Dostarlimab Active in dMMR Endometrial Cancer

Ana Oaknin, MD

Dostarlimab demonstrated clinically meaningful activity in patients with advanced or recurrent mismatch repair—deficient (dMMR) endometrial cancer who progressed following a platinum-based chemotherapy regimen, according to GlaxoSmithKline plc, the developer of the PD-1 inhibitor.¹

Updated results from the ongoing phase 1/2 GARNET trial showed an overall response rate (ORR) of 42% (95% CI, 31-55) with dostarlimab in a cohort of patients with dMMR endometrial cancer, comprising a complete response rate of 13% and a partial response rate of 30%. The disease control rate was 58% (95% CI, 45-69). At a median follow-up of 11.2 months, the median duration of response had not been reached (range, 1.87+ to 19.61+ months).

“There are limited treatment options for women with advanced or recurrent endometrial cancer, and prognosis of these patients is poor. The results observed in the GARNET trial indicate the potential of dostarlimab to offer a new treatment option for women with this challenging disease,” lead GARNET study investigator Ana Oaknin, MD, head of the Gynaecologic Cancer Program at Vall d’Hebron Institute of Oncology, Barcelona, stated in a press release.

The data for the dMMR cohort, which included 71 patients, were shared on a webinar as part of the 2020 Society of Gynecologic Oncology virtual congress. Dostarlimab was administered at 500 mg once every 3 weeks for 4 doses, followed by 1000 mg once every 6 weeks until progression. ORR and duration of response were the primary end points.

The safety analysis comprised all 104 patients with dMMR endometrial cancer who received at least 1 dose of dostarlimab. The most common treatment-related adverse events (TRAEs) were asthenia (15%), diarrhea (15%), fatigue (14%), and nausea (13%). TRAEs led to discontinuation in only 2% of patients and there were no deaths associated with study treatment.

Previous results from the GARNET trial were reported at the 2019 SGO Annual Meeting.² The findings showed an ORR of nearly 30% with dostarlimab in patients with MSI-H (n = 65) and microsatellite stable (MSS; n = 125) recurrent or advanced endometrial cancer. Dostarlimab was administered at 500 mg every 3 weeks for the first 4 cycles and 1000 mg every 6 weeks thereafter.

Patients were eligible to enroll on the trial if they had MSI-H or MSS recurrent or advanced endometrial cancer that progressed on or after treatment with a platinum-containing regimen, and previously received ≤2 prior lines of treatment for recurrent or advanced disease. Exclusion criteria included prior therapy with agents targeting PD-1, PD-L1, or PD-L2; active autoimmune disease that required systemic treatment within the last 2 years; and uncontrolled central nervous system metastases and/or carcinomatous meningitis or additional malignancy that progressed or required active treatment within the last 2 years.

The median age was 65 years (range, 32-86). The majority (54.4%) of patients received 1 prior treatment regimen and had stage IV disease (57.6%). Patients were diagnosed with endometrioid (51.2%), serious carcinoma (19.2%), clear cell carcinoma (3.2%), or another type of endometrial cancer (26.4%). In total, 94 patients had at least 1 tumor assessment (n = 79) or discontinued treatment prior to week 12 (n = 15).

Results showed that the ORR was 29.6% (95% CI, 21.8-38.4) in the entire population, 48.8% (95% CI, 32.9-64.9) in the MSI-H cohort, and 20.3% (95% CI, 12.0-30.8) in the MSS cohort. Six patients (2 MSI-H and 4 MSS) experienced a complete response (4.8%), and 31 patients (18 MSI-H and 12 MSS) had partial responses (24.8%) in the overall population. The disease control rate was 52.8% in the entire endometrial cancer population; it was 63.4% in MSI-H patients (95% CI, 46.9-77.9) and 46.8% in MSS patients (95% CI, 35.5-58.4).

Overall, 83.8% of the entire endometrial cancer population has experienced ongoing responses, including 85.0% of the MSI-H cohort and 81.3% of the MSS cohort. It was 100% in a cohort of patients whose MSI status was unknown (n = 5).

After a median follow-up of 10 months, median duration of response had not been reached. Overall, 89% of patients remained on treatment for >6 months and 49% for >1 year. In addition, 84% of responders were still on treatment. There was ≥50% reduction or more in the total tumor burden among 85% of the MSI-H responders and 69% in those with MSS disease.

In total, 88 patients (70.4%) experienced any-grade TRAEs, including fatigue (14.4%), diarrhea (12.8%), and nausea (12.0%). Grade 2 or higher immune-related AEs (5.6% total) included increased alanine aminotransferase (1.6%), increased aspartate aminotransferase (1.6%), hyperglycemia (1.6%), autoimmune hemolytic anemia (0.8%), colitis (0.8%), and infusion-related reactions (0.8%). No deaths occurred due to a TRAEs.

References

1. GSK presents new data from the GARNET study demonstrating potential of dostarlimab to treat a subset of women with recurrent or advanced endometrial cancer. Published April 24, 2020. https://bit.ly/3cR8fsd. Accessed Published April 24, 2020.
2. 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.

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The ongoing GARNET study is evaluating single-agent dostarlimab across several advanced solid tumors. There are 5 expansion cohorts that will make up part 2B of the study: dMMR/microsatellite instability-high (MSI-H) endometrial cancer; mismatch repair proficient endometrial cancer; non—small cell lung cancer; dMMR/MSI-H non-endometrial cancer; and platinum-resistant ovarian cancer without BRCA mutations.