Adding immunotherapy to chemotherapy improves survival for endometrial cancer patients

There is encouraging news for patients with endometrial cancer based on the results of two recent phase 3 clinical trials: Immunotherapy combined with chemotherapy may appreciably increase progression-free survival for patients with advanced or recurrent endometrial cancer.

Both trials—NRG-GY018 and RUBY— were presented at the Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer in Tampa, Florida. Both also appear in The New England Journal of Medicine.

The NRG-GY018 trial (doi:10.1056/NEJMoa2302312) was a double-blind, placebo-controlled, randomized study. Enrolled were 816 volunteers with stage III/IVA, stage IVB, or recurrent endometrial cancer who were randomized 1:1 to receive either pembrolizumab—an immune checkpoint inhibitor—plus chemotherapy with paclitaxel and carboplatin or a placebo plus chemotherapy for six cycles. They then received as many as 14 cycles of maintenance pembrolizumab or placebo.

All had newly diagnosed stage III or IVA disease with Response Evaluation Criteria for Solid Tumors– measurable disease or stage IVB or recurrent endometrial cancer with or without measurable disease.

The volunteers were divided into two cohorts: those who had mismatch repair–deficient (dMMR) disease and those who had mismatch repair–proficient (pMMR) disease. The primary outcome was progression-free survival in both cohorts. Interim analyses were scheduled after 84 events of death or progression in the cohort with dMMR disease and at least 196 events in the cohort with pMMR disease.

The double-blind, placebo-controlled RUBY trial (doi:10.1056/NEJMoa2216334) enrolled 494 patients with first recurrent or primary advanced stage III or IV endometrial cancer. Measurable disease was required for stages IIIA–C1, and 49 patients with carcinosarcoma—a rare and difficult-to-treat subset of endometrial cancer—were included. Volunteers were randomly assigned in a 1:1 ratio to receive 500 mg of dostarlimab or a placebo intravenously in combination with paclitaxel plus carboplatin. Doses were received every 3 weeks for the first six cycles. This was followed by 1000 mg of dostarlimab or the placebo intravenously every 6 weeks for up to 3 years.

Computed tomography or magnetic resonance imaging was performed every 6 weeks until Cycle 8 and then every 9 weeks until Week 52. Imaging was then performed every 12 weeks. There were 118 volunteers (23.9%) who had dMMR, microsatellite instability–high tumors.

For the NRG-GY018 study, the primary outcome was investigator-assessed progression-free survival according to the Response Evaluation Criteria for Solid Tumors (version 1.1). Key secondary outcomes included safety, overall survival, and health-related quality of life as assessed, the researchers reported.

“At 12-months, the percent of patients who were without evidence of disease progression or death in the dMMR cohort was 74% for the pembrolizumab group and 38% for the placebo group,” the researchers wrote. In the pMMR cohort, median progression-free survival was 13.1 months for the pembrolizumab group and 8.7 months for the placebo group. “Adverse events were as expected for pembrolizumab and combination chemotherapy,” they added.

In the RUBY study, researchers noted improved overall survival in all populations. Overall, they reported that progression-free survival at 24 months was 36.1% for the dostarlimab group and 18.1% for the placebo group; the overall survival at 24 months was 71.3% for the dostarlimab group and 56.0% for the placebo group.

In the study population group with dMMR, microsatellite instability– high tumors, the estimated rate of progression-free survival at 24 months was 61.4% for the dostarlimab group patients and 15.7% for the placebo group patients.

The researchers reported that the most common adverse event that occurred or worsened during treatment was nausea, which affected 53.9% of the patients in the dostarlimab group and 45.9% in the placebo group. This was followed by alopecia (53.5% and 50.0%, respectively), with fatigue (51.9% and 54.5%, respectively) reported as the third most common adverse event. The researchers added that “severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group.”

“We believe our study [NRG-GY018 trial] will establish a new standardof-care treatment option for patients with advanced stage or recurrent endometrial cancer,” says Ramez N. Eskander, MD, assistant professor of gynecologic oncology at the University of California San Diego. “Because of the novel design of the trial, with two independent patient cohorts, dMMR and pMMR endometrial cancer, there is confidence in the clinical benefit seen in both patient populations.”

Dr Eskander adds that the incorporation of pembrolizumab plus chemotherapy, continued as maintenance for up to 2 years of total treatment, resulted in a transformational 70% reduction in the risk of disease progression or death in the dMMR population, with 74% of the patients being free of disease recurrence or death at 12 months. “[These] results will define a new standard of care,” he says. “Furthermore, in the pMMR population, we did see an augmentation of response to immune checkpoint inhibition, when combined with chemotherapy, as evidenced in the 46% reduction in the risk of disease progression or death, and a 4.4-month improvement in median progression free survival when compared to the control arm.”

Dr Fleming agrees. She also notes that the benefit seen in patients with dMMR endometrial cancer is dramatic, with the NRG-GY018 trial showing that 74% of the patients treated with pembrolizumab were alive and without progressive disease at 12 months versus only 38% of those who received the placebo.

“More surprisingly,” she adds, “benefit was also seen in patients with pMMR disease, with a median time until disease progression of 13.1 months for women receiving pembrolizumab versus only 8.7 months for those getting a placebo.”

She also believes that the standard of care from now going forward will be the addition of immunotherapy to frontline chemotherapy for women with advanced endometrial cancer, regardless of their microsatellite status. “Clearly, it would be desirable to have better markers to choose which of the patients with microsatellite stable disease truly benefit, but these do not yet exist,” she says.

Dr Fleming notes that there are several differences between the two studies. One major difference, she says, is the inclusion of women with carcinosarcoma in the RUBY trial as well as the longer follow-up of the RUBY study. She hopes that future analyses will confirm that women with carcinosarcoma benefit along with all other patients with endometrial cancer. Moreover, she says, the duration of immunotherapy after the completion of chemotherapy was only fourteen 6-week cycles (84 weeks) for the NRG-GY018 trial and was 3 years for dostarlimab in the RUBY trial. Obviously, if a shorter duration of immunotherapy is as beneficial as a longer one, that would be a preferable regimen.