Dostarlimab Improves Antitumor Activity in Advanced Endometrial Cancer

The GARNET trial expansion cohorts showed durable antitumor activity across multiple populations of patients treated with dostarlimab in advanced endometrial cancer.

Patients with advanced endometrial cancer, specifically with mismatch repair deficient (dMMR)/microsatellite instability–high (MSI-H) or mismatch repair proficient (MMRp)/mismatch stable (MSS) disease experienced durable antitumor activity when treated with dostarlimab (Jemperli), according to results from 2 expansion cohorts in the GARNET trial (NCT02715284) presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

“Indeed, the probability of remaining in response at 24 months was 83.7% in the dMMR/MSI-high cohort,” Ana Oaknin, MD, principal investigator, Gynecological Malignancies Group, Vall d’Hebron Institute of Oncology, head of Gynecologic Tumors Unit, senior medical oncologist and attending physician, Medical Oncology Department, Vall d’Hebron University Hospital in Barcelona, Spain, said during a presentation of the data.

At the annual meeting, Oaknin reported on the efficacy and safety of dostarlimab monotherapy in 2 expansion cohorts from the GARNET study that enrolled patients with advanced/recurrent endometrial cancer—in particular, from the third pre-specified interim analysis. In the trial, patients with endometrial cancer were enrolled in cohort A1 (dMMR/MSI-H) or cohort A2 (MMRp/MSS). Median follow-up for both cohorts was 27.6 months and 33.0 months, respectively.

“Cohort A1 is the largest cohort of patients with dMMR/MSI-H studied with an anti–PD-1 monotherapy to date,” Oaknin said.

As of the data cutoff date of November, 1, 2021, the overall response rate (ORR) in cohort A1 was 45.5% (95% CI, 37.1%-54.0%), and included 23 complete responses (CRs; 16.1%), 42 partial responses (PRs; 29.4%), 21 patients with stable disease (SD; 14.7%), 51 with progressive disease (PD; 35.7%), and 6 who were not evaluable (4.2%). The ORR in cohort A2 was 15.4% (95% CI, 10.1%-22.0%), and included 4 CRs (2.6%), 20 PRs (12.8%), 29 patients with SD (18.6%), 88 with PD (56.4%), and 15 who were not evaluable.

The median time to CR in cohorts A1 and A2 were 2.79 months and 2.81 months, respectively. Similarly, time to PR in both cohorts were 2.69 months and 2.79 months.

The disease control rate in cohort A1 was 60.1% (95% CI, 51.6%-68.2%), and 34.0% (95% CI, 26.6%-42.0%) in cohort A2.

Responses are ongoing in 54 patients (83.1%) in the dMMR/MSI-H group and 9 patients (37.5%) in the MMRp/MSS group. The median duration of response (DOR) was not reached (NR; range, 1.18+ to 47.21+) in cohort A1, and was 19.4 months (range, 2.8-47.18+) in cohort A2.

The probability of maintaining responses at 6 months in the dMMR/MSI-H group and MMRp/MSS group was 96.8% and 82.6%, respectively, 93.3% and 60.3% at 12 months, and 83.7% and 44.2% at 24 months, according to Oaknin.

In cohort A1, median progression-free survival (PFS) was 6.0 months (95% CI, 4.1-18.0), with a probability for PFS at 24 months of 40.1% (95% CI, 31.6%-48.4%). In cohort A2, median PFS was 2.7 months (95% CI, 2.6-2.8), with a probability of 9.4% for PFS at 24 months (95% CI, 5.2%-15.0%).

Median overall survival (OS) for cohort A1 was NR (95% CI, 27.1-NR), with a probability of OS at 24 months of 60.5% (95% CI, 51.5%-68.4%), compared with a median OS of 16.9 months (95% CI, 13.0-21.8) and probability of 38.4% (95% CI, 32.0%-44.6%) in cohort A2.

Among patients who received 1 or more doses of dostarlimab (N = 314), most adverse events (AEs) were grade 1 or 2 and were manageable, according to Oaknin. In total, 27 patients (8.6%) discontinued treatment because of a treatment-related AE (TRAE); however, no deaths were associated with the agent or reported in these cohorts.

The most common any-grade AEs were fatigue (17.8%), diarrhea (14.6%), nausea (13.7%), and asthenia (11.8%). Any-grade TRAEs that led to treatment discontinuation included increased alanine aminotransferase (1.6%) and aspartate aminotransferase (1.0%), as well as pneumonitis (1.0%).

“Endometrial cancer is the most common gynecological malignancy in the United States and Europe and its incidence is rising globally,” Oaknin explained. “For patients with disease progression that occurs on or after first-line therapy, overall survivor is typically less than 1 year and there is no standard second-line therapy. So new therapeutic options are needed.”

In the multicenter, open-label, single-arm, phase 1 GARNET study, investigators aimed to evaluate the efficacy of dostarlimab monotherapy in patients with advanced or recurrent solid tumors.

Patients were administered 500 mg dostarlimab intravenously (IV) every 3 weeks for 4 cycles, followed by 1000 mg dostarlimab IV every 6 weeks until disease progression, discontinuation, or withdrawal.

Primary end points included evaluation of antitumor activity (ORR and DOR), safety, and tolerability.

To be eligible, patients must have had progression on or after platinum doublet therapy, have received 2 or more prior lines of treatment for recurrent or advanced disease, have measurable disease at baseline, and be anti–PD-(L)1 naïve.

In total, 153 patients were enrolled in cohort A1 and 161 patients in cohort A1, of which 143 patients and 156 patients were evaluable for efficacy, respectively. However, 108 patients in cohort A1 and 156 patients in cohort A2 discontinued treatment due to progression (n = 66 vs 108, respectively), AEs (n = 24 vs 22), patient request (n = 6 each), clinical criteria (n = 9 vs 16), and other reasons (n = 3 vs 4).

Demographics and baseline characteristics between both cohorts appeared similar, according to Oaknin; however, she pointed out that the majority of the dMMR/MSI-H cohort had grade 1 or 2 endometrioid carcinoma (64.3%), compared with the MMRp/MSS cohort (23.1%). All patients had received at least 1 prior line of platinum therapy, and 34.3% of those in cohort A1, versus 26.9% in cohort A2, received only adjuvant or neoadjuvant therapy.

Dostarlimab, an anti–PD-1 monoclonal antibody that blocks interaction with the ligands PD-L1 and -L2, is approved by the FDA to treat dMMR recurrent or advanced endometrial cancer that has progressed on platinum-containing regimens and to treat dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options. Both indications are approved under accelerated approval based on tumor response rate and durability of response.

“Dostarlimab is the only PD-1 therapy clinically tested with a 6-week dosing schedule in endometrial cancer,” Oaknin concluded.

Reference

Oaknin A, Pothuri B, Gilbert L, et al. Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): The GARNET study. J Clin Oncol. 2022;40(suppl 16):5509. doi:10.1200/JCO.2022.40.16_suppl.5509