GARNET Study Suggests Dostarlimab Promising for Uterine/Endometrial Cancer

MedMaven

by Dr. C.H. Weaver M.D. 3/2019

An early phase clinical trial evaluating dostarlimab in women with recurrent or advanced endometrial cancer appears promising. These data were presented at the 2019 Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer in Honolulu, Hawaii. (1) New data from the GARNET study released in April 2020 further demonstrated the potential of dostarlimab to treat specific subsets of women with advanced endometrial cancer. (2)

Endometrial cancer (EC) is the most common gynecologic malignancy in the U.S. but there are limited treatment options for women whose disease progresses on or after first-line therapy.

Microsatellite instability (MSI) is the condition of genetic hypermutability or a predisposition to mutations in cells that results from the bodies impaired DNA mismatch repair (MMR) mechanism. DNA MMR is an essential function and the way the body naturally corrects errors that spontaneously occur during cell division associated DNA replication.

Mismatch Repair Genes work like genetic “spell checkers.” When problems occur in these spell-checking MMR genes, it means that areas of DNA start to become unstable and the body is unable to correct the errors that occur during DNA replication and consequently accumulate errors. The accumulation of errors causes the creation of novel microsatellite fragments that can be measured. The presence of MSI represents evidence that the MMR function is not working normally and predisposition to developing cancer exists. Endometrial cancers may have MSI-H or dMMR identified when NGS testing is performed. EC can be classified as microsatellite stable (MSS/75%) or microsatellite instability-high (MSI-H/25%) and no effective treatments are currently available for either group.

About Dostarlimab

Dostarlimab (TSR-042) is a humanized anti-programmed death (PD)-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. Dostarlimab is a novel precision cancer immunotherapy drugs that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD -L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade an attack by the body’s immune cells. Dostarlimab works similar to other checkpoint inhibitors.

About Dostarlimab Clinical Trials

The ongoing GARNET clinical trial is evaluating dostarlimab in patients with advanced cancers including dMMR/MSI-H endometrial cancer and mismatch repair proficient endometrial cancer. (2,3) In addition to GARNET, dostarlimab is being investigated for women with recurrent or primary advanced endometrial cancer in combination with chemotherapy in the phase III RUBY trial. (4,5)

Key Study Findings From GARNET

A total of 125 women with recurrent EC were treated with Dostarlimab 500 mg once every 3 weeks for 4 doses, followed by 1000 mg once every 6 weeks until disease progression. In the initial analyses patients were categorized as MSI-H (33%), MSS (63%) and unknown MSI-status (4%).

Treatment with dostarlimab monotherapy resulted in a clinically meaningful response rate in recurrent EC who progressed on or after a platinum-based regimen regardless of MSI status. The overall response rates in the MSI-H population, and MSS population was 53%, 63% and 47%, respectively. At the time of data cutoff, treatment was still ongoing in 84% of responders, with 89% of the responders (33 of 37) having been on treatment for more than six months and 49% of responders (18 of 37) having been on treatment for more than one year.

An updated analysis included patients with dMMR EC; Treatment with dostarlimab showed an a response rate of 42% and a disease control rate of 58%. Overall, 13% of patients had a complete response and 30% of patients had a partial response. At the time of data cutoff, with a median follow up of 11.2 months ongoing responses were reported for up to 20 months.

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Dostarlimab is not currently approved for use anywhere in the world but submission to regulatory authorities is planned for later in 2020.

Reference:

  1. Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer
  2. A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients with Advanced Solid Tumors (GARNET). ClinicalTrials.gov.. Accessed February 2020.
  3. Oaknin A, Duska LR, Sullivan RJ, et al. Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H and MSS endometrial cancer. Presented at 2019 SGO Annual Meeting; March 16-19, 2019; Honolulu, HI. Abstract 33.
  4. Laken H, Kehry M, Mcneeley P, et al. Identification and characterization of TSR-042, a novel anti-human PD-1 therapeutic antibody. European Journal of Cancer. 2016;69,S102. doi:10.1016/s0959-8049(16)32902-1.
  5. A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients with Recurrent or Primary Advanced Endometrial Cancer (RUBY). ClinicalTrials.gov.. Accessed February 2020.
Comments (2)
No. 1-2
MedMaven
MedMaven

Editor

update shows benefit in dMMR patients identified by NGS testing

jimpandl
jimpandl

The overall response rates in the MSI-H population, and MSS population was 53%, 63% and 47%, respectively. happy wheels


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