Add-on dostarlimab boosts PFS in endometrial cancer

Adding dostarlimab, an immune checkpoint inhibitor, to standard-of-care chemotherapy significantly improves progression-free survival (PFS) in patients with primary advanced or recurrent endometrial cancer, including those with dMMR-MSI-H* disease, according to the first interim analysis of the ENGOT-EN6-NSGO/GOG-3031/RUBY trial presented at SGO 2023.

In the overall population, the 24-month PFS rate was significantly improved by 36 percent with dostarlimab plus chemo vs 18 percent with placebo plus chemo (hazard ratio [HR], 0.64; p<0.0001). Median PFS was longer in the dostarlimab vs the placebo group (11.8 vs 7.9 months). [SGO 2023, abstract 12]

Notably, the 24-month PFS rate was even greater for patients with dMMR/MSI-H tumours who received the dostarlimab-chemo combination compared with those receiving the placebo-chemo regimen (61.4 percent vs 15.7 percent; HR, 0.28; p<0.0001).

“This is the biggest news for patients with endometrial cancer in more than 30 years,” said lead author Dr Mansoor Mirza from the Department of Oncology, Rigshospitalet at Copenhagen University Hospital in Copenhagen, Denmark, in an interview.

“These results have shown an unprecedented improvement in PFS as a result of adding immunotherapy to standard chemotherapy, especially in the 25 percent of patients with so-called ‘hot’ endometrial tumours that have deficient DNA mismatch repair mechanisms,” Mirza continued. [www.ascopost.com/news/march-2023/ruby-trial-dostarlimab-plus-carboplatin-and-paclitaxel-in-advanced-endometrial-cancer]

“Testing for MMR and MSI status is important, because it is considered both prognostic and predictive for the potential use of immune checkpoint inhibitor treatments in endometrial cancer,” the researchers said in a recently published paper. [N Engl J Med 2023;doi:10.1056/NEJMoa2216334]

The researchers conducted a phase III, double-blind, multicentre study involving 494 patients with primary advanced stage III/IV or recurrent endometrial cancer, of whom 118 patients had dMMR/MSI-H tumours. Participants were randomized to receive dostarlimab 500 mg (n=245; median age 64 years) or placebo (n=249; median age 65 years) in addition to standard first-line carboplatin and paclitaxel chemotherapy** every 3 weeks for six cycles. Subsequently, participants continued on dostarlimab 1,000 mg alone or placebo every 6 weeks for up to 3 years.

Early trend in overall survival

At the time of this analysis, overall survival (OS) data had reached a maturity rate of 33 percent.

At 24 months, a clinically meaningful OS trend favouring dostarlimab-chemo over placebo-chemo was observed both in the overall population (71.3 percent vs 56.0 percent; HR, 0.64; p=0.0021) and the dMMR/MSI-H subgroup (88.3 percent vs 58.7 percent; HR, 0.30).

The researchers underlined that the OS trend favoured the experimental regimen despite having more patients in the placebo arm receiving subsequent immunotherapy (34.5 percent vs 15.5 percent [overall population] and 38.5 percent vs 15.1 percent [dMMR/MSI-H population]).

Adverse events

The incidence of any-grade treatment-emergent adverse events (TEAEs) was comparable between arms, but there were more grade ≥3 TEAEs reported with dostarlimab-chemo vs placebo-chemo (70.5 percent and 59.8 percent). “The side effects we have seen are usually what you see with single-agent carboplatin/paclitaxel or dostarlimab,” Mirza noted.

The safety profiles of both dostarlimab and chemo were manageable, with no new safety signals identified.

New standard of care

“The combination of dostarlimab and carboplatin plus paclitaxel demonstrated statistically significant and clinically meaningful PFS benefit with an early OS trend in the overall population, and with a substantial unprecedented benefit in dMMR/MSI-H patients,” said Mirza.

“[Hence, this combination] represents a new standard of care for patients with primary advanced or recurrent endometrial cancer,” Mirza added.

*dMMR/MSI-H: Mismatch repair-deficient/Microsatellite instability-high

**Carboplatin AUC 5 mg/mL/min and paclitaxel 175 mg/m²