February 26, 2021 - The European Medicines Agency’s Committee for Medicinal Products for Human Use granted a positive opinion to dostarlimab as a treatment for patients with recurrent or advanced microsatellite instability–high/mismatch repair deficient endometrial cancer who have progressed on or following platinum-based chemotherapy.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion to dostarlimab as a treatment for patients with recurrent or advanced microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) endometrial cancer who have progressed on or following platinum-based chemotherapy.1
The decision on the Marketing Authorisation Application is based on findings from the phase 1 GARNET trial (NCT02715284), in which dostarlimab elicited an objective response rate (ORR) of 44.7% in patients with advanced or recurrent MSI-H/dMMR endometrial cancer.2 The agent also showed a 13.4% ORR in those with mismatch repair deficient (MMRp) disease.
“Treatment options are limited for women with recurrent or advanced endometrial cancer and prognosis is typically poor,” said Axel Hoos, MD, senior vice president and head of oncology R&D, GlaxoSmithKline, the developer of dostarlimab. “This positive CHMP opinion brings us one step closer to providing dostarlimab as a new treatment option to women with endometrial cancer in Europe with the hope of improving outcomes. If approved by the European Commission, dostarlimab would be the first anti–PD-1 therapy approved for endometrial cancer in Europe.”
While endometrial cancer can be treated successfully when diagnosed early, according to GlaxoSmithKline, there is an unmet need for treatment options for patients with recurrent or advanced disease that progresses on or following frontline therapy.
In the ongoing, phase 1 GARNET trial, investigators are evaluating the investigational PD-1 inhibitor dostarlimab as a single agent in patients with advanced solid tumors. Part 2B of the trial comprised 5 expansion cohorts: dMMR/MSI-H endometrial cancer (cohort A1), MMRp/microsatellite stable (MSS) endometrial cancer (cohort A2), non–small cell lung cancer (cohort E), dMMR/MSI-H non-endometrial or POLE-mutant solid tumor basket cohort (cohort F), and platinum-resistant ovarian cancer without BRCA mutations (cohort G).
Updated data from the 2 endometrial-cancer cohorts were presented during the ESMO Virtual Congress 2020: dMMR (n = 103) and MMRp (n = 142). Mismatch repair status was determined by immunohistochemistry. In part 2B of the trial, the PD-1 inhibitor was administered at the recommended dose determined from parts 1 and 2A of the trial: 500 mg intravenously (IV) every 3 weeks for 4 cycles followed by 1000 mg IV every 6 weeks until progressive disease.
In order to be eligible for enrollment, patients must have progressed on or following platinum-doublet therapy, received 2 or fewer prior lines of treatment for their recurrent or advanced disease, and had to have measurable disease at baseline. Those who had prior PD-1/PD-L1 inhibitor treatment were excluded from the trial.
Additionally, screening was required based on local MMR/MSI testing performed in a certified local laboratory and patients needed confirmed MMR IHC results. The primary end points were ORR and duration of response (DOR).
In cohort A1, the ORR was comprised of 11 complete responses (CRs) and 35 partial responses (PRs). Thirteen patients achieved stable disease (SD), and 39 had progressive disease (PD). In the MMRp cohort (n = 142), 3 patients had CRs, 16 had PRs, 31 achieved SD and 77 patients experienced PD.
The median duration of response (DOR) was not reached in the dMMR cohort (range, 2.63-28.09+) nor the MMRp cohort (range, 1.54+ to 30.36+). Additionally, DCRs with dostarlimab in the dMMR cohort and the MMRp cohorts were 57.3% (95% CI, 47.2-67.0) and 35.2% (95% CI, 27.4-43.7), respectively.
Regarding safety, patients in the dMMR and MMRp cohorts experienced all-grade treatment-emergent adverse events (TEAEs) at 95.2% and 100%, respectively; grade 3 or higher TEAEs occurred at 48.4% and 55.9%, respectively. All-grade treatment-related adverse events (TRAEs) occurred in 63.5% of patients in the dMMR cohort and 71.7% of patients on the MMRp cohort; grade 3 or TRAEs occurred in 13.5% and 19.3% of patients, respectively.
The grade 3 or higher TRAEs in the dMMR and MMRp cohorts, respectively, consisted of anemia (4.0% vs 1.4%, respectively), increased alanine aminotransferase (ALT; 1.6% vs 1.4%), and diarrhea (1.6% vs 1.4%). In the dMMR cohort, 1 patient discontinued due to increased ALT, 1 patient due to increased aspartate aminotransferase, and 2 patients due to increased transaminases; these numbers were 2, 1, and 0 in the MMRp cohort, respectively.
The FDA is also reviewing dostarlimab for the treatment of women with recurrent or advanced endometrial cancer who have progressed on or following platinum-based chemotherapy and whose tumors are dMMR, GlaxoSmithKline stated. The agent is also under FDA review for the treatment of adult patients with dMMR recurrent or advanced solid tumors.
Dostarlimab is also being explored in the phase 3 RUBY (NCT03981796) study for patients with recurrent or primary advanced endometrial cancer in combination with standard chemotherapy, as well as in the phase 3 FIRST (NCT03602859) trial of dostarlimab and niraparib (Zejula) plus platinum-based chemotherapy versus standard platinum-based therapy alone as a frontline therapy for patients with stage III/IV non-mucinous epithelial ovarian cancer.