FDA Grants Regular Approval to Dostarlimab for dMMR Endometrial Cancer

The FDA has granted regular approval to dostarlimab-gxly (Jemperli) for the treatment of adult patients with mismatch repair–deficient (dMMR) recurrent or advanced endometrial cancer. Patients must have progressed on or following a prior platinum-containing regimen in any settings and are not eligible for curative surgery or radiation.¹

The decision follows an evaluation of data from the phase 1 GARNET trial (NCT02715284), which showed that among 141 patients with dMMR recurrent or advanced endometrial cancer treatment with the anti–PD-1 monoclonal antibody elicited a confirmed overall response rate of 45.4% (95% CI, 37.0%-54.0%) per RECIST 1.1 criteria. This included a complete response rate of 15.6% and a partial response rate of 29.8%.¹ Among responders, 85.9% had a response lasting at least 12 months and 54.7% had a response ongoing at 24 months or longer. The median duration of response was not reached.¹

In April 2021, the FDA granted accelerated approval for patients with dMMR endometrial cancer, based on data from cohort A1 of GARNET, which included a patient population of 71 evaluable individuals.² An accelerated approval was also given to the agent for the treatment of patients with dMMR recurrent or advanced solid tumors based on 209 patients from the GARNET trial in August 2021.³

Of note, GARNET excluded patients who had prior treatment with PD-1/PD-L1–blocking antibodies or other immune checkpoint inhibitor therapy, as well as those with autoimmune disease requiring systemic therapy with immunosuppressant agents within 2 years of enrollment.

In the cohort of patients with endometrial cancer, 89% of patients received prior anticancer surgery and 71% received prior anticancer radiotherapy. Most patients (63%) had 1 line of prior therapy with the remaining population having received 2 or more prior lines of therapy.⁴

The label contains warnings for immune-mediated adverse reactions, which can occur in any organ or tissue system. These include immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, and immune-mediated dermatologic reactions. Further, solid organ transplant rejection is possible.

It is important to note that although immune-mediated adverse reactions typically occur during treatment, they can also manifest after discontinuation of PD-1/PD-L1–blocking antibodies and patients should be monitored after discontinuation.⁴ Monitoring liver enzymes, creatinine clearance, and thyroid function at baseline and periodically during treatment and timely workup to exclude alternative etiologies, including infection at suspected event occurrence is advised.⁴

Other warnings and precautions include infusion-related reactions, complications for allogeneic hematopoietic stem cell transplant, and embryo-fetal toxicity.

Serious adverse events were reported in 38% of patients in the safety population (n = 150). These included urinary tract infection (4%), sepsis (3.3%), acute kidney injury (2.7%), and abdominal pain (2.7%). Overall, the most common all-grade events were fatigue/asthenia, anemia, rash, nausea, diarrhea, constipation, and vomiting.

A total of 15 patients discontinued treatment with citing reasons including increased transaminases, sepsis, bronchitis, pneumonitis, rash, pruritus, pancreatitis, encephalitis, and nephritis.

Dosage interruptions due to an adverse reaction occurred in 28% of patients, these events included anemia, diarrhea, asthenia, colitis, sepsis, and pneumonitis.

Dostarlimab is administered as an intravenous infusion over 30 minutes. The first dose through fourth dose should be given at 500 mg every 3 weeks. Subsequent doses should be administered at 1000 mg every 6 weeks. Dose modifications are not recommended for dostarlimab and for immune-mediated adverse events that are grade 3 in severity, the agent should be withheld. For recurring grade 3 events that require immunosuppressive treatment, if corticosteroids cannot be reduced to 10 mg or less within 12 weeks of starting therapy, or grade 4 events occur, it is recommended to discontinue dostarlimab.⁴

References

1. FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. FDA. February 9, 2023. Accessed February 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer. FDA. April 22, 2021. Accessed February 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
3. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated February 1, 2022. Accessed February 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
4. Jemperli. Prescribing information. GlaxoSmithKline LLC; 2023. Accessed February 9, 2023. https://www.accessdata.fda.gov/