If dose interruption or discontinuation required, administer systemic corticosteroids (1–2 mg/kg/day prednisone or equivalent) until improvement to ≤grade 1 and then initiate and continue a corticosteroid taper over at least 1 month.

Consider administration of other systemic immunosuppressants if reaction not controlled with corticosteroids.

Permanently discontinue therapy if no partial or complete resolution within 12 weeks of steroid initiation or if unable to decrease corticosteroid dosage to <10 mg of prednisone daily (or equivalent) within 12 weeks of steroid initiation.

Immune-mediated Pneumonitis

Immune-mediated pneumonitis, sometimes fatal, reported. Risk appears to be higher in patients who received prior thoracic radiation.

Withhold or permanently discontinue drug depending on severity.

Immune-mediated Colitis

Immune-mediated colitis reported.

Withhold or permanently discontinue drug depending on severity.

Immune-mediated Hepatitis

Immune-mediated hepatitis, sometimes fatal, reported.

Withhold or permanently discontinue drug depending on severity.

Immune-mediated Endocrinopathies

Immune-mediated endocrinopathies (e.g., hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, thyroiditis, diabetes mellitus) reported.

Monitor for manifestations of adrenal insufficiency. In patients with grade 2 or higher adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated. Withhold or permanently discontinue drug depending on severity.

Monitor for hypophysitis; symptoms may include headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue drug depending on severity.

Evaluate thyroid function prior to initiation of therapy and periodically during therapy. Initiate hormone replacement or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue drug depending on severity.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue drug depending on severity.

Immune-mediated Nephritis with Renal Dysfunction

Immune-mediated nephritis reported. Evaluate serum creatinine concentrations prior to initiation of therapy and periodically during therapy.

Depending on severity, interrupt or discontinue therapy.

Immune-mediated Dermatologic Adverse Reactions

Immune-mediated rash or dermatitis including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS) reported. Administration of topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rash. Withhold or permanently discontinue therapy depending on severity.

Other Immune-Mediated Adverse Reactions

Other immune-mediated adverse reactions affecting any organ system or tissue (including solid organ transplant rejection) have occurred; some reactions were severe or fatal.

Depending on severity, interrupt or discontinue therapy.

Infusion-related Reactions

Severe or life-threatening infusion-related reactions reported.

Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion or permanently discontinue the drug based on severity of the reaction.

Complications of Allogeneic HSCT

Serious complications reported in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after treatment with dostarlimab. Complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause).

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider benefits versus risks of treatment with a PD-1/PD-L1-blocking antibody prior to or after an allogeneic HSCT.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death.

Avoid pregnancy during therapy. Confirm pregnancy status prior to initiation of therapy in women of childbearing potential. Such women should use effective contraception during therapy and for at least 4 months after drug discontinuance.

Immunogenicity

Treatment-emergent anti-drug antibodies (ADAs) and neutralizing antibodies reported in the GARNET study. In the RUBY study, there was no formation of treatment-emergent ADAs or neutralizing antibodies.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether dostarlimab is distributed into human milk or if the drug has any effect on milk production or the nursing infant. Maternal IgG present in human milk. Effects of local GI exposure and limited systemic exposure in the breastfed child to dostarlimab unknown. Women should not breast-feed while receiving the drug and for 4 months after the drug is discontinued.

Females and Males of Reproductive Potential

Fertility studies not performed with dostarlimab. Women of childbearing potential should use effective contraception during treatment and for 4 months after the last dose.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No clinically important differences in safety or effectiveness observed between geriatric patients and younger adults.

Hepatic Impairment

No clinically significant pharmacokinetic differences observed based on mild to moderate hepatic impairment.

Renal Impairment

No clinically significant pharmacokinetic differences observed based on renal impairment.

Common Adverse Effects

Most common adverse reactions (≥20%) as a single agent in patients with dMMR solid tumors are fatigue/asthenia, nausea, diarrhea, anemia.

Most common adverse reactions (≥20%) as combination therapy in patients with dMMR/MSI-H endometrial cancer are rash, diarrhea, hypothroidism, hypertension.

Drug Interactions

When dostarlimab is administered in combination with carboplatin and paclitaxel, no evidence to suggest a clinically relevant change of dostarlimab clearance over time was observed and exposure was comparable to dostarlimab administration as a single agent.

Dostarlimab-gxly Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations and systemic exposure are dose proportional over the dose range of 1–10 mg/kg.

Exposures of dostarlimab-gxly given in combination with carboplatin and paclitaxel and as a single agent were comparable.

Distribution

Extent

Not known whether dostarlimab is distributed into breast milk.

Elimination

Metabolism

Metabolized principally by catabolic pathways into small peptides and amino acids.

Half-life

Mean half-life is 23.5 days.

Stability

Storage

Parenteral

Injection for IV Infusion

2–8°C in original carton to protect from light.

Diluted solution can be stored at room temperature for up to 6 hours after dilution (including infusion time) or under refrigeration (2–8°C) for up to 24 hours after dilution (including infusion time); if refrigerated, allow solution to come to room temperature prior to administration.

Actions

A humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody.
Overexpression of PD-1 ligands on surface of tumor cells results in activation of PD-1 activity and suppression of cytotoxic T-cell activity.
Binds to the PD-1 receptor on T cells, which blocks interaction with PD-1 ligands (PD-L1 and PD-L2) and prevents PD-1 pathway mediated inhibition of the immune response.
Anti-tumor activity is focused on preventing inhibition of active T cell immune surveillance of tumors.

Advice to Patients

Instruct patients to read the FDA-approved patient labeling.
Risk of immune-mediated adverse reactions (e.g., pneumonitis, colitis, hepatitis, immune-mediated endocrinopathies, nephritis, severe skin reactions, other immune-mediated adverse reactions involving any organ system). Advise patients that these reactions may be severe or fatal, may require the interruption or discontinuation of dostarlimab, and may require corticosteroid or other treatment.
Risk of pneumonitis; advise patients to contact their healthcare provider immediately if new or worsening cough, chest pain, or shortness of breath occurs.
Risk of colitis; advise patients to contact their healthcare provider immediately if diarrhea or severe abdominal pain occurs.
Risk of hepatitis; advise patients to contact their healthcare provider immediately if jaundice, severe nausea or vomiting, or easy bruising or bleeding occurs.
Risk of immune-mediated endocrinopathies: advise patients to contact their healthcare provider immediately if any signs or symptoms of hypothyroidism, hyperthyroidism, thyroiditis, adrenal insufficiency, hypophysitis, or type 1 diabetes mellitus occurs.
Risk of nephritis; advise patients to contact their healthcare provider immediately if any signs or symptoms of nephritis occur.
Risk of severe skin reactions; advise patients to contact their healthcare provider immediately if any signs or symptoms of severe skin reactions, including Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), occur.
Advise patients that other immune-mediated adverse reactions can occur and may involve any organ system (including solid organ transplant rejection), and to contact their healthcare provider immediately for any new signs or symptoms.
Risk of infusion-related reactions. Advise patients to notify their clinician if any signs or symptoms occur.
Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise females of reproductive potential to use effective contraception during treatment with dostarlimab and for 4 months after the last dose.
Advise women to avoid breast-feeding during treatment with dostarlimab and for 4 months after the last dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.
Advise patients to inform their clinician of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.