FDA Grants Regular Approval to Dostarlimab for dMMR Endometrial Cancer

FDA

The FDA has granted a regular approval to dostarlimab-gxly (Jemperli) for adult patients with mismatch repair–deficient (dMMR), recurrent or advanced endometrial cancer that has progressed on or after a prior platinum-containing regimen in any setting and who are not candidates for curative surgery or radiation.¹

Previously, in April 2021, the regulatory agency granted the agent accelerated approval for use in adult patients with dMMR recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen.²

The regular approval was supported by data from the phase 1 GARNET trial (NCT02715284), in which dostarlimab elicited a confirmed overall response rate (ORR) of 45.4% (95% CI, 37.0%-54.0%) by blinded independent central review (BICR) assessment and RECIST v1.1 criteria in a cohort of patients with dMMR endometrial cancer (n = 141); this included a complete response rate of 15.6% and a partial response rate of 29.8%. ^1,3

Moreover, the median duration of response (DOR) was not yet reached with the agent. Notably, the majority (85.9%) of patients experienced responses that lasted for 1 year or longer; more than half (54.7%) had responses that persisted for 2 years or longer (range, 1.2+-52.8+).^1,3

The multicenter, multicohort, open-label trial enrolled patients with advanced solid tumors.³ The endometrial cohort was comprised of patients with dMMR recurrent or advanced disease who progressed on or following a platinum-containing regimen. dMMR status was retrospectively confirmed by leveraging the VENTANA MMR RxDx panel assay.

Those who previously received PD-1/PD-L1 agents or other immune checkpoint inhibitors were excluded, as were those with autoimmune disease who required systemic treatment with immunosuppressant drugs within 2 years of enrollment.

Study participants received dostarlimab intravenously at a dose of 500 mg every 3 weeks for 4 doses followed by 1000 mg every 6 weeks. They received treatment until they experienced progressive disease or intolerable toxicity.

BICR-assessed ORR and DOR served as the major efficacy outcome measures of the trial.

In this cohort, the median age was 65 years, with 53% of patients at least 65 years of age. The majority (77%) were White, 4% were Asian, 4% were Hispanic or Latino, and 3% were Black. Moreover, 38% of patients had an ECOG performance status of 0 and 62% had a status of 1. The most common histology observed was endometriual carcinoma type 1 (65%), followed by grade 3 endometroid (15%), serous ((5%), mixed (5%), and undifferentiated (2.8%).

Notably, all participants previously received anticancer treatment. Specifically, 89% underwent prior surgery and 71% had received prior radiotherapy. More than half of patients (63%) received 1 prior line of therapy and 37% received 2 or more prior lines. Thirty-four percent of patients received therapy in the neoadjuvant or adjuvant settings prior to participating in GARNET.

The safety of dostarlimab was examined in 150 patients with dMMR advanced or recurrent endometrial cancer enrolled to the trial. Forty-one percent of the patients were exposed to the agent for over 1 year and 23% were exposed for over 2 years.

The most common toxicities observed with dostarlimab in 20% or more of patients included asthenia, anemia, rash, nausea, diarrhea, constipation, and vomiting. The grade 3 or 4 adverse effects that were most frequently experienced with the drug, and occurred in at least 2% of patients, were decreased lymphocytes, decreased sodium, increased alanine aminotransferase, increased creatinine, decreased neutrophils, decreased albumin, and increased alkaline phosphatase.

Thirty-eight percent of patients experienced serious toxicities with dostarlimab. Those that were observed in 2% or more patients included urinary tract infection (4%), sepsis (3.3%), acute kidney injury (2.7%), and abdominal pain (2.7%).

Only 1 patient who received dostarlimab experienced a fatal adverse reaction; this was because of concurrent immune-mediated encephalitis and urinary tract infection.

Ten percent of patients needed to permanently stop receiving dostarlimab because of toxicities such as increased transaminases, sepsis, bronchitis, pneumonitis, rash, pruritus, pancreatitis, encephalitis, and nephritis. Adverse reactions resulted in dose interruptions for 28% of patients; these effects included anemia, diarrhea, asthenia, colitis, sepsis, and pneumonitis.

References

1. FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. News release. FDA. February 9, 2023. Accessed February 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. FDA approves immunotherapy for endometrial cancer with specific biomarker. News release. FDA. April 22, 2020. Accessed February 9, 2023. https://www.fda.gov/news-events/press-announcements/
3. Dostarlimab-gxly (Jemperli). Prescribing information. GlaxoSmithKline; February 2023. Accessed February 9, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761174s003s004lbl.pdf