The FDA has granted accelerated approval to dostarlimab-gxly (Jemperli®, GlaxoSmithKline) for patients with mismatch repair deficient recurrent or advanced endometrial cancer that has progressed on or after a prior platinum-containing chemotherapy.
"The prognosis for patients with a diagnosis of advanced or recurrent endometrial cancer is poor, and, to our knowledge, there are no accepted consensus-based guidelines for standard of care after the disease progresses while undergoing or after treatment with a platinum-containing regimen," wrote the investigators of the phase 1 GARNET trial (NCT02715284), on which the approval was based, led by first author Ana Oaknin, MD, PhD, a Senior Medical Oncologist and Head of the Gynecologic Tumors Unit at the Vall d'Hebron Institute of Oncology in Barcelona, Spain. "Deficient mismatch mutation repair mechanisms may sensitize endometrial cancers to anti–programmed death 1 (PD-1) therapies. Dostarlimab is an investigational anti–PD-1 antibody that binds with high affinity to the PD-1 receptor."
The GARNET trial enrolled 71 patients with mismatch repair deficient recurrent or advanced endometrial cancer who had progressed on or after platinum-containing chemotherapy. In this nonrandomized, multicenter, multicohort, open-label trial, all eligible patients received 500 mg dostarlimab-gxly intravenously every three weeks for four doses. That regimen was followed by 1,000 mg dostarlimab-gxly given intravenously every six weeks. The primary end points were overall response rate and duration of response.
Dostarlimab-gxly produced a confirmed overall response rate of 42.3%, a complete response rate of 12.7%, and a partial response rate of 29.6%. The median duration of response was not reached, and 93.3% of patients had responses lasting at least 6 months.
Adverse reactions occurring in at least 20% of patients receiving dostarlimab-gxly included fatigue/asthenia, nausea, diarrhea, anemia, and constipation. Serious adverse events, which occurred in 34% of patients, included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia. Grade 3 or 4 adverse events experienced by at least 2% of patients included anemia and increased transaminase. Immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis, can also occur.
"In this nonrandomized trial, dostarlimab was associated with clinically meaningful and durable antitumor activity with an acceptable safety profile for patients with deficient mismatch mutation repair endometrial cancers after prior platinum-based chemotherapy," concluded Dr. Oaknin and colleagues in their October 2020 publication of the trial's results in JAMA Oncology.
The recommended dose of dostarlimab-gxly is 500 mg every three weeks for doses 1 through 4. Three weeks after dose 4, the recommended dose is 1,000 mg every six weeks until disease progression or unacceptable toxicity. All doses should be administered intravenously over a 30-minute period.
For More Information
Oaknin A, Tinker AV, Gilbert L, et al (2020). Clinical activity and safety of the anti-programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: a nonrandomized phase 1 clinical trial. JAMA Oncol, 6(11):1766-1772. DOI:10.1001/jamaoncol.2020.4515
Clinicaltrials.gov (2020). Study of TSR-042, an anti-programmed cell death-1 receptor (PD-1) monoclonal antibody, in participants with advanced solid tumors (GARNET). NLM identifier: NCT02715284.
US Food & Drug Administration (2021). FDA approves immunotherapy for endometrial cancer with specific biomarker. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-immunotherapy-endometrial-cancer-specific-biomarker
US Food & Drug Administration (2021). FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-endometrial-cancer
Image credit: Mikael Häggström, MD. Licensed under CC0 1.0