Phase III Trials 'Hit a Home Run' in Advanced Endometrial Cancer

TAMPA, Fla. -- Immunotherapy combined with standard chemotherapy significantly improved progression-free survival (PFS) in patients with advanced or recurrent endometrial cancer, according to results from two randomized phase III trials presented at the Society of Gynecologic Oncology (SGO) annual meeting.

In the NRG-GY018 trial, the PFS rates were estimated to be 74% with the addition of pembrolizumab (Keytruda) to paclitaxel plus carboplatin and 38% with placebo at 12 months among patients with mismatch repair-deficient (dMMR) disease (HR 0.30, 95% CI 0.19-0.48, P<0.001), reported Ramez N. Eskander, MD, of the University of California San Diego.

Among patients with mismatch repair-proficient (pMMR) disease, the median PFS was 13.1 months in the pembrolizumab group and 8.7 months in the placebo group (HR 0.54, 95% CI 0.41-0.71, P<0.001).

In the RUBY trial, the estimated PFS at 24 months was 61.4% with the addition of dostarlimab (Jemperli) to paclitaxel-carboplatin compared with 15.7% with placebo in patients with dMMR, microsatellite instability-high (MSI-H) tumors (HR 0.28, 95% CI 0.16-0.50, P<0.001), reported Mansoor R. Mirza, MD, of Copenhagen University Hospital in Denmark.

In the overall population, the PFS rate was 36.1% in the dostarlimab group and 18.1% in the placebo group (HR 0.64, 95% CI 0.51-0.80, P<0.001), while overall survival rates at 24 months were 71.3% and 56.0%, respectively (HR 0.64, 95% CI 0.46-0.87).

Both studies were also published in the New England Journal of Medicine.

Considering that endometrial cancer is one of the few malignancies for which mortality rates have actually increased over the last 40 years, SGO discussant Rebecca Arend, MD, of the University of Alabama at Birmingham, called the study results "groundbreaking," adding that both trials "hit a home run" in confirming the hypothesis that the addition of chemotherapy could improve the response to checkpoint inhibitors.

"For those of us who do research, whether it be in the lab or in the clinic, all dream to be part of something that actually changes clinical care," she said, noting that the investigators should be particularly commended for successfully conducting the trials during a pandemic, and for including a large number of traditionally underrepresented patients. "It's a huge win for patients."

Bhavana Pothuri, MD, of the NYU Langone Perlmutter Cancer Center in New York City, who was involved in both studies, said the results will "change the treatment paradigm in the frontline treatment of endometrial cancer."

She noted that the NRG-GY018 trial "adds significant value" on the efficacy of pembrolizumab in patients with pMMR endometrial cancer, and called the hazard ratio of 0.54 "really impressive."

"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," she added.

NRG-GY018 Trial

Eskander and colleagues enrolled 816 patients -- 225 in the dMMR cohort and 591 in the pMMR cohort -- with stage III, IVA, or IVB disease or recurrent disease. They were randomized 1:1 to receive pembrolizumab or placebo along with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks.

Median age in the dMMR patients was 66, and 79% were white, while in the pMMR group, median age was 65.5, and 72% were white.

Median follow-up was 12 months for the dMMR group and 7.9 months for the pMMR group.

"Importantly, at the time of interim PFS analysis crossing the efficacy boundary, an interim overall survival futility analysis was conducted that showed no evidence of a detriment, with findings consistent with the primary PFS endpoints," Eskander reported.

Grade ≥3 adverse events (AEs) in the dMMR population occurred in 63.3% and 47.2% of the pembrolizumab and placebo arms, respectively. For the pMMR cohort, these rates were 55.1% and 45.3%, respectively.

RUBY Trial

This trial enrolled 494 patients with histologically or cytologically confirmed primary advanced or recurrent stage III or IV endometrial cancer that was not amenable to curative therapy. They were randomly assigned 1:1 to receive dostarlimab 500 mg (median age 64, 77% white) or placebo (median age 65, 76.7% white), plus carboplatin and paclitaxel every 3 weeks, followed by dostarlimab 1,000 mg or placebo every 6 weeks for up to 3 years.

Of these patients, 23.9% had dMMR, MSI-H tumors.

"The side effects seen are usually what are seen with carboplatin-paclitaxel or with dostarlimab," Mirza observed. Any grade ≥3 AEs occurred in 70.5% of patients receiving dostarlimab versus 59.8% in the placebo arm.

The most common AEs that occurred or worsened during treatment 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%).

The combination demonstrated "a statistically significant and clinically meaningful PFS benefit, with an early OS trend in the overall population, with substantial, unprecedented benefit in dMMR patients, and a clinically meaningful, long-term benefit observed in the MMR-proficient patients," Mirza concluded. "Dostarlimab plus carboplatin/paclitaxel represents a new standard of care for patients with primary advanced or recurrent endometrial cancer."

Correction: An earlier version of this story stated that Pothuri was not involved in the trials.