Add-on immunotherapy improves PFS in 1L advanced or recurrent endometrial cancer

Adding dostarlimab or pembrolizumab to standard first-line (1L) chemotherapy significantly improves progression-free survival (PFS) in patients with advanced or recurrent endometrial cancer, two phase III trials have shown.

These trials, presented at the Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer (SGO 2023) and published in the New England Journal of Medicine, are anticipated to change the 1L treatment landscape of the disease.

Dostarlimab: The RUBY trial

In the RUBY trial, 494 patients with newly diagnosed primary advanced stage III or IV or first recurrent endometrial cancer were randomized 1:1 to receive dostarlimab 500 mg (n=245; median age, 64 years) or placebo (n=249; median age, 65 years) in combination with carboplatin and paclitaxel, followed by dostarlimab 1,000 mg or placebo every 6 weeks for up to 3 years. Primary endpoints were PFS in the mismatch repair–deficient (dMMR), microsatellite instability–high (MSI-H) population (n=118; dostarlimab group, n=53; placebo group, n=65) and overall population, and overall survival (OS) in the overall population. [Mirza M, et al, SGO 2023, abstract 12; N Engl J Med 2023;doi:10.1056/NEJMoa2216334]

“Dostarlimab in combination with carboplatin and paclitaxel significantly improved outcomes for patients with newly diagnosed primary advanced or recurrent endometrial cancer, with substantial benefit seen in dMMR–MSI-H tumours,” the researchers reported.

“The PFS improvement is unprecedented, especially in the 25 percent of patients with so-called ‘hot’ endometrial tumours that have deficient DNA mismatch repair mechanisms,” said lead author, Dr Mansoor Mirza of Copenhagen University Hospital in Denmark.

At the first interim analysis, 24-month PFS rate in the dMMR–MSI-H population was 61.4 percent in the dostarlimab group vs 15.7 percent in the placebo group (hazard ratio [HR], 0.28; 95 percent confidence interval [CI], 0.16–0.50; p<0.001), after a median follow-up of 24.8 months. In the overall population, 24-month PFS rate was 36.1 percent vs 18.1 percent (HR, 0.64; 95 percent CI, 0.51–0.80; p<0.001), after a median follow-up of 25.4 months.

“Results appeared to favour the dostarlimab regimen across most evaluated subgroups. However, results in patients with stage III disease and patients with no disease at baseline were not consistent with those in other subgroups. Results in subgroups of the overall population were more heterogeneous than those in the dMMR–MSI-H population,” the investigators noted.

In patients with mismatch repair–proficient (pMMR), microsatellite-stable (MSS) tumours, a prespecified exploratory analysis showed PFS benefit with dostarlimab vs placebo, with 24-month PFS rates of 28.4 percent vs 18.8 percent (HR, 0.76; 95 percent CI, 0.59–0.98).

“There was also an early indication of improved OS with dostarlimab,” said Mirza.

At 24 months, OS rate in the overall population was 71.3 percent vs 45.9 percent in the dostarlimab vs placebo group (HR, 0.64; 95 percent CI, 0.46–0.87; p=0.0021), which did not reach the level of statistical significance established as the stopping boundary (p<0.00177). Corresponding 24-month OS rates in the dMMR–MSI-H population were 83.8 percent vs 58.7 percent (HR, 0.30; 95 percent CI, 0.13–0.70).

“Dostarlimab plus carboplatin and paclitaxel represents a new standard of care for patients with primary advanced or recurrent endometrial cancer,” Mirza suggested.

In the trial, severe and serious adverse events (AEs) were more frequent in the dostarlimab vs placebo group. However, the safety profile of the combination regimen was generally consistent with the known safety profiles of individual drug components.

The most common AEs that occurred or worsened during treatment were nausea (53.9 percent vs 45.9 percent in the dostarlimab vs placebo group), alopecia (53.5 percent vs 50.0 percent), and fatigue (51.9 percent vs 54.5 percent).

Pembrolizumab: The NRG-GY018 trial

In the NRG-GY018 trial, 816 patients with newly diagnosed measurable (stage III or IVA) or stage IVB or recurrent endometrial cancer were randomized 1:1 to receive pembrolizumab or placebo (6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks), along with carboplatin plus paclitaxel. Patients were stratified into dMMR (n=225; median age, 66 years; pembrolizumab group, n=112; placebo group, n=113) and pMMR (n=588; median age, 65.5 years; pembrolizumab group, n=293; placebo group, n=295) cohorts. Previous adjuvant chemotherapy was permitted if the treatment-free interval before study baseline was ≥12 months. The primary outcome was PFS in the dMMR and pMMR cohorts. [Eskander R, et al, SGO 2023, abstract 338166; N Engl J Med 2023;doi:10.1056/NEJMoa2302312]

After a median follow-up of 12 months in the dMMR cohort, median PFS was not reached in the pembrolizumab group vs 7.6 months in the placebo group, while PFS rates were 74 percent vs 38 percent (HR, 0.30; 95 percent CI, 0.19–0.48; p<0.001). In the pMMR cohort, median PFS was 13.1 months vs 8.7 months (HR, 0.54; 95 percent CI, 0.41–0.71; p<0.001), after a median follow-up of 7.9 months.

“These data suggest that incorporating immunotherapy into 1L treatment of patients with advanced or recurrent endometrial cancer translates into improved oncologic outcomes, regardless of MMR status or histologic findings,” the investigators noted.

“Subgroup analyses of PFS in both the dMMR and pMMR cohorts appeared to favour the pembrolizumab group, including during the maintenance phase, although efficacy results appeared heterogeneous according to geographic location and the numbers of patients in some subgroups were small,” they continued.

AEs reported in the trial were as expected for pembrolizumab and carboplatin/paclitaxel combination chemotherapy. “The addition of pembrolizumab did not appear to increase the frequency of AEs commonly associated with chemotherapy,” the investigators wrote. “Similar frequencies of grade 3/4 AEs [regardless of attribution] were identified in the dMMR and pMMR cohorts.”

A “home run” in endometrial cancer

“Both trials hit a home run, and this changes clinical care,” said Dr Rebecca Arend of the University of Alabama at Birmingham and the O’Neal Comprehensive Cancer Center, Alabama, US, who was invited to discuss the studies at SGO 2023.

“Unanswered questions include whether immunotherapy is the best option for all patients, and whether other agents can be added or sequenced to improve efficacy of immune checkpoint inhibitor therapy in pMMR tumours,” she pointed out.