Dostarlimab plus chemotherapy provides clinical benefit to patients with primary advanced or recurrent endometrial carcinoma, irrespective of the molecular subtype
Previously, the phase III RUBY trial showed that the addition of dostarlimab and carboplatin-paclitaxel (CP) improved the progression-free (PFS) and overall survival (OS) of patients with primary advanced or recurrent endometrial carcinoma (pA/rEC). At ESMO 2023, the results of an exploratory analysis confirmed the survival benefits of the dostarlimab plus CP combination in different molecular subgroups, supporting this combination as a new standard of care for patients with pA/rEC.
The phase III RUBY trial previously demonstrated that dostarlimab (D) in combination with carboplatin-paclitaxel (CP) significantly improved the progression-free survival (PFS) compared to CP alone in patients with primary advanced or recurrent endometrial cancer (pA/rEC), both in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) (HR[95%CI]: 0.28[0.162-0.495]; P<0.001) and overall populations (HR[95%CI]: 0.64[0.507-0.800]; p<0.001). At the time of the analysis, the overall survival results (OS) were not mature, but already showed a trend for a more favourable OS trend in both the dMMR/MSI-H (HR[95%CI]: 0.30[0.127-0.699]) and overall patient population (HR[95%CI]: 0.64[0.464-0.870). Furthermore, the study identified four molecular EC subgroups with potential prognostic and predictive value: polymerase epsilon (POLε) mutation (mut), dMMR, TP53 abnormal, and no specific molecular profile (NSMP). During ESMO 2023, exploratory efficacy outcomes were reported across these molecular classifications.
Methods
The phase III ENGOT-EN6-NSGO/GOG-3031/RUBY enrolled patients with stage III-IV disease or first recurrent EC with low potential for cure by radiation therapy or surgery. Additionally, these patients were either systemic treatment-naïve or had experienced recurrence or disease progression (PD) ≥6 months after completing systemic anticancer therapy. In total, 494 patients with pA/rEC were randomly assigned (1:1) to receive dostarlimab, or placebo, both combined with CP, followed by dostarlimab or placebo monotherapy for up to three years. The POLε and TP53 status was determined by DNAseq, while the MMR/MSI status was determined by the test that was used for study enrolment (immunohistochemistry, polymerase chain reaction, or next-generation sequencing). Patients were first classified by POLεmut status (pathogenic, non-pathogenic) after which patients with a non-pathogenic variant were further classified into a mismatch repair deficient or proficient (dMMR/MMRp) subgroup. Subsequently, MMRp patients were classified into TP53mut or NSMP. PFS and OS were assessed for each subgroup.
Results
Among the 494 patients enrolled and randomised, mutational data were available for 400 patients (81.0%). These patients were classified as followed: 5 (1.3%) POLεmut, 91 (22.8%) dMMR/MSI-H, 88 (22.0%) TP53mut, and 216 (54.0%) NSMP. Notably, none of the five patients with POLε mutations experienced disease progression, regardless of whether they received placebo or dostarlimab. A significant PFS benefit was observed for patients receiving dostarlimab in the dMMR/MSI-H population, with 24-month PFS rates of 57.0% vs. 10.2% in the dostarlimab and placebo groups, respectively (HR[95%CI]: 0.31[0.17-0.56]). Additionally, dostarlimab was also associated with a PFS benefit in the TP53mut (HR[95%]: 0.55[0.30-0.99]) and NSMP (HR[95%CI]: 0.77[0.55-1.07]) subgroups. At 24 months, PFS rates were 32.4 % vs. 17.8% for dostarlimab and placebo in the TP53mut subgroup, and 31.0% vs. 20.1% in the NSMP group.
Similar results were observed in the OS analysis. In the POLε subgroup, all patients remained alive at the time of the analysis. There was a significant OS improvement in the dMMR/MSI-H population, with 24-month OS rates of 77.7% vs. 55.3% in the dostarlimab and placebo groups, respectively (HR[95%CI]: 0.40[0.17-0.95]). Surprisingly, a comparable HR([95%CI]: 0.41[0.20-0.82]) was observed in the T53mut population, with 24-month OS rates of 70.8% vs. 33.2% in the dostarlimab and placebo groups, respectively. There were not enough events in the NSMP subgroup to make a formal analysis.
Conclusions
Dostarlimab plus CP consistently demonstrated a clinical benefit in the dMMR/MSI-H, NSMP, and TP53mut populations. In the POLε subgroup, no patients progressed in either arm. These findings further support the use of dostarlimab plus CP as a new standard of care for patients with newly diagnosed pA/rEC.
Reference
Mirza MR. Dostarlimab + chemotherapy for the treatment of primary advanced or recurrent endometrial cancer (pA/rEC): Analysis of progression-free survival (PFS) and overall survival (OS) outcomes by molecular classification in the ENGOT-EN6-NSGO/GOG-3031/RUBY trial. Presented at ESMO 2023; Abstract 740MO .
