According to results from the ongoing phase I/II GARNET trial, dostarlimab induced an overall response rate of nearly 30% in patients with recurrent or advanced endometrial cancer. Results presented at the 2019 SGO Annual Meeting also demonstrated durable responses in both patients with microsatellite instability-high and microsatellite stable tumors.
Ana Oaknin, MD, PhD
Ana Oaknin, MD, PhD
According to findings from the ongoing phase I/II GARNET trial, dostarlimab (TSR-042) induced an overall response rate (ORR) of nearly 30% in patients with recurrent or advanced endometrial cancer. Results presented at the 2019 SGO Annual Meeting also demonstrated durable responses in both patients with microsatellite instability-high (MSI-H) and microsatellite stable (MSS) tumors.
“Endometrial cancer is the most common gynecologic malignancy in the United States. There are limited treatment options for patients who progress on or after first-line therapy,” said Ana Oaknin, MD, PhD, head of the Gynecologic Tumors Unit, senior medical oncologist, and attending physician of the Medical Oncology Department, Vall d´Hebron University Hospital.
With typical chemotherapy treatment, response rates are around 7% to 13%, while the only approved therapy for patients in the recurrent setting is pembrolizumab (Keytruda) for MSI-H tumors. Dostarlimab, an investigational humanized PD-1 monoclonal antibody inhibits the PD-1 receptor by blocking ligand binding; this agent has demonstrated significant clinical activity in various tumor types.
In the phase I/II findings presented at the 2019 SGO Annual Meeting, Oaknin presented safety and efficacy data from the previously treated recurrent or advanced endometrial cancer cohorts, along with pharmacokinetics and receptor occupancy findings at the recommended phase II dose (RP2D).
In total, 110 patients with previously treated recurrent or advanced endometrial cancer received the RP2D of dostarlimab, which Oaknin said was a “a unique and convenient dosing schedule” of 500 mg every 3 weeks for the first 4 cycles and 1000 mg every 6 weeks thereafter, Oaknin said.
The primary endpoints in the endometrial expansion cohorts were ORR and duration of response (DOR) in MSI-H (n = 65) and MSS (n = 125) patients, as well as safety and tolerability.
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 of patients received 1 prior treatment regimen (54.4%) 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 DOR has not been reached. Overall, 89% of patients remained on treatment for >6 months and 49% for >1 year. In addition, 84% of responders are still on treatment.
Lastly, 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 treatment-related adverse events (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 treatment-related TEAEs.
Dostarlimab pharmacokinetics was linear and dose-proportional, Oaknin said, adding that maximal receptor occupancy was observed at the RP2D consistent with previous results and was maintained through the treatment course.
“GARNET Is the single largest study of antiPD-1 monotherapy in patients with advanced/recurrent endometrial cancer,” Oaknin said. “Further investigation of dostarlimab in combination with chemotherapy in first-line endometrial cancer in a phase III trial will be initiated in [the second half of] 2019.”
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 antiPD-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.