Jemperli

 Endometrial Cancer

JEMPERLI, in combination with carboplatin and paclitaxel, followed by JEMPERLI as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer (EC).

JEMPERLI, as a single agent, is indicated for the treatment of adult patients with mismatch repair deficient (dMMR) recurrent or advanced EC, as determined by an FDA-approved test, 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 [see Dosage and Administration ].

 Mismatch Repair Deficient Recurrent or Advanced Solid Tumors

JEMPERLI, as a single agent, is indicated for the treatment of adult patients with dMMR recurrent or advanced solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options [see Dosage and Administration ]. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

 Patient Selection

Single Agent

Select patients for treatment with JEMPERLI as a single agent based on the presence of dMMR in tumor specimens in:

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recurrent or advanced EC [see Clinical Studies ].

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recurrent or advanced solid tumors [see Clinical Studies ].

Information on FDA-approved tests for the detection of dMMR status is available at https://www.fda.gov/companiondiagnostics.

Because the effect of prior chemotherapy on test results for dMMR in patients with high-grade gliomas is unclear, it is recommended to test for this marker in the primary tumor specimen obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas.

 Recommended Dosage

The recommended dosage for JEMPERLI is presented in Table 1.

 Dosage Modifications for Adverse Reactions

No dose reductions of JEMPERLI are recommended. In general, withhold JEMPERLI for severe (Grade 3) immune‑mediated adverse reactions. Permanently discontinue JEMPERLI 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 of prednisone equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for JEMPERLI for adverse reactions that require management different from these general guidelines are summarized in Table 2.

 Preparation and Administration

Preparation for Intravenous Infusion

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Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to yellow. Discard the vial if visible particles are observed.

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Do not shake.

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

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For the 500-mg dose, withdraw 10 mL of JEMPERLI from a vial using a disposable sterile syringe made of polypropylene and dilute into an intravenous infusion bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration between 2 to 10 mg/mL (maximum 250 mL).

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For the 1,000-mg dose, withdraw 10 mL from each of 2 vials (withdraw 20 mL total) and dilute into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration between 4 to 10 mg/mL (maximum 250 mL).

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Mix diluted solution by gentle inversion. Do not shake.

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Discard any unused portion left in the vial.

Storage of Infusion Solution

Store in the original carton until time of preparation in order to protect from light. The prepared dose may be stored either:

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At room temperature for no more than 6 hours from the time of preparation until the end of infusion.

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Under refrigeration at 2°C to 8°C (36ºF to 46ºF) for no more than 24 hours from time of preparation until end of infusion. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Discard after 6 hours at room temperature or after 24 hours under refrigeration.

Do not freeze.

Administration

Administer infusion solution intravenously over 30 minutes through an intravenous 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.

JEMPERLI must not be administered as an intravenous push or bolus injection. Do not co‑administer other drugs through the same infusion line.

 Pregnancy

Risk Summary

Based on its mechanism of action, JEMPERLI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ]. There are no available data on the use of JEMPERLI in pregnant women. 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 (see ). Human IgG4 immunoglobulins (IgG4) are known to cross the placental barrier; therefore, dostarlimab-gxly has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data: Animal reproduction studies have not been conducted with JEMPERLI to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering JEMPERLI during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to dostarlimab-gxly may increase the risk of developing immune-mediated disorders or altering the normal immune response.

 Lactation

Risk Summary

There is no information regarding the presence of dostarlimab-gxly in human milk or its effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to JEMPERLI are unknown. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment and for 4 months after the last dose of JEMPERLI.

 Females and Males of Reproductive Potential

JEMPERLI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating JEMPERLI [see Use in Specific Populations ].

Contraception

Females: Advise females of reproductive potential to use effective contraception during treatment with JEMPERLI and for 4 months after the last dose.

 Pediatric Use

The safety and efficacy of JEMPERLI have not been established in pediatric patients.

 Geriatric Use

In Combination with Carboplatin and Paclitaxel

Of the 241 patients treated with JEMPERLI in RUBY, 52.3% were younger than 65 years, 36.5% were aged 65 through 74 years, and 11.2% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

As a Single Agent

Of the 605 patients treated with JEMPERLI in GARNET, 51.6% were younger than 65 years, 36.9% were aged 65 through 74 years, and 11.5% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

 Severe and Fatal Immune-Mediated Adverse Reactions

JEMPERLI is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance, and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed in WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune‑mediated reactions.

Immune-mediated adverse reactions, which can be severe or fatal, can occur in any organ system or tissue. Immune‑mediated adverse reactions can occur at any time after starting a PD-1/PD-L1–blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1–blocking antibodies, they can also manifest after discontinuation of PD-1/PD-L1–blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD‑1/PD‑L1–blocking antibodies. Monitor closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function tests at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration ]. In general, if JEMPERLI requires interruption or discontinuation, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroids.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies, dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

JEMPERLI can cause immune-mediated pneumonitis, which can be fatal. In patients treated with other PD-1/PD-L1–blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

Immune-mediated pneumonitis occurred in 2.3% (14/605) of patients receiving JEMPERLI, including Grade 2 (1.3%), Grade 3 (0.8%) and Grade 4 (0.2%) pneumonitis. Pneumonitis led to discontinuation of JEMPERLI in 1.3% of patients.

Systemic corticosteroids were required in 79% (11/14) of patients with pneumonitis. Pneumonitis resolved in 11 of the 14 patients. JEMPERLI was withheld for 9 patients. Five patients reinitiated JEMPERLI after symptom improvement; of these, 2 patients had recurrence of pneumonitis.

Immune-Mediated Colitis

JEMPERLI can cause immune-mediated colitis. Cytomegalovirus infection/reactivation have occurred in patients with corticosteroid-refractory immune-mediated colitis treated with PD-1/PD-L1–blocking antibodies. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated colitis occurred in 1.3% (8/605) of patients receiving JEMPERLI, including Grade 2 (0.7%) and Grade 3 (0.7%) adverse reactions. Colitis led to discontinuation of JEMPERLI in 1 (0.2%) patient.

Systemic corticosteroids were required in 75% (6/8) of patients with colitis. Colitis resolved in 5 of the 8 patients. Of the 4 patients in whom JEMPERLI was withheld for colitis, all reinitiated treatment with JEMPERLI; of these, 1 patient had recurrence of colitis.

Immune-Mediated Hepatitis

JEMPERLI can cause immune-mediated hepatitis, which can be fatal.

Immune-mediated hepatitis occurred in 0.5% (3/605) of patients receiving JEMPERLI, all were Grade 3. Hepatitis led to discontinuation of JEMPERLI in 1 (0.2%) patient. Systemic corticosteroids were required in 2 patients with hepatitis and the events resolved in 2 of the 3 patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency: JEMPERLI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration ].

Adrenal insufficiency occurred in 1.2% (7/605) patients receiving JEMPERLI, including Grade 2 (0.5%) and Grade 3 (0.7%). Adrenal insufficiency resulted in discontinuation in 1 (0.2%) patient and resolved in 4 of the 7 patients. Of the 4 patients in whom JEMPERLI was withheld for adrenal insufficiency, all reinitiated treatment with JEMPERLI. Systemic corticosteroids were required in 5 of the 7 patients with adrenal insufficiency.

Hypophysitis: JEMPERLI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration ].

          JEMPERLI in Combination with Carboplatin and Paclitaxel: Hypophysitis (Grade 3) occurred in 0.4% (1/241) of patients receiving JEMPERLI in combination with carboplatin and paclitaxel. Systemic corticosteroids were required, and the event resolved. JEMPERLI was withheld and the patient reinitiated treatment.

          JEMPERLI as a Single Agent: Hypophysitis (Grade 2) occurred in 0.2% (1/605) of patients receiving JEMPERLI as a single agent. Systemic corticosteroids were required, and the event did not resolve. JEMPERLI was withheld and the patient reinitiated treatment.

Thyroid Disorders: JEMPERLI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate thyroid hormone replacement or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration ].

Thyroiditis: Thyroiditis occurred in 0.5% (3/605) of patients receiving JEMPERLI; all were Grade 2. Systemic corticosteroids were required in 1 of 3 patients and anti-thyroid therapy was required for 2 of 3 patients with thyroiditis. JEMPERLI was withheld for 1 patient and the patient reinitiated treatment. None of the events of thyroiditis resolved; there were no discontinuations of JEMPERLI due to thyroiditis.

Hypothyroidism: JEMPERLI in Combination with Carboplatin and Paclitaxel: Hypothyroidism occurred in 12% (30/241) of patients receiving JEMPERLI in combination with carboplatin and paclitaxel, all of which were Grade 2. Hypothyroidism led to discontinuation of JEMPERLI in 1 patient and resolved in 23% (7/30) of patients. JEMPERLI was withheld for 5 patients and all reinitiated treatment with JEMPERLI. Thyroid hormone replacement was required for 27 of the 30 patients with hypothyroidism.

          JEMPERLI as a Single Agent: Hypothyroidism occurred in 8% (46/605) of patients receiving JEMPERLI as a single agent, all of which were Grade 2. Hypothyroidism did not lead to discontinuation of JEMPERLI and resolved in 37% (17/46) of patients. JEMPERLI was withheld for 2 patients and both reinitiated treatment. Thyroid hormone replacement therapy was required for 45 of the 46 patients with hypothyroidism.

Hyperthyroidism: JEMPERLI in Combination with Carboplatin and Paclitaxel: Hyperthyroidism occurred in 3.3% (8/241) of patients receiving JEMPERLI in combination with carboplatin and paclitaxel, including Grade 2 (2.9%) and Grade 3 (0.4%). Hyperthyroidism did not lead to discontinuation of JEMPERLI and resolved in 75% (6/8) of patients. JEMPERLI was withheld for 1 patient and the patient reinitiated treatment. Anti-thyroid therapy was required for 2 of the 8 patients while systemic corticosteroids were required for 1 of the 8 patients with hyperthyroidism.

          JEMPERLI as a Single Agent: Hyperthyroidism occurred in 2.3% (14/605) of patients receiving JEMPERLI as a single agent, including Grade 2 (2.1%) and Grade 3 (0.2%). Hyperthyroidism did not lead to discontinuation of JEMPERLI and resolved in 71% (10/14) of the 14 patients. JEMPERLI was withheld for 2 patients and both reinitiated treatment. Anti-thyroid therapy was required for 10 of the 14 patients with hyperthyroidism.

Type 1 Diabetes Mellitus, Which Can Present with Diabetic Ketoacidosis: JEMPERLI can cause type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration ].

          JEMPERLI in Combination with Carboplatin and Paclitaxel: Type 1 diabetes mellitus (Grade 3) occurred in 0.4% (1/241) of patients receiving JEMPERLI in combination with carboplatin and paclitaxel. Type 1 diabetes mellitus led to withholding JEMPERLI; the patient reinitiated treatment and required long-term insulin therapy.

          JEMPERLI as a Single Agent: Type 1 diabetes mellitus occurred in 0.2% (1/605) of patients receiving JEMPERLI as a single agent, which was Grade 3. Type 1 diabetes mellitus did not result in treatment discontinuation and did not resolve.

Immune-Mediated Nephritis with Renal Dysfunction

JEMPERLI can cause immune-mediated nephritis, which can be fatal. Nephritis, including tubulointerstitial nephritis, occurred in 0.5% (3/605) of patients receiving JEMPERLI; all were Grade 2. Nephritis led to discontinuation of JEMPERLI in 1 (0.2%) patient and resolved in all patients. JEMPERLI was withheld for 1 patient and the patient reinitiated treatment. Systemic corticosteroids were required in 2 of the 3 patients experiencing nephritis.

Immune-Mediated Dermatologic Adverse Reactions

JEMPERLI can cause immune-mediated rash or dermatitis. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), have occurred with PD‑1/PD‑L1–blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes. Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration ].

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred in <1% of the 605 patients treated with JEMPERLI or were reported with the use of other PD-1/PD-L1–blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain‑Barré syndrome, nerve paresis, autoimmune neuropathy.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis.

Ocular: Uveitis, iritis, other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune‑mediated adverse reactions, consider a Vogt‑Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis, including increases in serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.

Endocrine: Hypoparathyroidism.

Other (Hematologic/Immune): Autoimmune hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection.

 Infusion-Related Reactions

Severe or life-threatening infusion-related reactions have been reported with PD-1/PD-L1–blocking antibodies. Severe infusion-related reactions (Grade 3) occurred in 0.2% (1/605) of patients receiving JEMPERLI. All patients recovered from the infusion-related reactions.

Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion or permanently discontinue JEMPERLI based on severity of reaction [see Dosage and Administration ].

 Complications of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1–blocking antibody. Transplant-related 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). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

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

 Embryo-Fetal Toxicity

Based on its mechanism of action, JEMPERLI can cause fetal harm when administered to a pregnant woman. 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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with JEMPERLI and for 4 months after the last dose [see Use in Specific Populations ].