What is the difference between Dostarlimab (antibody-drug) and Pembrolizumab (pembrolizumab) in treating carcinoma endometrium?

Dostarlimab vs Pembrolizumab in Endometrial Cancer Treatment: Key Differences

Dostarlimab plus chemotherapy shows superior efficacy compared to pembrolizumab monotherapy in endometrial cancer treatment, particularly in dMMR/MSI-H tumors, with dostarlimab demonstrating a 61.4% 2-year progression-free survival rate in the RUBY trial versus pembrolizumab's more modest outcomes. 1

Mechanism and Potency

• Both dostarlimab and pembrolizumab are anti-PD-1 monoclonal antibodies with similar peripheral PD-1 suppression potency (half-maximal effective concentration of 1.95 μg/ml for dostarlimab vs 1.59 μg/ml for pembrolizumab) 2
• Pharmacometric studies suggest both drugs are equipotent for PD-1 target engagement in advanced solid tumors 2

FDA Approvals and Indications

• Dostarlimab is FDA-approved specifically for dMMR recurrent or advanced endometrial cancer that progressed on or after platinum-based therapy 1
• Pembrolizumab has broader approval for MSI-H/dMMR solid tumors (including endometrial cancer) that progressed following prior treatment 1
• Pembrolizumab plus lenvatinib is uniquely approved for advanced endometrial cancer that is not MSI-H/dMMR after platinum-based chemotherapy 1

Clinical Trial Designs and Outcomes

• RUBY Trial (Dostarlimab): Phase 3 randomized trial evaluating dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel, showing:

  • 61.4% 2-year PFS in dMMR/MSI-H patients (vs 15.7% with placebo) 3
  • 36.1% 2-year PFS in the overall population (vs 18.1% with placebo) 3
  • Significant overall survival benefit at 24 months (71.3% vs 56.0%) 3

• KEYNOTE-158 (Pembrolizumab): Phase 2 non-randomized trial evaluating pembrolizumab monotherapy in previously treated MSI-H/dMMR endometrial cancer, showing:

  • 48% objective response rate 4
  • Median duration of response not reached (range 2.9-49.7+ months) 4
  • Median PFS of 13.1 months 4

• GARNET Trial (Dostarlimab): Phase 1 non-randomized trial evaluating dostarlimab monotherapy in dMMR endometrial cancer, showing:

  • 42.3% objective response rate 1, 5
  • 12.7% complete response rate and 29.6% partial response rate 5
  • Durable responses with 96.4% maintaining response at 6 months 5

Efficacy in Different Molecular Subtypes

• Both drugs show robust activity in dMMR/MSI-H endometrial cancers 1
• Pembrolizumab plus lenvatinib has established efficacy in pMMR/MSS endometrial cancer (median PFS 6.6 months in KEYNOTE-775) 1, 6
• Dostarlimab plus chemotherapy shows substantial PFS benefit in dMMR/MSI-H patients in the RUBY trial 1, 3

Safety Profiles

• Pembrolizumab monotherapy: 76% of patients experienced ≥1 treatment-related adverse event (grades 3-4: 12%) with no fatal events 4
• Dostarlimab plus chemotherapy: Common adverse events include nausea (53.9%), alopecia (53.5%), and fatigue (51.9%), with higher rates of severe and serious adverse events compared to chemotherapy alone 3
• Dostarlimab monotherapy: Most common grade 3+ treatment-related adverse events were anemia (2.9%), colitis (1.9%), and diarrhea (1.9%) 5

Clinical Implications

• Biomarker testing (MMR IHC and MSI) is essential to determine eligibility for both dostarlimab and pembrolizumab treatment 1
• Dostarlimab plus chemotherapy appears particularly effective in dMMR/MSI-H patients based on the RUBY trial results 1, 3
• For MSS/pMMR endometrial cancer, pembrolizumab plus lenvatinib remains an established option 1, 6

Key Differences in Treatment Approach

• Dostarlimab is increasingly used in combination with chemotherapy (carboplatin-paclitaxel) as demonstrated in the RUBY trial 3
• Pembrolizumab has established efficacy as monotherapy in dMMR/MSI-H tumors and in combination with lenvatinib for MSS/pMMR tumors 1, 4
• The RUBY trial represents a higher level of evidence (phase 3 randomized) for dostarlimab compared to the phase 2 KEYNOTE-158 trial for pembrolizumab 4, 3