Pembrolizumab monotherapy produced meaningful, durable responses in patients with previously treated, advanced microsatellite instability–high or mismatch repair–deficient endometrial cancer.
David O'Malley, MD
Pembrolizumab (Keytruda) monotherapy produced meaningful, durable responses in patients with previously treated, advanced microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) endometrial cancer, according to data from the phase 2 KEYNOTE-158 trial (NCT02628067) published in the Journal of Clinical Oncology.1
The immunotherapy induced an objective response rate (ORR) of 48% (95% CI, 37%-60%) per independent central radiologic (ICR) review in 79 patients who comprised the efficacy analysis population. Of those who responded, 14% achieved a complete response (CR), and 34% experienced a partial response (PR). Notably, 21 of the 38 patients who achieved a CR, including 8 of 11 who had a confirmed CR, had ongoing responses at the time of data cutoff, which was October 5, 2020. Eighteen percent of patients had stable disease, and 13 of those 14 patients experienced a reduction in tumor size from baseline.
Moreover, patients who received less than 2 lines of prior therapy (n = 38) experienced an ORR of 53% (95% CI, 36%-69%) vs an ORR of 44% (95% CI, 28%-60%) in those who received at least 2 prior lines (n = 41). Patients who were administered prior radiation therapy (n = 56) experienced an ORR of 52% (95% CI, 38%-65%) with single-agent pembrolizumab vs an ORR of 39% (95% CI, 20%-61%) in those who did not receive prior radiation therapy (n = 23).
“Pembrolizumab demonstrated robust and durable antitumor activity with manageable toxicity in patients with advanced MSI-H/dMMR endometrial cancer,” lead study author David M. O’Malley, MD, of The Ohio State University Comprehensive Cancer Center, and colleagues, wrote. “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.”
Approximately 25% to 31% of patients with endometrial cancer have tumors with high levels of MSI-H and dMMR. Specifically, dMMR occurs as a mutation in 1 of the following MMR genes: MLH1, PMS2, MSH2, and MSH6 mutations; it can also occur as sporadic methylation of the MLH1 promoter.2 MSI-H and dMMR tumors have a clear increase in somatic mutations compared with non–MSI-H and dMMR tumors.3
Previously, pembrolizumab elicited an ORR of 13% in patients with PD-L1–positive endometrial cancer who were enrolled to the phase 1b KEYNOTE-028 trial (NCT02054806).4 Results from a prospective analysis of the phase 2 KEYNOTE-016 trial (NCT01876511) showed that the immunotherapy produced an objective response in 53% of those with dMMR endometrial cancer.5 Moreover, findings from an initial analysis of the phase 2 KEYNOTE-158 trial showed that pembrolizumab induced an ORR of 34.3% in patients with previously treated unresectable or metastatic MSI-H and dMMR non–colorectal cancers (CRCs).6
The open-label, multicohort KEYNOTE-158 trial enrolled patients with several types of advanced solid tumors. Cohort D of the trial was comprised of those with endometrial carcinoma, and cohort K included those with any advanced solid tumor except for CRC that was MSI-H/dMMR, including endometrial cancer.
To be eligible for enrollment, patients needed to be at least 18 years of age with histologically or cytologically documented advanced metastatic and/or unresectable disease that was incurable. Patients had to have experienced disease progression on, or have intolerance to, standard therapies. Patients also needed to have radiologically measurable disease per RECIST v. 1.1 criteria and ICR review, an ECOG performance status of 0 or 1, and adequate organ function.
If patients had a diagnosis of immunodeficiency, received systemic steroid therapy or immunosuppressive therapy within 7 days of first dose, had active autoimmune disease requiring systemic therapy within 2 years, or received treatment with a monoclonal antibody or an investigational agent within 4 weeks, they were excluded.
Other key exclusion criteria included use of chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks; known active central nervous system metastases and/or carcinomatous meningitis; current pneumonitis or history of pneumonitis that required steroids; and an active infection requiring systemic therapy.
Participants were given pembrolizumab intravenously at a dose of 200 mg on day 1 of each 3-week treatment cycle for 35 cycles, which equated to approximately 2 years. Treatment was administered until documented disease progression, unacceptable adverse effects (AEs), intercurrent illness preventing further treatment, investigator decision, or patient withdrawal of consent.
Notably, patients who achieved CR, PR, or stable disease with pembrolizumab were eligible to receive up to 17 cycles of retreatment with the immunotherapy after disease progression, if safety criteria were met.
The primary end point of the trial was ORR, which was defined as the proportion of patients achieving CR or partial response per RECIST v1.1 criteria and ICR review, for patients with an enrolled tumor type and a positive tumor sample for 1 of the prespecified biomarkers, including MSI-H and dMMR. Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Results from an initial analysis of KEYNOTE-158 showed that single-agent pembrolizumab elicited an ORR of 57% in the first 49 patients with MSI-H/dMMR endometrial cancer.7 In the paper, O’Malley and colleagues shared safety and efficacy findings in a larger number of patients, with longer follow-up in those with previously treated, advanced MSI-H/dMMR disease.
A total of 90 patients with MSI-H and dMMR endometrial cancer were enrolled to cohorts D (n = 11) and K (n = 79) between February 1, 2016, and September 23, 2020. As of the data cutoff, 79 patients were eligible for efficacy analysis after having received at least 1 dose of pembrolizumab and having been enrolled to the trial for at least 26 weeks before cutoff.
The median age of these participants was 64 years (range, 42-86), and 61% had an ECOG performance status of 1. Moreover, 48% had received at least 2 lines of prior therapy, and 68% had previously received radiation treatment. The median duration of treatment was 8.3 months (range, 1 day to 26.9 months).
At data cutoff, 58% of patients had discontinued treatment with pembrolizumab, 20% had completed 35 cycles, and 22% were still on study treatment. Two patients received a second course of the immunotherapy. In the efficacy population, the median time from first dose to data cutoff was 42.6 months (range, 6.4-56.1).
Additional data indicated that among 75 evaluable patients in the efficacy population who had at least 1 post-baseline tumor assessment, 75% experienced a reduction in target lesion size with pembrolizumab.
The median DOR was not yet reached (NR; range, 2.9-49.7+). Moreover, 88% of patients were estimated to have a response duration of 1 year or longer, and 73% of patients were estimated to have a response duration of 2 years or longer. The Kaplan-Meier estimate of the proportion of patients with response duration at 3 years or longer was 68%.
The median PFS with pembrolizumab was 13.1 months (95% CI, 4.3-34.4). The estimated 1- and 2-year PFS rates were 51% and 41%, respectively; at 3 and 4 years, this rate was 37%. Moreover, the median OS was NR in these patients. The Kaplan-Meier estimated 1-year, 2-year, and 3- and 4-year OS rates were 69%, 64%, and 60%, respectively. Fifty-seven percent of patients experienced disease progression or died.
Study authors noted no new safety signals with pembrolizumab.
AEs considered by the investigator to be related to study treatment occurred in 76%, with grade 3 or 4 treatment-related AEs occurring in 12% of patients. Notably, no fatal treatment-related toxicities were observed.
The most common AEs of any grade included pruritus (24%), fatigue (21%), and diarrhea (16%). The only grade 3 or higher treatment-related AEs to occur in 2 or more patients were hyperglycemia (2%), decreased lymphocyte count (2%), and increased transaminases (2%). Two grade 4 treatment-related AEs were reported and included enterocolitis and decreased neutrophil count; they occurred in the same patient.
Seven percent of patients discontinued treatment because of a treatment-related toxicity, which included increased transaminases (n = 2), arthritis (n = 1), drug-induced liver injury (n = 1), enterocolitis (n = 1), and rash (n = 1).
Immune-mediated AEs were reported in 28% of patients and the most frequent effects included hypothyroidism (14%), hyperthyroidism (8%), and infusion reactions (4%). Most of these toxicities were either grade 1 or 2 in severity. However, 7% of patients reported grade 3 or 4 immune-mediated toxicities, and these included severe skin reactions (n = 2), adrenal insufficiency (n = 1), colitis (n = 1), hepatitis (n = 1), and type 1 diabetes mellitus (n = 1).
Two patients discontinued treatment because of an immune-mediated toxicity, 1 of which was colitis and the other was hepatitis.