By 2040, endometrial cancer is projected to be the third most prevalent cancer and the fourth leading cause of cancer death among women. With limited treatment advancements for advanced endometrial cancer, there is a need for novel approaches.
A study conducted by researchers at the UC San Diego School of Medicine and Moores Cancer Center at UC San Diego Health demonstrated that a combination of immunotherapy and chemotherapy led to a significant reduction in disease growth among patients with advanced or recurrent/advanced endometrial cancer when compared with chemotherapy alone.
Data from the Phase III, NRG-GY018 study showed that pembrolizumab combined with carboplatin and paclitaxel, followed by maintenance pembrolizumab, was associated with a statistically significant and clinically meaningful improvement in progression-free survival, regardless of mismatch repair status, the study authors reported. These findings were presented during the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting and published simultaneously in the New England Journal of Medicine (2023; doi:10.1056/NEJMoa2302312).
Currently, pembrolizumab has two FDA-approved indications in the U.S. for the treatment of endometrial cancer. In March 2022, it was approved as a single agent for patients with advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair-deficient, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation.
Prior to this, in July 2021, the FDA approved pembrolizumab in combination with lenvatinib for patients with advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair-deficient.
"Outcomes for women with metastatic or recurrent endometrial cancer remain suboptimal," noted principal investigator and lead study author Ramez N. Eskander, MD, Associate Professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences at UC San Diego School of Medicine, while discussing the rationale behind this research with Oncology Times. "With improved understanding of the molecular features of endometrial cancer, we looked to examine if the addition of the immune checkpoint inhibitor pembrolizumab to chemotherapy could improve outcomes.
"These results may transform the way we care for patients with advanced stage or recurrent/advanced uterine cancer. Currently, chemotherapy alone is used in the first-line treatment for patients with this disease," he emphasized, in a statement. "It is critical that we work to identify effective and innovative treatments and combination therapies, such as immunotherapy and chemotherapy, to attack this cancer and give patients more time to live their lives fully."
Study Methodology
Patients enrolled in this double-blind, placebo-controlled, randomized, Phase III trial included adult women with advanced-stage, metastatic, or recurrent endometrial cancer of any histologic subtype except for carcinosarcoma. Study participants were divided into two cohorts based on whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease.
All patients had newly diagnosed Stage III or IVA disease, Stage IVB, or recurrent endometrial cancer. Patients who previously underwent adjuvant chemotherapy were eligible if the treatment-free interval was at least 12 months, according to the study authors. Prior radiation or hormonal therapy was also permitted.
Eskander and colleagues randomized patients in a 1:1 ratio to receive pembrolizumab or placebo along with the combination therapy of paclitaxel plus carboplatin for 6 cycles followed by pembrolizumab or placebo maintenance every 6 weeks for up to 14 cycles. Patients could undergo a maximum of 20 cycles of pembrolizumab or placebo.
"Patients received 200 mg of pembrolizumab or placebo administered intravenously in a 30-minute infusion every 3 weeks in combination with chemotherapy, followed by 400 mg of pembrolizumab or placebo maintenance, administered intravenously in a 30-minute infusion every 6 weeks," the study authors stated. "On Day 1 in the chemotherapy portion of the therapy, patients received paclitaxel administered intravenously in a 3-hour infusion at a dose of 175 mg per square meter of body-surface area plus carboplatin at an area under the curve of 5 mg per milliliter per minute administered intravenously over 30 to 60 minutes," they detailed in their NEJM paper.
For patients with measurable disease who had RECIST-defined stable disease or a partial response at the completion of Cycle 6, the treating investigator had the option to administer paclitaxel plus carboplatin-with pembrolizumab or placebo-for up to 10 cycles.
The primary endpoint of the study was investigator-assessed progression-free survival by RECIST v1.1. Secondary endpoints included overall survival, safety, and quality-of-life measures. The research team scheduled interim analyses to be initiated after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR group.
Key Findings & Implications
From July 2019 through December 2022, Eskander and colleagues enrolled a total of 816 patients, with 225 in the dMMR cohort and 591 in the pMMR cohort. Of these patients, 588 were available for evaluation for efficacy analysis. The study authors reported that most demographic characteristics, as well as clinical and pathological factors, were well balanced between patients in the pembrolizumab and placebo arms.
"Of the 223 patients with centrally determined dMMR status (with two confirmations pending at the time of analysis), the results had been locally identified as pMMR in 17 patients (7.6%)," the investigators wrote. "Of the 573 patients with centrally determined pMMR status (with 15 confirmations pending), the results had been locally identified as dMMR in 12 patients (2.1%)."
Approximately 6 percent of patients in the dMMR cohort and 25.3 percent in the pMMR group received adjuvant chemotherapy prior to study enrollment. Additionally, the study authors noted that approximately 43 percent of dMMR patients and 39.6 percent of those in the pMMR cohort were administered radiotherapy.
In terms of race, patients identified their race as Black in 8.9 percent of the dMMR cohort compared with 16.3 percent of the pMMR cohort, according to Eskander and colleagues, who noted that this "reflects the higher incidence of histologic and molecular subtypes associated with poor prognosis among Black women than among women of other races."
In the dMMR and pMMR cohorts, the median follow-up was 12 months and 7.9 months, respectively. At the time of the primary analysis, the study authors highlighted that 39.6 percent of the patients in the dMMR group and 41.8 percent of individuals in the pMMR group were still receiving either pembrolizumab or placebo. Additionally, they noted that 57 percent of patients in the trial discontinued treatment in the pembrolizumab and placebo arms, largely due to disease progression.
When discussing efficacy results, Eskander reported to Oncology Times, "As presented in the dMMR cohort, the addition of pembrolizumab to chemotherapy resulted in a 70 percent reduction in the risk of disease progression or death (HR: 0.30; P<0.00001). The median PFS in the pembrolizumab arm was not reached versus 7.6 months in the placebo arm of the trial.
"In the pMMR cohort, the addition of pembrolizumab to chemotherapy resulted in a 46 percent reduction in the risk of disease progression or death (HR: 0.54; P<0.0001)," he continued. "Median PFS in the pembrolizumab arm was 13.1 months versus 8.7 months in the placebo arm of the trial."
Pembrolizumab's safety profile was consistent with previously reported studies with no new safety signals identified. In the pMMR cohort, researchers observed Grade 3-5 adverse events in 55.1 percent of patients who received the pembrolizumab regimen compared with 45.3 percent in those who underwent chemotherapy alone.
Among the dMMR cohort, Grade 3-5 adverse events were reported in 63.3 percent of patients in the pembrolizumab arm versus 47.2 percent in the placebo arm. Pembrolizumab-related adverse events did not lead to death in either cohort.
Eskander and his team assessed quality of life among 588 patients in the pMMR cohort at baseline and in similar percentages of patients in the pembrolizumab and placebo groups-86 percent and 87 percent, respectively-at 6 weeks following randomization. "In the two cohorts, assessments of quality of life at subsequent preplanned intervals (Weeks 18, 30, and 54) were in progress at the time of this report," they noted in their current analysis.
The study authors acknowledged that the relatively short duration of follow-up in this trial is a limitation. They noted that, while protocol-specified criteria were met for the primary efficacy analysis of progression-free survival in both patient cohorts, safety and efficacy monitoring will continue.
"Our results show that pembrolizumab in combination with chemotherapy and continued as maintenance therapy led to significantly longer progression-free survival than placebo in patients with dMMR and pMMR endometrial cancers," Eskander and colleagues said.
When asked what questions remain unanswered, Eskander proposed the following: In the dMMR population, is pembrolizumab alone sufficient? In the pMMR population, what is driving these responses? As a next step, the research team will continue to analyze the secondary endpoints as noted in the protocol, including additional biomarker responses, response rate, safety data, and overall survival.
"These are exciting results that are both statistically significant and reflective of a clinically meaningful benefit," according to Eskander, who concluded, "We anticipate that these dramatic results will change the standard of care treatment for patients with advanced stage or recurrent endometrial cancer."
Catlin Nalley is a contributing writer.
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