Immune Checkpoint Inhibitor-Chemo Combo Boosts OS in Advanced Endometrial Cancer

SAN DIEGO — The addition of an immune checkpoint inhibitor (ICI) to chemotherapy up front improved overall survival (OS) in patients with advanced or recurrent endometrial cancer, regardless of mismatch repair (MMR) status, according to two trials.

In the phase III RUBY Part 1, patients treated with dostarlimab (Jemperli) and chemotherapy had a median OS of 44.6 months compared with 28.2 months for patients treated with chemotherapy plus placebo, for a 16.4-month improvement, reported Matthew A. Powell, MD, of Washington University in St. Louis.

“This is despite the fact that over 38% of patients went on to receive immunotherapy in the placebo arm,” Powell said, during a presentation at the Society of Gynecologic Oncology (SGO) annual meeting.

Moreover, there was an “unprecedented benefit” in patients who were MMR deficient (dMMR) he said, with a 68% improvement in survival (HR 0.32, 95% CI 0.17-0.63, P=0.0002) among patients receiving dostarlimab.

This is the first trial demonstrating an OS benefit among patients with primary advanced or recurrent endometrial cancer, Powell stated, and confirms “dostarlimab plus carboplatin/pacitaxel as a new standard of care for patients with primary advanced or recurrent endometrial cancer, regardless of MMR status.”

The second study at SGO was an interim OS analysis of the phase III NRG-GY018/KEYNOTE-868 trial, which was immature with an information fraction of 27.2% for patients with proficient MMR (pMMR) and 18.0% for dMMR disease.

The trial showed that the addition of pembrolizumab (Keytruda) to standard chemotherapy resulted in a favorable OS trend (HR 0.79, 95% CI 0.53-1.17, P=0.1157) for pMMR patients. That trend also was favorable among dMMR patients (HR 0.55, 95% CI 0.25-1.19, P=0.0617).

“And this was despite 55% of patients in the control arm receiving subsequent immunotherapy at the time of data cutoff,” reported Ramez N. Eskander, MD, of the University of California San Diego.

A ‘Huge Win’

“Sold,” said SGO discussant Gini Fleming, MD, of the University of Chicago, in assessing the results of the two studies. “I think this is a huge win for our patients — something that none of us have seen before in many years of working with endometrial cancer — and it should be incorporated into everyone’s practice as of yesterday.”

“I think the data for GY018 data are on par with the RUBY data; they’re simply less mature” she added. “And remember, these benefits were observed despite substantial crossover of patients who got placebo subsequently getting immune checkpoint inhibitor therapy.”

ICI therapy “should be given first line to patients with advanced/recurrent MSI [microsatellite instability] endometrial cancer,” Fleming emphasized. “And it should be considered as front line in patients with microsatellite stable disease.”

RUBY Part 1

Last year the FDA approved dostarlimab in combination with chemotherapy as an option for adults with primary advanced or recurrent endometrial cancer that is dMMR or MSI-high (MSI-H).

Approval was based on interim results from part 1 of the RUBY trial showing that adding dostarlimab to frontline chemotherapy in the dMMR/MSI-H population reduced the risk for disease progression or death by 71% versus chemotherapy alone. Also in these patients, the interim analysis showed a median progression-free survival (PFS) of 30.3 months in the dostarlimab arm versus 7.7 months in the placebo arm. Powell reported PFS2 data at SGO.

The trial included 494 patients with primary advanced or recurrent endometrial cancer (118 with dMMR/MSI-H status) who were randomly assigned to receive dostarlimab IV plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel every 3 weeks for six cycles, followed by dostarlimab at 1,000 mg or placebo alone, every 6 weeks for up to 3 years or until disease progression.

The median age between the two arms was 64.5, with about half of patients at least age 65. A total of 87.3% of patients had measurable disease at baseline and 20.3% had previously received anticancer therapy.

The 16.4-month improvement in median OS translated in a 31% reduced risk of death among patients treated with dostarlimab plus chemotherapy versus chemotherapy alone (HR 0.69, 95% CI 0.54-0.89, P=0.002). OS at 24 months was 70.1% and 54.3%, respectively, while 36-month OS was 54.9% and 42.9%.

In addition to the OS benefit observed in the dMMR/MSI-H population, Powell reported that there was also a benefit seen in the pMMR/microsatellite stable population (HR. 0.79, 95% CI 0.60-1.04, P=0.0493).

Regarding the PFS2 endpoint, there was a substantial benefit in favor of the dostarlimab regimen in the overall population (HR 0.66, 95% CI o.52-0.84) that was even more pronounced in the dMMR/MSI-H population (HR 0.33, 95% CI 0.18-0.63).

Powell reported there were no new safety signals observed in this updated analysis.

NRG GY018/KEYNOTE-868

In this phase III trial, 81o patients (588 with pMMR; 222 with dMMR status) were randomized to pembrolizumab or placebo along with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in six cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks.

Previously reported PFS results demonstrated a significant and clinically meaningful benefit with pembrolizumab plus chemotherapy, followed by pembrolizumab, in both patients with dMMR (HR 0.30, 95% CI 0.19-0.48, P<0.001), and pMMR disease (HR 0.54, 95% CI 0.41-0.71, P<0.001).

In addition to the interim OS results described above, Eskander reported that the vast majority of patients in this study had tumors expressing PD-L1 “and that the therapeutic benefit of pembrolizumab persisted irrespective of PD-L1 status.”

Specifically, in the PD-L1-positive pMMR cohort, the median PFS was 13.1 months with pembrolizumab versus 8.5 months with placebo (HR 0.59, 95% CI 0.43-0.80), while the median PFS was 15.1 months with pembrolizumab versus 11 months with placebo (HR 0.44, 95% CI 0.26-0.75) in the PD-L1-negative pMMR cohort.

Median PFS also favored pembrolizumab in the dMMR population irrespective of PD-L1 status, with HRs of 0.30 (95% CI 0.11-0.83) among PD-L1-negative patients and 0.27 (95% CI 0.16-0.47) among PD-L1 positive patients.

“These data strongly support the incorporation of pembrolizumab in conjunction with chemotherapy, and continued as maintenance, for the treatment and management of patients with advanced or recurrent endometrial cancer, irrespective of MMR status,” Eskander concluded.

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