Dostarlimab gains full FDA approval for dMMR recurrent or advanced EC following the positive long-term results of the GARNET trial

The third interim analysis of the GARNET trial confirmed the durable antitumor activity of dostarlimab among patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC) with extended follow-up.1 Based on the positive long-term results, the United States (US) Food and Drug Administration (FDA) converted the drug’s status on February 9, 2023, from accelerated to regular (full) approval for the treatment of dMMR recurrent or advanced EC that has progressed on or following a prior platinum-containing regimen, or where curative surgery or radiation is not appropriate.2


EC is one of the most common female cancers, with the incidence increasing significantly by 0.69% per year between 1990 and 2019.3 The dMMR or microsatellite unstable molecular subtype accounts for 25%-30% of all ECs.3 The type of EC carries a high mutational burden (hypermutated) due to the loss of deoxyribonucleic acid (DNA) mismatch pair, which is associated with an intermediate prognosis.3 In fact, hypermutated dMMR/ high microsatellite instability (MSI-H) ECs are known to be highly immunogenic tumors.3 Studies have found that tumors with a high mutational burden generally have a substantially increased production of tumor-mutated antigens (i.e., neoantigens), resulting in a high abundance of tumor-infiltrating lymphocytes (TILs) with an upregulated T-cell mediated antitumor response.3 In order to escape from the host immunity, cancers can upregulate the inhibitory immune checkpoint receptors, such as programmed death-ligand 1 (PD-L1), which blocks the activated T-cell mediated tumor cell death.3 Nevertheless, this immune escape mechanism makes these tumors susceptible to the reactivated host immune response when patients are being treated with novel immunotherapies such as dostarlimab, a programmed death 1 (PD-1) inhibitor.1,3

GARNET is a multicenter, open-label, single-arm phase 1 study which was designed to evaluate the efficacy and safety of dostarlimab among patients with dMMR/MSI-H advanced or recurrent EC (cohort A1; n=153), or dMMR/MSI-H/polymerase epsilon mutation (POLɛ-mut) non-EC solid tumors (cohort F; n=210).1 Eligible patients were administrated with dostarlimab 500mg intravenously (IV) every 3 weeks for 4 cycles, followed by 1,000mg every 6 weeks until disease progression, treatment discontinuation or withdrawal.1 The primary endpoints were objective response rate (ORR) and duration of response (DoR) by the blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECSIT v1.1).1

The efficacy analysis of GARNET was performed for 143 dMMR/MSI-H EC patients. With a median follow-up of 27.6 months for EC patients, the ORR was 45.4% (n=65/143) (95% CI: 37.0-54.0), with 15.6% of patients achieving complete response (CR) and 29.8% partial response (PR).2 The median DoR was not reached with 85.9% of patients having response lasting for ≥12 months and 54.7% having durations of ≥24 months.1,2 The progression-free survival (PFS) rates at 6 months, 9 months, and 12 months were 49.5%, 48.0%, and 46.4%, respectively.1 The median overall survival (OS) was not reached for both cohorts.1

Dostarlimab was generally well tolerated with acceptable and manageable toxicities.1 The most common treatment-emergent adverse events (TEAEs) occurring in ≥12% of patients were diarrhea, asthenia, fatigue, nausea, and pruritis.1 Less than 10% of patients discontinued the treatment due to TEAEs.1

In summary, dostarlimab demonstrated high and sustainable antitumor activity in patients with dMMR/MSI-H advanced or recurrent EC in the phase 1 GARNET trial with extended follow-up.1 Dostarlimab also showed a manageable safety profile.1 The full FDA approval marks a major advance in the EC treatment landscape, continuing to address the unmet needs of patients.  

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