The addition of dostarlimab to standard combination chemotherapy in the phase 3 RUBY study showed a significant survival improvement in patients with primary advanced or recurrent endometrial cancer.
Dostarlimab (Jemperli) combined with chemotherapy has demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with an early trend toward overall survival (OS) improvement in patients with primary advanced or recurrent endometrial cancer treated in the phase 3 RUBY trial (ENGOT-EN6-NSGO/GOG-3031, NCT03981796).1,2
Results also showed that dostarlimab plus the chemotherapy combination of carboplatin and paclitaxel had a manageable safety profile, according to a presentation given my Mansoor Raza Mirza, MD, chief, Department of Oncology, Rigshospitalet, Copenhagen University Hospital, during the ESMO Virtual Plenary in March.1
At median follow-up of 25.38 months, the estimated 12-month PFS rate observed with dostarlimab plus carboplatin and paclitaxel was 48.2% compared with 29.0% in the placebo/chemotherapy arm, in the overall population. At 24 months, the PFS rate was estimated to be 36.1% with dostarlimab and chemotherapy vs 18.2 % with placebo and chemotherapy. The hazard ratio for the difference between treatment arms was 0.64 (95% CI, 0.507-0.800; P < .0001).
“Dostarlimab plus carboplatin/paclitaxel represents a new standard of care for patients with primary advanced or recurrent endometrial cancer,” said Mirza, during his presentation.
Carboplatin plus paclitaxel is the golden standard for primary advanced or recurrent endometrial cancer. The long-term median OS shown with this treatment, however, is under 3 years. Considering the current role of anti-PD-1-based therapy in patients with endometrial cancer that is previously treated with platinum-based chemotherapy, investigators of RUBY hypothesized that adding an agent like dostarlimab to chemotherapy may help address the need for advances in first-line endometrial cancer.
Dostarlimab, an immune checkpoint inhibitor, has previously shown durable activity in patients with previously treated, mismatch repair deficient (dMMR) and microsatellite instable (MSI) endometrial cancer, as well as those with MMR profient (MMRp) and microsatellite stable (MSS) disease. The dMMR/MSI-high endometrial cancer population, specifically, has a higher response to anti-PD-1 therapy. When combined with chemotherapy, dostarlimab was hypothesized to help with immunogenic cell death, lower immunosuppression in the tumor microenvironment, and demonstrated clinical activity.
In the study, 494 patients with primary advanced or recurrent endometrial cancer were randomized to receive either primary advanced or recurrent endometrial cancer intravenous (IV) dostarlimab with carboplatin 500 mg area under the curve 5 mg/mL/min, and paclitaxel 175 mg/m, every 3 weeks for 6 cycles or matching placebo with carboplatin and paclitaxel. All patients enrolled had histologically or cytologically confirmed disease, stage III/IV disease or first recurrent EC with low potential for cure by radiation therapy or surgery alone or in combination, were previously untreated with systemic therapy or systemic anticancer therapy, and had a recurrence or progressive disease ≥6 months after completing treatment. All patients were required to have a ECOG performance status of 0 or 1, and adequate organ function.
Stratified by their MMR/MSI status, prior external pelvic radiotherapy, and disease status, patients were assessed for the co-primary end points of PFS and OS. The secondary end points of the study included PFS by blinded independent review committee (BICR), time to second progression (PFS2), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), health-related quality of life (HRQOL), patient-reported outcomes (PROs), and safety.
Of the 494 patients randomized, 53 patients (21.6%) in the dostarlimab arm and 65 patients (26.1%) in the placebo arm had dMMR/MSI-high tumors. Also, in the dostarlimab arm, 192 patients (78.4%) had MMRp/MSS tumors, as did 184 patients (73.9%) in the placebo arm. Most patients in both arms did not have prior external pelvic radiation. In terms of disease status, the majority of patients had recurrent disease, including 117 patients (47.8%) in the dostarlimab arm and 119 patients (47.8%) in the placebo arm. Patients in the study were predominantly aged 65 years or older, and White.
In the overall population, OS had reached 33% maturity at the time of the analysis. The estimated 12-month OS in the dostarlimab/chemotherapy arm was 84.6% compared with 81.3% with placebo/chemotherapy. At 24-months, the estimated OS was 71.3% in the dostarlimab/chemotherapy arm vs 56.0% in the placebo/chemotherapy arm.
The prespecified subgroups analyses of the RUBY trial were also presented during the ESMO Plenary. Overall, dostarlimab/chemotherapy demonstrated longer survival compared with placebo/chemotherapy across all populations.
The 12-month PFS in the dMMR/MSI-high population was estimated to be 63.5% with dostarlimab/chemotherapy vs 24.4% in the placebo/chemotherapy arm. The estimated 24-month PFS was 61.4% with dostarlimab and chemotherapy vs 15.7% with placebo/chemotherapy (HR, 0.28; 95% CI, 0.162–0.495; P < .0001).
In the MMRp/MSS population, the estimated 12-month PFS rate was 43.5% with dostarlimab/chemotherapy vs 30.6% with placebo/chemotherapy. The estimated 24-month PFS in the dostarlimab-treated group was 28.4% vs 18.8% among those treated with placebo (HR, 0.76; 95% CI, 0.572-0.981).
“When we look at the subgroup of the MMR deficient population, the overall survival here at 24 months has increased from 58% to 83%. Again, you see the plateauing of the Kaplan Meier curve in the dostarlimab [arm], indicating long-term benefit of the studies. The hazard ratio was at .30, and this is despite the fact that subsequent immune therapy is given to 38% of the patients in placebo arm and 15% of the patients in the study.”
In terms of OS in the MMRp/MSS subgroup, the 12-month estimate was 83.1% with dostarlimab/chemotherapy vs 81.8% with placebo/chemotherapy. The estimated 24-month OS was 67.7% vs 55.1%, respectively. The HR for the difference between these arms was 0.73 (95% CI, 0.515-1.024).
Responses and response duration were evaluated in the dMMR/MSI0high subgroup as well as the MMRp/MSS subgroup. Dostarlimab plus chemotherapy achieved an ORR of 77.6% (95% CI, 63.4%-88.2%). In comparison, the placebo plus chemotherapy arm had an ORR of 69.0% (95% CI, 55.5%-80.5%). The DOR was not evaluable (NE) for the dostarlimab arm (95% CI, 10.1-NE) vs 5.4 months in the placebo plus chemotherapy arm (95% CI, 3.5-8.1 months)
In the MMRp/MSS subgroup, the ORR observed with the dostarlimab combination was 68.1% (95% CI, 60.3%-75.2) compared with 63.4% (95% CI, 55.4%-70.8%), with placebo plus chemotherapy. The median DOR was 9.6 months (95% CI, 6.9-12.1 months) with dostarlimab vs 6.3 months (95% CI, 4.4-6.9 months) with placebo.
Any-grade treatment-emergent adverse events (TEAE) occurred in all patients during the study. Grade 3 or higher TEAEs occurred in 70.5% of the dostarlimab/chemotherapy arm compared with 59.8% of the placebo/chemotherapy arm, and serious TEAEs were observed in 37.8% vs 27.6%, respectively. Any-grade treatment-related, immune-related AEs were seen in 38.2% of the dostarlimab arm vs 15.4% of the placebo arm.
AEs resulted in discontinuation of dostarlimab or placebo in 17.4% of the dostarlimab arm vs 9.3% of the placebo arm. Treatment discontinuation resulting from a TEAE occurred in 10.0% of patients, each treated with carboplatin or paclitaxel in the dostarlimab arm vs 7.7% and 9.3%, respectively, in the placebo arm. TEAEs led to death in 2.1% of patients treated with dostarlimab vs no patients in the placebo arm.
The most common TEAEs observed during the study were alopecia, nausea, fatigue, peripheral neuropathy, and anemia. Moreover, PROs data show that adding dostarlimab to carboplatin/paclitaxel did not negatively impact the quality-of-life of patients.
1. Mirza MR, Chase D, Slomovitz BM, et al. Dostarlimab+chemotherapy for the treatment of primary advanced or recurrent endometrial cancer: The placebo-controlled randomised phase III RUBY trial. Presented at ESMO Virtual Plenary; March 27-28, 2023.
2. Mirza MR, Chase D, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. Published online March 23, 2023. doi:10.1056/NEJMoa2302312