Approximately 15,000 individuals in the United States are diagnosed with either advanced or recurrent endometrial cancer (EC) annually. Some of the risk factors for EC are hormone therapy, obesity, metabolic syndrome, diabetes, family history, and certain genetic syndromes (e.g. Lynch syndrome). A common sign of EC is irregular vaginal bleeding, which usually occurs early in the cancer process, leading to a diagnosis of EC while the cancer is in an early stage. When identified in an early stage, EC can be successfully treated with either surgery alone, or in combination with radiotherapy and/or chemotherapy, which is often platinum based. If identified in later stages, or if it is recurrent or refractory to treatment, the prognosis for EC is poor. The current treatment options are limited.
There are genes within the cells of the body that correct mistakes made when the deoxyribonucleic acid (DNA) is copied. The process is called mismatch repair. Mismatch repair deficiency (dMMR) can result in errors in short, repetitive DNA sequences called microsatellites, which are genetic mutations. If a tumor has a high number of these mutations, it is classified as expressing microsatellite instability (MSI). EC tumors with dMMR and microsatellite instability-high (MSI-H) expression are difficult to treat. Based on clinical studies involving other drugs, tumors with dMMR and MSI-H respond well to anti-programmed death 1 (PD-1)-based immune checkpoint inhibitor immunotherapy.
Dostarlimab-gxly (Jemperli) is a programmed death-1 (PD-1)-blocking immunoglobulin G4 (IgG4) humanized monoclonal antibody. Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, part of the body's immune response against foreign material, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors leading to tumor growth. Dostarlimab-gxly (Jemperli) binds to the PD-1 receptor on the T cells and blocks its interaction with PD-L1 and PD-L2 which allows the anti-tumor immune response to occur.
Dostarlimab-gxly (Jemperli) was approved by the US Food and Drug Administration (FDA) on April 22, 2021 for the treatment of individuals with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.
Dostarlimab-gxly (Jemperli) was evaluated in the GARNET
study, which is an ongoing multicenter, multicohort, open-label study conducted
in individuals with advanced solid tumors. The efficacy population consisted of
a cohort of 71 individuals with mismatch repair deficient (dMMR) recurrent or
advanced EC who had progressed on or after treatment with a platinum-containing
regimen. The major efficacy outcome measures were overall response rate (ORR)
and duration of response (DOR).
At the time of study entry 66 percent of the individuals with dMMR EC had stage IV disease. All individuals with dMMR EC had received prior anticancer treatment, with 90 percent having received prior anticancer surgery and 79 percent having received prior anticancer radiotherapy. Approximately 40 percent had two lines or more of prior anticancer treatment, 11 percent had received three regimens, and four percent had received four or more prior regimens. The ORR was 42.3 percent with 12.7 percent achieving complete response and 29.6 percent achieving a partial response. The DOR was not reached, but 93.3 percent of individuals had a duration of response greater than or equal to six months. A couple limitations of the study were the lack of a comparator group and the small cohort size. Additional studies are currently enrolling participants.
There may be additional
indications contained in the Policy section of this document due to evaluation
of criteria highlighted in the Company’s off-label policy, and/or review of
clinical guidelines issued by leading professional organizations and government