The New England Journal of Medicine June 08, 2023

Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer

Mansoor R. Mirza, Dana M. Chase, Brian M. Slomovitz, et al.

Bottom Line

The addition of the PD-1 inhibitor dostarlimab to standard first-line chemotherapy significantly improved progression-free and overall survival in patients with primary advanced or recurrent endometrial cancer, establishing a new standard of care particularly for those with dMMR/MSI-H tumors.

Key Findings

1. In the dMMR/MSI-H population (n=118), estimated progression-free survival (PFS) at 24 months was 61.4% with dostarlimab versus 15.7% with placebo (HR 0.28; 95% CI, 0.16 to 0.50; P<0.001).

2. In the overall population (n=494), PFS at 24 months was 36.1% in the dostarlimab group compared to 18.1% in the placebo group (HR 0.64; 95% CI, 0.51 to 0.80; P<0.001).

3. Overall survival (OS) at 24 months in the overall population was 71.3% with dostarlimab and 56.0% with placebo (HR 0.64; 95% CI, 0.46 to 0.87).

4. In the dMMR/MSI-H population, the 24-month OS rate was 83.3% with dostarlimab versus 58.7% with placebo (HR 0.30; 95% CI, 0.13 to 0.70).

5. Discontinuation of dostarlimab or placebo due to adverse events occurred in 17.4% of patients receiving dostarlimab plus chemotherapy and 9.3% of patients receiving placebo plus chemotherapy.

Study Design

Design

RCT

Double-Blind

Sample

494

Patients

Duration

25 mo

Median

Setting

Global, multicenter

Population Adult patients with primary advanced stage III or IV, or first recurrent endometrial cancer.

Intervention Dostarlimab (500 mg) + carboplatin (AUC 5) and paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, followed by dostarlimab (1000 mg) every 6 weeks for up to 3 years.

Comparator Placebo + carboplatin (AUC 5) and paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, followed by placebo every 6 weeks for up to 3 years.

Outcome Progression-free survival (assessed by investigator per RECIST v1.1) and overall survival.

Study Limitations

• The median follow-up at the time of the primary analysis was relatively short (approximately 25 months), rendering long-term overall survival and duration of response data immature.

• The survival and progression-free benefits in the overall population were heavily driven by the profound efficacy observed in the dMMR/MSI-H subgroup; benefit in the mismatch repair-proficient (pMMR) cohort was present but substantially more modest.

• A significant proportion of patients in the placebo arm (approximately one-third) subsequently received immunotherapy upon progression, which could potentially confound mature overall survival analyses.

Clinical Significance

The RUBY trial represents a paradigm shift in gynecologic oncology. By demonstrating a 72% reduction in the risk of disease progression or death in the dMMR/MSI-H population and a significant overall survival benefit early in the trial, it firmly established dostarlimab plus chemotherapy as the new frontline standard of care for advanced or recurrent endometrial cancer. This landmark finding catalyzed immediate changes to clinical guidelines and global regulatory approvals, emphasizing the absolute necessity of upfront MMR/MSI biomarker testing for all newly diagnosed endometrial cancers.

Historical Context

For decades, the standard first-line treatment for advanced or recurrent endometrial cancer was platinum-based chemotherapy (carboplatin plus paclitaxel), as solidified by GOG-209. Despite this standard, long-term outcomes remained poor, with a median overall survival historically under 3 years and limited options upon recurrence. Following the success of PD-1 inhibitors as monotherapy in the second-line setting for dMMR/MSI-H tumors, trials sought to move immunotherapy into the first line. Published concurrently with NRG-GY018 (which evaluated pembrolizumab), the RUBY trial was a watershed moment, proving that chemoimmunotherapy could shatter the efficacy ceiling of chemotherapy alone.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanistic rationale for combining a PD-1 inhibitor like dostarlimab with cytotoxic chemotherapy in endometrial cancer, and why are dMMR/MSI-H tumors particularly susceptible to this therapy?

Key Response

dMMR/MSI-H tumors lack DNA mismatch repair, leading to a high mutational burden and abundant neoantigens. Chemotherapy induces tumor cell death and antigen release, which synergizes with PD-1 blockade that lifts the inhibitory brakes on the T-cell immune response against these neoantigens.

Resident

A patient with newly diagnosed stage IV endometrial cancer presents to clinic. Based on the RUBY trial, how must her tumor's mismatch repair status influence your upfront choice of systemic therapy?

Key Response

MMR testing is now mandatory upfront. If the tumor is dMMR, the new standard of care is carboplatin, paclitaxel, and dostarlimab, followed by dostarlimab maintenance, given the unprecedented progression-free survival benefit (HR ~0.28) demonstrated in this subgroup.

Fellow

The RUBY trial demonstrated a PFS benefit in both dMMR and pMMR cohorts. As an oncology fellow, how do you interpret the clinical meaningfulness of the benefit in the pMMR population, and how does this compare to findings from NRG-GY018?

Key Response

While the dMMR benefit is undeniable, the pMMR benefit is more modest (HR ~0.76). Evaluating this requires balancing added immune-related toxicities and financial costs against incremental PFS/OS gains. Comparing it to GY018 (which tested pembrolizumab) helps confirm the class effect of anti-PD-1 in pMMR tumors but highlights the ongoing need for better biomarkers.

Attending

With the integration of dostarlimab into frontline therapy for advanced endometrial cancer, how does this paradigm shift impact our approach to second-line therapies, particularly regarding the use of lenvatinib plus pembrolizumab?

Key Response

Previously, lenvatinib/pembrolizumab was the standard second-line for pMMR after chemotherapy. With PD-1 inhibitors moving to the frontline, the efficacy of reusing immunotherapy in the second line is largely unknown, necessitating a complete paradigm shift in sequencing and urgent new trials for post-immunotherapy progression.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The RUBY trial utilized a dual primary endpoint design evaluating PFS in the dMMR/MSI-H population and in the overall population. What are the statistical implications of hierarchical testing here, and how does it manage alpha spending?

Key Response

A hierarchical step-down procedure allows the trial to formally test the overall population only if the dMMR subgroup (the most likely to benefit) meets significance. This strictly controls the family-wise error rate while maximizing power and allowing a statistical path to broad label approval if the primary hypothesis holds.

Journal Editor

As a peer reviewer, what concerns might you raise regarding the trial's control arm performance, informative censoring, or post-progression crossover, particularly when interpreting the overall survival data in the pMMR cohort?

Key Response

A critical reviewer would scrutinize whether placebo patients had high rates of crossover to immunotherapy upon progression. If crossover was high, OS differences might be blunted; conversely, lack of access to standard-of-care second-line immunotherapy in the control arm across different global sites could artificially inflate the OS benefit of the investigational arm.

Guideline Committee

Based on the RUBY trial, how should NCCN or ESMO update the level of evidence for frontline chemoimmunotherapy in advanced endometrial cancer, and should pMMR and dMMR patients receive distinct algorithmic pathways?

Key Response

The unprecedented outcomes in dMMR patients elevate dostarlimab plus chemotherapy to a definitive Category 1 recommendation, replacing chemo alone. For pMMR, the committee must weigh the smaller magnitude of benefit, leading to a nuanced recommendation that splits the systemic therapy algorithms distinctly based on upfront MMR status.

Clinical Landscape

Noteworthy Related Trials

2020

GARNET Trial

n = 104 · JAMA Oncol

Tested

Dostarlimab monotherapy

Population

Patients with dMMR advanced or recurrent endometrial cancer who progressed on or after platinum-based therapy

Comparator

None (Single-arm study)

Endpoint

Objective response rate

Key result: Dostarlimab monotherapy demonstrated highly durable objective responses and an acceptable safety profile in patients with dMMR endometrial cancer.

2022

KEYNOTE-775 Trial

n = 827 · NEJM

Tested

Lenvatinib plus pembrolizumab

Population

Patients with advanced endometrial cancer previously treated with systemic therapy

Comparator

Chemotherapy (doxorubicin or paclitaxel)

Endpoint

Progression-free survival and Overall survival

Key result: The combination of lenvatinib and pembrolizumab led to significantly longer progression-free and overall survival than standard chemotherapy across all mismatch repair subgroups.

2023

NRG-GY018 Trial

n = 816 · NEJM

Tested

Pembrolizumab plus carboplatin and paclitaxel

Population

Patients with advanced or recurrent endometrial cancer

Comparator

Placebo plus carboplatin and paclitaxel

Endpoint

Progression-free survival

Key result: Pembrolizumab combined with chemotherapy significantly improved progression-free survival compared to chemotherapy alone in both dMMR and pMMR patient cohorts.

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