Dostarlimab Elicits Survival Benefit in dMMR/MSI-H Advanced Endometrial Cancer

Single-agent dostarlimab-gxly (Jemperli) produced progression-free survival (PFS) and overall survival (OS) benefits in patients with advanced or recurrent mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) endometrial cancer, according to long-term follow-up data of key secondary end points from the phase 1 GARNET trial (NCT02715284).

Findings presented at the 2022 ESMO Congress showed patients with dMMR/MSI-H endometrial cancer from cohort A1 (n = 143) achieved a median PFS of 6.0 months (95% CI, 4.1-18.0). The landmark PFS rate was 49.5% (95% CI, 41.0%-57.5%) at 6 months, 46.4% (95% CI, 37.8%-54.5%) at 12 months, and 40.1% (95% CI, 31.6%-48.4%) at both 24 months and 36 months. The median OS was not reached (NR; 95% CI, 27.1 months–NR). The 6-, 12-, 24- and 36-month estimated OS rates were 84.9% (95% CI, 78.0%-89.8%), 73.3% (95% CI, 65.2%-79.8%), 60.5% (95% CI, 51.5%-68.4%), and 58.4% (95% CI, 49.2%-66.5%), respectively.

For patients with MMR-proficient (MMRp)/microsatellite stable (MSS) endometrial cancer in cohort A2 (n = 156), the median PFS was 2.7 months (95% CI, 2.6-2.8). The landmark PFS rates were 22.9% (95% CI, 16.5%-30.0%) at 6 months, 13.3% (95% CI, 8.3%-19.5%) at 12 months, 9.4% (95% CI, 5.2%-15.0%) at 24 months, and 6.8% (95% CI, 3.3%-12.0%) at 36 months. The median OS was 16.9 months (95% CI, 13.0-21.8). The estimated OS rates at 6, 12, 24, and 36 months were 74.3% (95% CI, 66.6%-80.6%), 60.6% (95% CI, 52.3%-67.9%), 38.4% (95% CI, 30.5%-46.2%), and 22.2% (95% CI, 14.9%-30.5%), respectively.

“Both PFS and OS were numerically lower in the MMRp/MSS cohort. However, these secondary end points provide further evidence that a subset of patients with MMRp/MSS endometrial cancer may have durable benefits from dostarlimab,” lead study author Anna V. Tinker, MD, FRCPC, a clinical associate professor and medical oncologist in the Division of Oncology at the University of British Columbia in Vancouver, Canada, wrote in a poster presentation of the data.

Patients with endometrial cancer who progress on or after first-line therapy typically have an OS of less than 1 year, and there is no standard second-line therapy.

Notably, approximately 25% to 30% of patients with endometrial cancer are dMMR/MSI-H, and dMMR/MSI-H tumors may be sensitive to anti–PD-1 therapy. Dostarlimab is an anti–PD-1 monoclonal antibody, and GARNET evaluated its use in patients with advanced or recurrent endometrial cancer.

Patients with endometrial cancer were examined in 2 expansion cohorts from the phase 1 trial. Cohort A1 featured patients with dMMR/MSI-H endometrial cancer, and cohort A2 enrolled patients with MMRp/MSS endometrial cancer.

Patients in both cohorts were required to have disease progression on or after platinum doublet chemotherapy, have received no more than 2 prior lines of therapy for recurrent or advanced disease, and be naïve to anti­–PD-L1 therapy.

Eligible patients were assigned to cohort A1 or cohort A2 based on MMR immunohistochemistry. All patients received 500 mg of intravenous dostarlimab every 3 weeks for 4 cycles, followed by 1000 mg every 6 weeks thereafter, until disease progression, discontinuation, or patient withdrawal.

The co-primary end points of the trial were objective response rate (ORR) and duration of response (DOR) by blinded independent central review per RECIST v1.1 criteria, plus safety and tolerability. PFS and OS comprised key secondary end points.

The median age of patients included in cohort A1 was 65 years (range, 39-85), and the median age of cohort A2 was 66 years (range, 30-86). In cohort A1, 56.6% of patients had stage III or IV disease, and 62.8% of patients in cohort A2 had stage III or IV disease.

Histologies ranging across both cohorts included grade 1 or 2 endometroid carcinoma (64.3% and 23.1% in cohorts A1 and A2, respectively), serous (4.9% and 40.4%), grade 3 endometroid (14.7% and 9.0%), clear cell (0.7% and 7.1%), squamous (0.7% and 1.9%), undifferentiated (2.8% and 1.9%), carcinosarcoma (0 and 1.3%), mixed carcinoma (4.% and 7.1%), unspecified (2.8% and 5.8%), other (2.8% and 2.6%), and unknown (1.4% and 0).

All patients in both cohorts received prior anticancer treatment. In cohort A1, 62.9% of patients had 1 prior line of therapy, 24.5% had 2 prior lines of therapy, and 12.6% had 3 or more prior lines of therapy. Those rates were 46.2%, 42.9%, and 10.9%, respectively, in cohort A2. Additionally, 34.3% and 26.9% of patients received only adjuvant or neoadjuvant therapy in cohorts A1 and A2, respectively. The majority of patients in cohorts A1 and A2 received prior radiation (70.6% and 60.9%, respectively).

Additional data showed that patients with MMRp/MSS endometrial cancer experienced a numerically lower ORR compared with the dMMR/MSI-H cohort.

At a median follow-up of 27.6 months, patients with dMMR/MSI-H endometrial cancer achieved an ORR of 45.5% (95% CI, 37.1%-54.0%), including a complete response (CR) rate of 16.1% and a partial response (PR) rate of 29.4%. Additionally, 14.7% of patients had stable disease, 35.7% of patients experienced progressive disease, and 4.2% of patients were not evaluable. The median DOR was NR (95% CI, 1.18+ months to 47.21+ months). The probability of patients maintaining a response at 6, 12, and 24 months was 96.8%, 93.3%, and 83.7%, respectively.

At a median follow-up of 33 months, patients with MMRp/MSS endometrial cancer experienced an ORR of 15.4% (95% CI, 10.1%-22.0%) with a CR rate of 2.6% and a PR rate of 12.8%. Notably, 18.6% of patients had stable disease, 56.4% experienced progressive disease, and 9.6% were not evaluable. The median DOR was 19.4 months (95% CI, 1.54 to 47.18+), and the probability of maintaining a response at 6, 12, and 24 months was 82.6%, 60.3%, and 44.2%, respectively.

Regarding safety, 99.7% of all patients with endometrial cancer who received at least 1 dose of dostarlimab (n = 314) experienced at least 1 any-grade treatment-emergent adverse effect (TEAE), and 58% had at least 1 TEAE of grade 3 or higher. Treatment-related AEs (TRAES) of any grade occurred in 71% of patients, including grade 3 or higher TRAEs in 19.1% of patients.

Rates of immune-related TRAEs of any grade and grade 3 or higher were 23.2% and 8.0%, respectively. Serious TRAEs were reported in 10.2% of patients. Additionally, 8.6% of patients discontinued treatment due to TRAES, which included increased alanine aminotransferase (1.6%), increased aspartate aminotransferase (1.0%), and pneumonitis (1.0%). No TRAEs led to death.

The most common TRAES of any grade included fatigue (17.8%), diarrhea (14.6%), nausea (13.7%, and asthenia (11.8%).

Reference

1. Tinker AV, Pothuri B, Gilbert L, et al. Progression-free survival (PFS) and overall survival (OS) in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC) treated with dostarlimab in the GARNET study. Ann Oncol. 2022;33(suppl 7):S798-S799. doi:10.1016/j.annonc.2022.07.676