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Adding immunotherapy to standard chemotherapy in the first-line treatment of patients with advanced or recurrent endometrial cancer significantly improves outcomes, according to findings from two separate randomized phase 3 trials.

One trial added pembrolizumab (Keytruda), is fenofibrate good for you and the other added dostarlimab (Jemperli).

Both studies were presented at the Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer and were published at the same time in the New England Journal of Medicine.

At the meeting, invited discussant Rebecca C. Arend, MD, MSPH, from the University of Alabama at Birmingham and the O’Neal Comprehensive Cancer Center, noted that endometrial cancer is the only gynecologic cancer for which the mortality rate is rising. That is why these two new studies are important, she added.

“Both of these trials hit a home run,” she said. “And this changes clinical care.”

Approached for comment, Bhavana Pothuri, MD, gynecologic oncologist at the New York University Langone Perlmutter Cancer Center, agreed. She predicted that these two papers will change the treatment paradigm in the frontline treatment of endometrial cancer.

“The most exciting thing taking these two studies together is that the treatment landscape will change to incorporate immunotherapy into the treatment of all patients with endometrial cancer irrespective of biomarker status,” said Pothuri. “Hopefully race and ethnicity will be reported, as Black women have twice the mortality of a White woman diagnosed with endometrial cancer and they represent the greatest medical need.”

Dostarlimab Already Approved for Endometrial Cancer

Dostarlimab is already approved in both the European Union and the United States for use in patients with advanced or recurrent endometrial cancer who have tumors that are mismatch repair–deficient (dMMR).

The results from the two new studies show that there is also clinically relevant benefit from adding immunotherapy to standard chemotherapy first-line in patients who have mismatch repair–proficient (pMMR) disease.

Results from the phase 3 trial with dostarlimab, known as ENGOT-EN-6-NSGO/GOG-3031/RUBY, show that the largest benefit from adding this immunotherapy to standard chemotherapy is seen in patients with dMMR disease. In this subgroup (which comprised 24% of the total study population), there was a 72% lower risk for progression or death. But the results also show a 36% lower risk in the overall population.

“There was also an early trend toward improved overall survival in all populations,” noted lead author Mansoor R. Mirza, MD, chief oncologist at the Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark.

He concluded that “dostarlimab plus carboplatin/paclitaxel represents a new standard of care for patients with primary advanced or recurrent endometrial cancer.”

Details of Dostarlimab Trial

The dostarlimab trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m2 of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years.

Within the cohort, 118 patients (23.9%) had dMMR, microsatellite instability–high (MSI-H) tumors.

In the dMMR–MSI-H subgroup, the estimated progression-free survival at 24 months was 61.4% in the dostarlimab group vs 15.7 in the placebo group (hazard ratio [HR] for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < 0.001).

A prespecified exploratory analysis of progression-free survival in pMMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.

Overall survival also favored dostarlimab, although Mirza cautioned that it was only mature for 33% of the population. But at 24 months, overall survival was 71.3% vs 56.0% among placebo recipients (HR for death, 0.64).

The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR–MSS population.

The most common adverse events observed were nausea (53.9% in the dostarlimab group and 45.9% in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Grade 3 and higher adverse events were more frequent in the dostarlimab group than in the placebo group (70.5% vs 59.8%).

“The safety profile for dostarlimab and chemotherapy was manageable and generally consistent with that of the individual drugs,” said Mirza.

Details of Pembrolizumab Trial

Endometrial cancer is one of the few types of cancer with a rising incidence and mortality, and it is projected to be the third most prevalent cancer and the fourth leading cause of cancer death among women, noted Ramez N. Eskander, MD, associate clinical professor in Ob/Gyn & Reproductive Sciences at the University of California, San Diego.

“Unlike many solid malignancies, survival for women with advanced stage or metastatic endometrial cancer has not improved over the past four decades,” he said. “This reflects limited therapeutic advancements.”

Eskander was the lead author on the pembrolizumab presentation, which showcased the results from the NRG-GYO18 trial. This involved 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer who were randomized to receive pembrolizumab or placebo alongside standard chemotherapy with paclitaxel plus carboplatin.

The cohort was stratified into two arms according to whether they had dMMR or pMMR tumors.

Previous treatment with chemotherapy was permitted only if it had been administered in the adjuvant setting at least 12 months before baseline.

The primary outcome was progression-free survival in the two cohorts.

In the dMMR cohort, median progression-free survival was not reached in the pembrolizumab arm but was 7.6 months in the placebo arm (HR, 0.30; P < .001); in the pMMR cohort, it was 13.1 months vs 8.7 months (HR, 0.54; P < .001).

“Subgroup analysis showed consistent benefit for pembrolizumab across all subgroups,” said Eskander.

Quality of life was assessed in the pMMR cohort at baseline and was similar in pembrolizumab group and the placebo group (86% and 87%, respectively) at 6 weeks after randomization. Assessments at subsequent preplanned intervals (weeks 18, 30, and 54) are in progress.

Adverse events were as expected for pembrolizumab and combination chemotherapy, Eskander commented. Toxicity was similar in both groups. In the dMMR cohort, adverse events of any cause occurred in 98.2% of the patients in the pembrolizumab group vs 99.1% in the placebo group. In the pMMR cohort, these percentages were 93.5% vs 93.4%, respectively. In the dMMR cohort, 63.3% of the pembrolizumab group vs 47.2% of the placebo group had grade 3 or higher adverse events. Similar results were observed in the pMMR cohort: 55.1% vs 45.3%.

Commenting on this study, Pothuri said, “The GY-018 trial adds significant value by also evaluating efficacy of pembrolizumab in patients with MMR-proficient endometrial cancer in a prespecified analytic cohort…. In this subgroup, the HR was 0.54, which also is really impressive.”

A ‘Home Run’

At the meeting, invited discussant Arend said that both trials “hit a home run.”

More remarkable is that both trials were conducted in the time of a global pandemic. “Additionally, in both trials, nearly one quarter of the patients were underrepresented minorities,” she commented.

But although both studies were “huge wins,” there remain unanswered questions, she pointed out.

Questions that remain are whether immunotherapy the best option for all patients, and whether other agents can be added or sequenced to improve the efficacy of immune checkpoint inhibitor therapy in pMMR tumors, she said.

“We also need to know how the analysis of overall survival impacts decision-making and how regulatory approvals affect the clinical trial landscape in endometrial cancer going forward,” she added.

The GY018 study was supported by grants from the National Cancer Institute (NCI). Funding and support were received from Merck & Co (manufacturer of pembrolizumab), through a Cooperative Research and Developmental Agreement with NCI. Merck also provided supplemental funding to NRG Oncology for this study. The RUBY study was funded by GlaxoSmithKline (manufacturer of dostarlimab). Eskander reports relationships with AstraZeneca, Cardiff Oncology, Clovis Oncology, Daiichi Sankyo, Eisai, Elevar Therapeutics, Gilead, GSK/Tesaro, ImmunoGen, Merck, Mersana, Myriad, Novocure, and Seagen. Mirza reports relationships with Apexigen, AstraZeneca, Biocad, Deciphera, GSK, Karyopharm, Merck, Roche, Ultimovacs, and Zai Lab. Arend reports relationships with Exelixis, Immunogen, Merck, Seagen, Sutro, GSK, VBL Therapeutics, and Kiyatec.

Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 17, 2023; published online March 27, 2023. Pembrolizumab study; dostarlimab study

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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