Anna K.L. Reyners

Quality-adjusted time without symptoms of disease progression or toxicity of treatment in patients with primary advanced or recurrent endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel

In part 1 of the phase 3 RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer, dostarlimab plus carboplatin-paclitaxel significantly improved progression-free and overall survival vs placebo plus carboplatin-paclitaxel. Post hoc analyses examined the impact of adding dostarlimab to chemotherapy, compared with placebo plus chemotherapy, on quality-adjusted time without symptoms of disease progression or toxicity of treatment in this patient population. Patients were randomized 1:1 to receive dostarlimab/placebo plus chemotherapy every 3 weeks for 6 cycles, followed by dostarlimab/placebo monotherapy every 6 weeks for up to 3 years. Data from the first interim analysis (September 28, 2022) were used, and quality of life (QoL) was assessed with the EuroQoL 5-Dimensions 5-Level questionnaire. Quality-adjusted time without symptoms of disease progression or toxicity of treatment was calculated as the sum product of the restricted mean survival times spent in 3 mutually exclusive states: toxicity, time without symptoms of disease progression or treatment toxicity, and relapse, and utilized each state's corresponding QoL. In the dostarlimab and placebo arms, 241 and 246 patients were analyzed for safety, respectively. In the overall population, the mean (95% CI) duration of quality-adjusted time without symptoms of disease progression or toxicity of treatment was significantly longer in the dostarlimab arm (24.75 months [22.88 to 26.65 months]) than in the placebo arm (20.34 months [18.95 to 21.76 months]; the mean difference [95% CI] of 4.41 months [2.01 to 6.77 months], p < .001). Benefits in quality-adjusted time without symptoms of disease progression or toxicity of treatment after dostarlimab treatment were observed regardless of mismatch repair/microsatellite instability status or toxicity criteria used and were predominantly driven by the time without symptoms of disease. Dostarlimab plus carboplatin-paclitaxel treatment is associated with meaningful improvement in survival, avoidance of substantial toxicity, and maintenance of patient-reported QoL in patients with primary advanced or recurrent endometrial cancer.

Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study

Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.