Unprecedented Benefit With Dostarlimab/Chemo in Endometrial Cancer

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Dostarlimab-gxly (Jemperli) and carboplatin/paclitaxel chemotherapy delivered a 31% improvement in overall survival (OS) vs placebo/chemotherapy in patients with primary advanced or recurrent endometrial cancer, regardless of microsatellite instability (MSI) status, according to findings from a second interim analysis of part 1 of the ENGOT-EN6-NSGO/GOG-3031/RUBY trial (NCT03981796).¹

The results, which were presented during the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer, showed that the median OS was 44.6 months (95% CI, 32.6-not estimated [NE]) and 28.2 months (95% CI, 22.1-35.6) with dostarlimab and placebo/chemotherapy, respectively (HR, 0.69; 95% CI, 0.54-0.89; P = .002) at 51.2% maturity and a median follow-up of 37.2 months. These data crossed the prespecified stopping boundary for OS (P = .01101) and were found to be statistically significant and clinically relevant. The 2- and 3-year OS rates for the dostarlimab arm were 70.1% and 54.9%, respectively; in the placebo arm, these rates were 54.3% and 42.9%, respectively.

At a median follow-up of 36.6 months in patients whose tumors were mismatch repair deficient (dMMR)/ MSI-high (MSI-H), the maturity rate was 39.8%. Here, the median OS was NE (95% CI, NE-NE) with dostarlimab compared with 31.4 months (95% CI, 20.3-NE) for placebo (HR, 0.32; 95% CI, 0.17-0.63), which was a substantial and unprecedented benefit in OS, explained lead study author Matthew A. Powell, MD, in an oral presentation during the meeting. The 2- and 3-year OS rates were 82.8% and 78.0%, respectively, with dostarlimab and 57.5% and 46.0%, respectively, with placebo.

In the proficient mismatch repair (pMMR)/microsatellite stable (MSS) subgroup, the median OS was 34.0 months (95% CI, 28.6-NE) with dostarlimab and 27.0 months (95% CI, 21.5-35.6) with placebo (HR, 0.79; 95% CI, 0.60-1.04) at a median follow-up of 37.5 months. The OS maturity rate was 54.8%. Two- and 3-year OS rates with dostarlimab were 66.5% and 48.6%, respectively; these rates were 53.2% and 41.9%, respectively, in the placebo arm.

“These data confirm dostarlimab plus carboplatin/paclitaxel is a new standard of care for patients with primary advanced or recurrent endometrial cancer, regardless of their mismatch repair status,” Powell, professor of obstetrics and gynecology, and chief in the Division of Gynecologic Oncology, at Washington University in St. Louis, in Missouri, said in an oral presentation during the meeting.

Historical standard frontline therapy for patients with primary advanced or recurrent endometrial cancer has been chemotherapy, but this is associated with a median OS of less than 3 years.

In part 1 of RUBY, investigators enrolled 494 patients with primary advanced or recurrent endometrial cancer and were randomly assigned 1:1 to receive dostarlimab intravenously at 500 mg plus carboplatin/paclitaxel (n = 245) or placebo plus carboplatin/paclitaxel (n = 249) every 3 weeks for 6 cycles, followed by dostarlimab at 1000 mg or placebo alone, every 6 weeks for up to 3 years or until disease progression.

To be eligible for enrollment, patients had to have stage III/IV disease or first recurrent endometrial cancer, with all histologies permitted except sarcomas. Patients could either not have previously received systemic therapy or had disease recurrence or progression within 6 months after completion of systemic anticancer treatment.

Patients were stratified by MMR/MSI status, prior external pelvic radiation, and disease status.

The dual primary end points were investigator-assessed progression-free survival (PFS) at the first interim analysis in both the overall and dMMR/MSI-H populations and OS in the overall study population at both interim analyses. For the second interim analysis, investigators conducted prespecified analyses of OS in the dMMR/MSI-H and pMMR/MSS populations.

Secondary end points were PFS via blinded independent central review at the first analysis; PFS2 and safety at both the first and second interim analyses; objective response rate, duration of response, disease control rate, and health-related quality of life/patient-reported outcomes at the first interim analysis.

The median age between the 2 arms was 64.5 years (range, 28-85), and approximately half of patients were at least 65 years old (51.2%). A total of 87.3% of patients had measurable disease at baseline and 20.3% had previously received anticancer therapy. The most common histology was endometrioid (54.7%), and carcinosarcoma was in 8.9% of patients.

Previous data of the RUBY part 1 trial, which were presented at the 2023 Annual Global Meeting of the International Gynecologic Cancer Society (IGCS), showed that dostarlimab/chemotherapy led to a 36% reduction in the risk of disease progression or death compared with placebo/chemotherapy (HR, 0.64; 95% CI, 0.507-0.800; P <.0001) at a median follow-up of 25.4 months in the overall study population.² In patients with dMMR/MSI-H tumors, dostarlimab/chemotherapy demonstrated a 72% reduction in the risk of progression or death (HR, 0.28; 95% CI, 0.162-0.495; P <.0001) at a median follow-up of 24.8 months.

Based on the previous interim findings, the FDA approved dostarlimab in combination with carboplatin and paclitaxel, followed by single-agent dostarlimab, in July 2023 for use in patients with primary advanced or recurrent endometrial cancer that is dMMR, as determined by an FDA-approved test, or MSI-H.³

With the longer follow-up, Powell reported that 130 patients on dostarlimab discontinued the study due to death from any cause (n = 96), withdrawn consent (n = 26), was lost to follow-up (n = 5), or other (n = 3). Twenty-seven patients remain on dostarlimab. In the placebo arm, 160 patients discontinued from study due to death from any cause (n = 133), withdrawn consent (n = 20), were lost to follow-up (n = 5), or other (n = 2). Twenty-two patients remain on the placebo arm.

Additional results from the second interim analysis showed that 17.1% and 38.2% of patients on dostarlimab and placebo overall, respectively, received subsequent immunotherapy. These rates were 15.1% and 41.5%, respectively, in the dMMR/MSI-H subset, and were 17.7% and 37.0%, respectively, in the pMMR/MSS group.

The OS benefit was consistent across most exploratory subgroups, with exceptions comprising those in Europe (HR, 1.15; 95% CI, 0.72-1.83) and those with primary stage III disease (HR, 1.32; 95% CI, 0.66-2.66).

“There are a few small outliers that are small subsets that are underpowered and not yet mature,” Powell noted.

In the dMMR/MSI-H subgroup, the median PFS2 at a median follow-up of 36.6 months was NE (95% CI, NE-NE) in the dostarlimab arm compared with 21.6 months (95% CI, 13.4-39.1) with placebo (HR, 0.33; 95% CI, 0.18-0.63), which Powell stated was substantial. The 2- and 3-year PFS rates were 77.6% and 73.1%, respectively, with dostarlimab compared with 46.8% and 39.2%, respectively, with placebo.

There was a clinically meaningful difference in PFS2 favoring dostarlimab in the overall (median OS: 32.3 months vs 18.4 months; HR, 0.66; 95% CI, 0.52-0.84) and pMMR/MSS populations (median OS: 24.6 months vs 15.9 months; HR, 0.74; 95% CI, 0.57-0.97). In the overall population, the 2- and 3-year PFS2 rates were 56.8% and 48.7%, respectively, with dostarlimab compared with 40.8% and 33.2%, respectively, with placebo. In the pMMR/MSS subgroup, the 2- and 3-year PFS rates were 51.0% and 42.0%, respectively, with dostarlimab and 38.7% and 31.2%, with placebo.

Safety findings were similar to those of prior analyses with the study regimen. The median duration of treatment overall was 43.0 weeks (95% CI, 3.0-192.6) in the dostarlimab arm compared with 36.0 weeks (95% CI, 2.1-193.1) in the placebo arm.

All patients experienced treatment-emergent adverse effects (TEAEs); grade 3 or higher TEAEs occurred in 72.2% of patients treated with dostarlimab and in 60.2% of those on placebo/chemotherapy. Serious TEAEs occurred in 39.8% and 28.0% of patients, respectively, and any treatment-related immune-related adverse effects were in 40.7% and 16.3%, respectively. TEAEs that led to discontinuation of either dostarlimab or placebo occurred in 19.1% of patients on the dostarlimab arm and 8.1% of those on placebo. Five TEAEs led to death on the dostarlimab arm, 2 of which were related to dostarlimab treatment.

“Most treatment-emergent adverse events were grade 1 or 2, the exception being anemia, which is commonly grade 3, but manageable,” Powell said.

REFERENCES:

1. Powell MA, Auranen A, Willmott LJ, et al. Overall survival among patients with primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy in the ENGOT-EN6-NSGO/GOG-3031/RUBY Trial. Presented at: Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.

2. Mirza MR. Dostarlimab in combination with chemotherapy for the treatment of primary advanced or recurrent endometrial cancer: a placebo-controlled randomized phase 3 trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). Presented at 2023 Annual Global Meeting of the International Gynecologic Cancer Society; November 5-7, 2023; Seoul, Korea; abstract SE008/1309.

3. Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed March 16, 2024. https://shorturl.at/ozCI4