Pembrolizumab plus chemo improves PFS in endometrial cancer regardless of MMR status

The addition of pembrolizumab to standard chemotherapy significantly improves progression-free survival (PFS) in patients with advanced or recurrent endometrial cancer, regardless of whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease, according to the NRG-GY018 trial presented at the SGO 2023.

Among patients with dMMR tumours, the median PFS was not reached in the pembrolizumab + chemo group and was 7.6 months in the placebo + chemo group (hazard ratio [HR], 0.30; p<0.00001) at a median follow-up of 12 months.

At 12 months, 74 percent of the patients in the dMMR cohort receiving pembrolizumab + chemo were still alive and free of disease progression compared with 38 percent of those treated with placebo + chemo.

Among patients with pMMR tumours, the median PFS was significantly longer with pembrolizumab + chemo than with placebo + chemo (13.1 vs 8.7 months; HR, 0.54; p<0.00001) at a median follow-up of 7.9 months.

Taken together, the combination of pembrolizumab and chemo resulted in a 70-percent reduction in the risk of disease progression or death in the dMMR cohort and a 46-percent reduction in the pMMR cohort. [SGO 2023, abstract 338166]

“Furthermore, the efficacy curves separated early in the course of treatment, with a preserved separation throughout the evaluation period in both populations,” said lead author Dr Ramez Eskander from the University of California San Diego Moores Cancer Center in San Diego, California, US.

“Therefore, these data suggest that the incorporation of immunotherapy into the first-line treatment of patients with advanced or recurrent endometrial cancer translates into improved oncologic outcomes, regardless of MMR status or histologic findings,” the researchers said in a recently published paper. [N Engl J Med 2023;doi:10.1056/NEJMoa2302312]

This phase III, international, prospective study analysed 816 patients with stage III/IVA or measurable or nonmeasurable stage IVB or recurrent endometrial cancer who were stratified according to their MMR status: dMMR (n=225; median age 66 years) and pMMR (n=591; median age 65.5 years).

Participants were randomized to receive intravenous pembrolizumab 200 mg Q3W + chemo* (n=112 [dMMR] and n=293 [pMMR]) or placebo + chemo (n=113 [dMMR] and 295 [pMMR]) for six cycles, followed by pembrolizumab or placebo maintenance every 6 weeks for an additional of 14 cycles.

The PFS benefit was consistently observed in the pembrolizumab vs the placebo group across all relevant subgroups, such as age, performance status 0/1, prior radiation therapy, prior chemotherapy, and aggressive histologies, particularly serous and clear cell, in both dMMR and pMMR cohorts, Eskander noted.

In terms of safety, adverse events (AEs) of any grade were reported in almost all patients in both pembrolizumab and placebo groups (dMMR: 98.2 percent and 99.1 percent, respectively; and pMMR: 93.5 percent and 93.4 percent).

Grade 3–5 AEs occurred at a higher rate in the pembrolizumab vs the placebo group in both the dMMR (63.3 percent vs 47.2 percent) and pMMR cohorts (55.1 percent vs 45.3 percent). “Nevertheless, the addition of pembrolizumab did not appear to increase the frequency of immune-related AEs or the AEs commonly associated with systemic cytotoxic chemotherapy,” said Eskander.

‘Huge win’ for dMMR, pMMR endometrial cancers

“Our results show that pembrolizumab in combination with chemotherapy and continued as maintenance therapy led to significantly longer PFS than placebo in patients with dMMR and pMMR endometrial cancers,” the researchers concluded.

“Both RUBY and NRG-GY018 trials hypothesized that the addition of chemotherapy could improve the response to checkpoint inhibitors, and both of these trials hit a home run,” commented discussant Dr Rebecca Arend from the Division of Gynecology Oncology at the University of Alabama at Birmingham, Alabama, US.

“Overall, this is a huge win for our patients,” Arend stated.

*Intravenous paclitaxel 175 mg/m² Q3W + carboplatin AUC 5 Q3W