In April 2021, the US Food and Drug Administration (FDA) approved dostarlimab-gxly (Jemperli®, GlaxoSmithKline), a programmed death receptor-1 (PD-1)-blocking antibody, for the treatment of adult patients with mismatch repair-deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed while or after receiving a platinum-containing regimen.  Accelerated approval of Jemperli was based on tumor response rate and durability of response. Continued approval may be contingent on a finding of clinical benefit in confirmatory trials. 
 
Dostarlimab-gxly, a humanized monoclonal antibody of the immunoglobulin G4 (IgG4) isotype, binds to the PD-1 receptor on T cells and blocks its interaction with the PD-1 ligands PD-L1 and PD-L2, thus releasing PD-1 pathway-mediated inhibition of the immune response, including an antitumor immune response. Decreased tumor growth was observed in syngeneic mouse tumor models in which PD-1 activity was blocked. 

Clinical Trials

The approval of Jemperli was based on the results of 1 clinical trial, GARNET (ClinicalTrials.gov Identifier: NCT02715284), which evaluated the efficacy of the drug in patients with advanced solid tumors. The study was a multicenter, open-label, multicohort clinical trial. Patients included in the study had dMMR recurrent or advanced endometrial cancer and exhibited disease progression while or after receiving a platinum-based regimen. Excluded from the study were (1) patients previously treated with PD-1/PD-L1-blocking antibodies or other immune checkpoint inhibitors and (2) patients with autoimmune disease that required immunosuppressant therapy during the past 2 years. 
 
Patients received Jemperli 500 mg administered intravenously (IV) every 3 weeks for 4 doses, then 1000 mg IV every 6 weeks until disease progressed or unacceptable toxicity developed. Overall response rate and duration of response were the major efficacy endpoints of the study (Table 1) and were based on Response Evaluation Criteria in Solid Tumors (v1.1), as evaluated by blinded independent central review.

Seventy-one patients were included in the efficacy population. Median age was 64 years; 49% were at least 65 years old. Eighty-two percent of patients were White, 3% were Asian, and 1% were Black. At baseline, 32% of patients were reported to have had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, and 68% had an ECOG Performance Status of 1. 
 
Baseline demographics revealed that 66% of the patients with dMMR endometrial cancer had International Federation of Gynecology and Obstetrics Stage IV disease at entry into the study. Of those patients, 70% had endometrioid carcinoma type 1; 6% had serous carcinoma, 2.8% had mixed carcinoma, and 2.8% had undifferentiated carcinoma. The VENTANA MMR RxDx Panel Assay was used to retrospectively confirm patients’ dMMR tumor status. 
 
All study patients with dMMR endometrial cancer had received anticancer treatment previously: 90% received anticancer surgery, and 79% received anticancer radiotherapy. Approximately 40% received at least 2 prior regimens, 11% received 3 regimens, and 4% received 4 or more regimens. 

The pooled safety population comprised 444 patients with advanced or recurrent solid tumors who were exposed to Jemperli. Of those patients, 268 had endometrial cancer and 176 had a different solid tumor. Thirty-eight percent of patients were exposed to Jemperli for at least 6 months; 12% were exposed for greater than 1 year. 
 
Safety data were also assessed in 104 patients with advanced or recurrent dMMR endometrial cancer who were exposed to at least 1 dose of Jemperli. Forty-seven percent of patients were exposed to Jemperli for at least 6 months; 20% were exposed for greater than 1 year. 
 
Thirty-four percent of patients who received Jemperli experienced a serious adverse reaction. Serious adverse reactions experienced by at least 2% of patients were sepsis (2.9%), acute kidney injury (2.9%), urinary tract infection (2.9%), abdominal pain (2.9%), and pyrexia (2.9%). 
 
Adverse reactions resulting in permanent discontinuation of Jemperli occurred in 4.8% (n=5) of patients; these reactions included increased transaminase levels, sepsis, bronchitis, and pneumonitis. Adverse reactions resulting in dose interruption of Jemperli occurred in 23% of patients. Adverse reactions that led to dose interruption of Jemperli that occurred in at least 1% of patients were anemia, diarrhea, increased lipase level, and pyrexia. 
 
Adverse reactions experienced by at least 20% of patients were fatigue or asthenia, nausea, diarrhea, anemia, and constipation. Grade 3 or 4 adverse reactions that occurred in at least 2% of patients included anemia and increased transaminase levels.
 
Grade 3 or 4 laboratory abnormalities that became worse from baseline and occurred in at least 1% of patients were lymphopenia; leukopenia; hypoalbuminemia; increased levels of alkaline phosphatase, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST); hyponatremia; hypercalcemia; and hypokalemia. 
 
In GARNET, immunogenicity was assessed by determining the presence of treatment-emergent antidrug antibodies against Jemperli; these were detected in 2.5% of the total of 315 patients exposed to Jemperli at the recommended therapeutic dose. Neutralizing antibodies were detected in 1.3% of patients. The effect of immunogenicity on the safety and efficacy of Jemperli was deemed inconclusive because of the small number of patients who developed antidrug antibodies.

Dosage and Administration

Jemperli is supplied as a 500-mg/10-mL solution in a single-dose vial. The recommended dosage of Jemperli is 500 mg IV every 3 weeks for 4 doses, then 1000 mg IV every 6 weeks thereafter until disease progresses or unacceptable toxicity develops. 
 
Jemperli must be diluted prior to infusion:
● To prepare the 500-mg dose, remove 10 mL of Jemperli from the vial using a sterile disposable polypropylene syringe and add to an IV infusion bag containing 0.9% sodium chloride injection, USP, or 5% dextrose injection, USP. The final concentration of the solution should be 2 to 10 mg/mL (maximum, 250 mL).
● To prepare the 1000-mg dose, remove 10 mL of Jemperli from 2 vials and add to an IV infusion bag containing 0.9% sodium chloride injection, USP, or 5% dextrose injection, USP. The final concentration of the solution should be 4 to 10 mg/mL (maximum, 250 mL).
● The solution should be mixed through gentle inversion. 
 
Jemperli is administered by IV infusion over 30 minutes. Do not administer by IV push or bolus injection. Jemperli should not be administered with other agents using the same infusion line. 
 
Only polyolefin, ethylene vinyl acetate, or polyvinyl chloride with di(2- ethylhexyl) phthalate infusion bags should be used. Intravenous lines must consist of polyvinyl chloride or platinum-cured silicon tubing; polyvinyl chloride or polycarbonate fittings should be used. A sterile, nonpyrogenic, low protein-binding, 0.2-micron in-line or add-on filter is required. 
 
The diluted solution can be stored at room temperature for as long as 6 hours or refrigerated for as long as 24 hours.

Contraindications, Warnings, Precautions, and Adverse Reactions

Immune-mediated adverse reactions
 
By blocking the PD-1/PD-L1 pathway and removing immune response inhibition, Jemperli can induce immune-mediated adverse reactions. These reactions, which can be severe or fatal, can occur in any organ system or tissue during treatment with, or after discontinuation, of a PD-1/PD-L1-blocking antibody.
 
To ensure PD-1/PD-L1-blocking antibodies are used safely, it is essential to identify and manage immune-mediated adverse reactions early through close monitoring of signs and symptoms that are potential clinical manifestations of underlying reactions. Liver enzymes, creatinine, and thyroid function should be assessed at baseline as well as periodically throughout treatment. If an immune-mediated adverse reaction is suspected, appropriate workup should be initiated to exclude alternative causes, and medical management should be instituted promptly. 
 
Based on the severity of the reaction, Jemperli should be withheld or permanently discontinued. Dose reduction of Jemperli is not recommended. 
 
If dose interruption or discontinuation of Jemperli is required, a systemic corticosteroid (1-2 mg/kg/d of prednisone or equivalent) should be initiated and continued until the patient improves to grade 1 or better. Corticosteroid taper should continue over at least 1 month once improvement is observed. For patients with reactions that are not effectively managed with a corticosteroid, other systemic immunosuppressants are recommended. 
 
In general, Jemperli should be withheld in patients with severe (grade 3) immune-mediated adverse reactions and permanently discontinued in patients with life-threatening (grade 4) reactions. Permanent discontinuation of Jemperli is also recommended in patients with recurrent severe (grade 3) reactions who require treatment with systemic immunosuppressants or cannot reduce a corticosteroid dosage to less than 10 mg of prednisone or equivalent daily within 12 weeks after starting a steroid. 
 
For patients who experience grade 2 immune-mediated pneumonitis (Figure 1), Jemperli should be withheld. For patients who experience complete or partial resolution (grade 0 or 1) of their reaction, Jemperli can be resumed following corticosteroid taper. If a patient’s reaction does not fully or partially resolve or their prednisone dosage cannot be reduced to less than 10 mg/d (or equivalent) within 12 weeks after starting a steroid, Jemperli should be permanently discontinued. Permanent discontinuation should also be instituted in patients with grade 3, grade 4, or recurrent grade 2 pneumonitis. 

Withhold Jemperli in patients who experience grade 2 or 3 immune-mediated colitis (Figure 2). For patients who experience complete or partial resolution (grade 0 or 1) of their reaction, Jemperli can be resumed following corticosteroid taper. If a patient’s reaction does not fully or partially resolve or their prednisone dosage cannot be reduced to less than 10 mg/d (or equivalent) within 12 weeks after starting a steroid, Jemperli should be permanently discontinued. Grade 4 colitis reactions also require permanent discontinuation of the drug. 

In patients with hepatitis without tumor involvement of the liver, dose modification must be based on laboratory findings. Jemperli should be withheld when the AST or ALT level increases to 3 to 8 times the upper limit of normal (ULN) and when the total bilirubin level increases to 1.5 to 3 times the ULN. For patients who experience complete or partial resolution (grade 0 or 1) of their reaction, Jemperli can be resumed following corticosteroid taper (Figure 3). If a patient’s reaction does not fully or partially resolve or their prednisone dosage cannot be reduced to less than 10 mg/d (or equivalent) within 12 weeks after starting a steroid, Jemperli should be permanently discontinued. Permanent discontinuation is also recommended in patients with (1) an AST or ALT level elevated to greater than 8 times the ULN or (2) a total bilirubin level elevated to greater than 3 times the ULN. 

For patients with hepatitis with tumor involvement of the liver, Jemperli should be withheld in patients with a baseline AST or ALT 1 to 3 times the ULN that increases to 5 to 10 times the ULN. Jemperli should also be withheld in patients with a baseline AST or ALT 3 to 5 times the ULN that increases to 8 to 10 times the ULN. For patients who experience complete or partial resolution (grade 0 or 1) of their reaction, Jemperli can be resumed following corticosteroid taper. If a patient’s reaction does not fully or partially resolve or their prednisone dosage cannot be reduced to less than 10 mg/d (or equivalent) within 12 weeks after starting a steroid, Jemperli should be permanently discontinued. Permanent discontinuation is also recommended in patients whose (1) AST or ALT level increases to greater than 10 times the ULN or (2) total bilirubin level increases to greater than 3 times the ULN.
 
Jemperli should be withheld in patients who are clinically unstable and experience a grade 2, 3, or 4 endocrinopathy (Figure 4). For patients who experience complete or partial resolution (grade 0 or 1 endocrinopathy) of their reaction, Jemperli can be resumed following corticosteroid taper. If a patient’s reaction does not fully or partially resolve, or their prednisone dosage cannot be reduced to less than 10 mg/d (or equivalent) within 12 weeks after starting a steroid, Jemperli should be permanently discontinued.

Jemperli should be withheld in patients who experience grade 2 or 3 nephritis with renal dysfunction and an increased blood creatinine level (Figure 5). For patients who experience complete or partial resolution (grade 0 or 1) of their reaction, Jemperli can be resumed following corticosteroid taper. If a patient’s reaction does not fully or partially resolve or their prednisone dosage cannot be reduced to less than 10 mg/d (or equivalent) within 12 weeks after starting a steroid, Jemperli should be permanently discontinued. Jemperli should also be permanently discontinued in patients who experience grade 4 nephritis with renal dysfunction and an increased blood creatinine level.

Jemperli should be withheld in patients when Stevens-Johnson syndrome/toxic epidermal necrolysis, or drug rash with eosinophilia and systemic symptoms is suspected (Figure 6). For patients who experience complete or partial resolution (Grade 0 or 1) of their reaction, Jemperli can be resumed following corticosteroid taper. If a patient’s reaction does not fully or partially resolve or their prednisone dosage cannot be reduced to less than 10 mg/d (or equivalent) within 12 weeks after starting a steroid, Jemperli should be permanently discontinued. Permanent discontinuation is also recommended in patients with a confirmed exfoliative dermatologic condition.

Permanent discontinuation of Jemperli is recommended in patients who experience grade 2, 3, or 4 myocarditis (Figure 7). Jemperli should be withheld in patients who experience grade 2 neurologic toxicities. For patients who experience complete or partial resolution (grade 0 or 1) of their reaction, Jemperli can be resumed following corticosteroid taper. If a patient’s reaction does not fully or partially resolve or their prednisone dosage cannot be reduced to less than 10 mg/d (or equivalent) within 12 weeks after starting a steroid, Jemperli should be permanently discontinued. Jemperli should also be permanently discontinued if grade 3 or 4 neurologic toxicity occurs. 

Infusion-related reactions
 
Severe or life-threatening infusion-related reactions have occurred in patients treated with PD-1/PD-L1-blocking antibodies. In GARNET, 0.2% (1/444) of patients receiving Jemperli experienced a severe (grade 3) infusion-related reaction (from which that patient recovered). 
 
Patients should be monitored for symptoms of an infusion-related reaction. For patients who experience a grade 1 or 2 infusion-related reaction, infusion should be interrupted or the rate of infusion decreased. For grade 3 and 4 reactions, Jemperli should be permanently discontinued. 
 
Complications of allogeneic HSCT after a PD-1/PD-L1-blocking antibody
 
In patients who have undergone allogeneic hematopoietic stem-cell transplantation (HSCT), treatment with a PD-1/PD-L1-blocking antibody has resulted in serious or fatal transplant-related complications. These include hyperacute graft-vs-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease following reduced intensity conditioning, and steroid-requiring febrile syndrome. These complications are possible even with intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.
 
Transplant-related complications should be closely monitored for and managed promptly. The risks vs the benefit of PD-1/PD-L1-blocking antibody treatment should be considered prior to or following allogeneic HSCT. 
 
Embryo-fetal toxicity
 
Based on its mechanism of action as well as animal study findings, Jemperli can cause fetal harm if administered during pregnancy. Women of reproductive potential should be advised about the potential for fetal death that is due to inhibition of the PD-1/PD-L1 pathway when Jemperli is taken during pregnancy. Effective contraception is recommended for women of reproductive potential during treatment with Jemperli and for 4 months after the last dose. 

Considerations for Specific Populations

There are insufficient data on the risk associated with the use of Jemperli during pregnancy. Based on what is known about the drug’s mechanism of action and the findings of animal studies, Jemperli can be considered to cause fetal harm if administered to a pregnant woman. Animal studies have shown that PD-1/PD-L1 pathway inhibition is associated with an increased risk of fetal death, abortion, and stillbirth due to immune-mediated rejection of the developing fetus. Transmission of Jemperli from mother to developing fetus is possible because human IgG4 has been found to cross the placenta. 
 
Pregnant women should be advised about the potential risk of Jemperli to a developing fetus. The pregnancy status of women of reproductive potential should be verified before starting Jemperli. 

Patient Counseling
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Patient Counseling
Effective contraception is recommended for women of reproductive potential during treatment with Jemperli and for 4 months after the final dose.

No data exist on the presence of Jemperli in breast milk, its effect in a breastfed child, or its effect on milk production. Because of the risk of serious adverse reactions in breastfed infants, women should not breastfeed during treatment with Jemperli and for 4 months after the final dose.
 
The efficacy and safety of Jemperli have not been established in pediatric patients. Clinically significant findings were not observed during GARNET when assessing the comparative safety and efficacy of Jemperli in older and younger patients. 
 
No clinically significant findings were observed regarding the effects of Jemperli based on patients’ age, gender, race or ethnicity, or tumor type. Findings revealed no significant difference in the pharmacokinetics of Jemperli in patients with renal or hepatic impairment. 

Key Takeaways

  • Jemperli is approved for the treatment of dMMR recurrent or advanced endometrial cancer in adults, as assessed by an FDA-approved test, whose disease has progressed during or after treatment with a platinum-containing regimen.
  • No dose reductions of Jemperli are recommended. In general, treatment should be withheld or permanently discontinued based on the severity of the adverse reaction.
  • Jemperli can cause immune-mediated adverse reactions, infusion-related reactions, complications related to allogeneic HSCT following therapy, and embryo-fetal toxicity.

Reference

Jemperli®. Prescribing information. GlaxoSmithKline; April 2021. Accessed July 4, 2021.  

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cancer Therapy Advisor had no role in this content’s preparation.