Pembrolizumab Demonstrates Sustained, Robust Clinical Activity in Advanced MSI-H/dMMR Endometrial Cancer
Patients with microsatellite instability–high and mismatch repair–deficient advanced endometrial cancer experienced a long lasting benefit following treatment with pembrolizumab.
Treatment with pembrolizumab (Keytruda) resulted in efficacious, long-lasting benefit in patients with microsatellite instability–high (MSI-H) and mismatch repair–deficient (dMMR) advanced endometrial cancer, according to findings from the phase 2 KEYNOTE-158 study (NCT02628067).1
Patients who received treatment with pembrolizumab experienced an objective response rate (ORR) of 48% (95% CI, 37%-60%) with a median duration of response (DOR) that was not reached (95% CI, 2.9-49.7+). Additionally, patients achieved a median progression-free survival (PFS) of 13.1 months (95% CI, 4.3-34.4). The median overall survival (OS) was not reached (95% CI, 27.2–not reached).
“These findings suggest a long-term benefit to patients. Even the potential for curative intent is now possible in patients with recurrent or metastatic uterine cancer,” lead author David O’Malley, MD, a gynecologic oncologist at the Ohio State University Comprehensive Cancer Center–The James, said in a press release.2
The open label trial enrolled patients with different types of solid, advanced tumors, with cohort D being comprised of patients with endometrial carcinoma. To be eligible for the study, patients needed to be 18 years or older with histologically or cytologically confirmed metastatic and/or unresectable endometrial cancer. Patient disease needed to be uncurable and patients needed to progress on or be intolerant to standard therapies. An ECOG performance status of 0 or 1 and adequate organ function were also required.
Pembrolizumab was administered intravenously at a dose of 200 mg on day 1 of every 3-week cycle, totaling 35 cycles until disease progression, unacceptable toxicities, investigator decision, or withdrawal of patient consent. Imaging via CT or MRI was performed every 9 weeks within the first year and every 12 weeks subsequently.
The study had a primary end point of ORR, with key secondary end points including DOR, PFS, OS, and safety.
Investigators enrolled 90 patients who had been diagnosed with MSI-H/dMMR endometrial cancer from February 1, 2016, to September 23, 2020. At the data cutoff of October 5, 2020, a total of 79 patients had been treated with 1 or more doses of pembrolizumab. The population had a median age of 64 years (range, 42-86) and the majority had an ECOG performance status of 1 (61%). Almost half (48%) of the patients received 2 or more previous lines of therapy, with 68% previously undergoing treatment with radiation therapy.
Patients had a median treatment duration of 8.3 months. A total of 58% of patients had discontinued treatment, 20% completed all 35 cycles of treatment, and 22% were continuing treatment at the time of data cut off. The median time from first dose to data cut off was 42.6 months. Investigators stated that 14% of patients had a complete response (CR), 34% had a partial response, and 18% had stable disease, nearly all of whom experienced a reduction in tumor size (n = 13). Among the 75 patients who were evaluable for efficacy, 75% had a reduction from baseline in lesion size. Moreover, 21 of 38 patients confirmed responders had an ongoing response at the time of data cut off, 8 of whom with a CR.
A total of 57% of the patient population had progressed or died at the data cut off, 37% of whom had died. Investigators reported that the estimated PFS rate was 51% at 1 year, 41% at 2 years, and 37% at 3 and 4 years.
Adverse effects (AEs) occurred in 76% of patients, with 12% of patients experiencing grade 3/4 AEs. Notably, investigators did not report any fatal treatment-related AEs. The most common any-grade AEs were pruritus (24%), fatigue (21%), and diarrhea (16%). Few grade 3 AEs or higher occurred during the study and included hyperglycemia (2%), decreased lymphocyte count (2%), and increased transaminases (2%). Two instances of grade 4 enterocolitis and decreased neutrophil count took place in 1 patient, with both AEs having been resolved.
Immune-mediated AEs occurred in 28% of patients, the more frequent being hypothyroidism (14%), hyperthyroidism (8%), and infusion reactions (4%). Although most immune-mediated AEs were grade 1/2, 6 patients had grade 3/4 toxicities, including severe skin reactions (n = 2), adrenal insufficiency (n = 1), colitis (n = 1), hepatitis (n = 1), and type 1 diabetes mellitus (n = 1).
“Pembrolizumab demonstrated robust and durable antitumor activity with manageable toxicity in patients with advanced MSI-H/dMMR endometrial cancer. These findings support the use of pembrolizumab as a treatment option for patients with advanced MSI-H/dMMR endometrial cancer with treatment failure on prior therapy,” the investigators concluded.
References
- O'Malley D, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability–high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol. Published online January 6, 2022. doi:10.1200/JCO.21.01874
- Immunotherapy drug shows promise in advanced endometrial cancer. News release. Ohio State University Comprehensive Cancer Center–The James. January 6, 2022. Accessed January 10, 2022. https://bit.ly/3n7LEiz
Dostarlimab With Chemo Changes Practice for dMMR Endometrial Cancer
August 20th 2024“The dMMR population, which are patients who have deficiency in their mismatch repair proteins, had the most pronounced impact in PFS, and we’re seeing that trend for prolonged periods of time; we may be curing many of these patients,” said Ritu Salani, MD.
