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

Differences Between Dostarlimab and Pembrolizumab in Endometrial Cancer Treatment

Both dostarlimab and pembrolizumab show similar efficacy in endometrial cancer treatment, but dostarlimab demonstrated superior progression-free survival in dMMR/MSI-H endometrial cancer with a 61.4% 2-year PFS rate compared to pembrolizumab's outcomes in similar populations. 1

Mechanism and Potency

• Both dostarlimab and pembrolizumab are anti-PD-1 immune checkpoint inhibitors with similar mechanisms of action 1
• Pharmacologically, they appear equipotent for peripheral PD-1 suppression based on ex vivo IL-2 stimulation ratio analysis 2
• The estimated half-maximal effective concentration is 1.95 μg/ml for dostarlimab and 1.59 μg/ml for pembrolizumab, suggesting comparable potency 2

Clinical Trial Design and Patient Populations

• GARNET trial (dostarlimab): Single-arm phase I study in dMMR endometrial cancer patients who progressed after platinum-based therapy 1, 3
• KEYNOTE-158 (pembrolizumab): Multi-cohort phase II study in MSI-H/dMMR endometrial cancer patients who had received prior therapy 4
• RUBY trial (dostarlimab): Phase III randomized trial combining dostarlimab with carboplatin-paclitaxel in primary advanced or recurrent endometrial cancer 1, 5
• KEYNOTE-775 (pembrolizumab): Phase III trial of pembrolizumab plus lenvatinib in previously treated pMMR/MSS endometrial cancer 1

Efficacy in dMMR/MSI-H Endometrial Cancer

• Dostarlimab showed an objective response rate (ORR) of 42.3% in the GARNET trial for dMMR endometrial cancer 1, 3
• Pembrolizumab demonstrated an ORR of 46% in KEYNOTE-158 for MSI-H/dMMR endometrial cancer 1, 4
• In the RUBY trial, dostarlimab plus chemotherapy showed a significant 2-year PFS rate of 61.4% vs 15.7% with chemotherapy alone in dMMR/MSI-H patients (HR 0.28) 1, 5
• Median duration of response was not reached for dostarlimab in GARNET, indicating durable responses 1

Efficacy in Overall Endometrial Cancer Population

• In the RUBY trial, dostarlimab plus chemotherapy showed a 2-year PFS rate of 36.1% vs 18.1% with chemotherapy alone in the overall population (HR 0.64) 1
• 2-year OS rates were 71.3% with dostarlimab plus chemotherapy vs 56.0% with chemotherapy alone 1
• Pembrolizumab plus lenvatinib showed efficacy in pMMR/MSS endometrial cancer with median PFS of 6.6 months vs 3.8 months with chemotherapy 1

Biomarker Testing and Companion Diagnostics

• Both drugs use the VENTANA MMR RxDx Panel as an IHC companion diagnostic for assessing dMMR status 1
• FoundationOne CDx is approved as a companion diagnostic for MSI-H status determination for pembrolizumab treatment 1
• MMR IHC is recommended as the first-line biomarker test for both drugs, with MSI and NGS testing as second-line options 1

Safety Profile

• In the RUBY trial, dostarlimab plus chemotherapy showed grade ≥3 adverse events in 70.5% of patients vs 59.8% with chemotherapy alone 1
• Common immune-related adverse events with dostarlimab included hypothyroidism (11.2%) and rash (6.6%) 1
• In the GARNET trial, the most common grade 3 or higher treatment-related adverse events with dostarlimab were anemia (2.9%), colitis (1.9%), and diarrhea (1.9%) 3
• Pembrolizumab showed treatment-related adverse events in 76% of patients (grades 3-4 in 12%) with no fatal events in KEYNOTE-158 4

Dosing Regimens

• Dostarlimab monotherapy: 500 mg every 3 weeks for 4 cycles, followed by 1000 mg every 6 weeks 2, 3
• In combination therapy (RUBY trial): dostarlimab 500 mg with carboplatin-paclitaxel every 3 weeks for 6 cycles, followed by dostarlimab 1000 mg every 6 weeks for up to 3 years 1
• Pembrolizumab monotherapy: 200 mg every 3 weeks for up to 35 cycles 4

FDA Approvals

• Dostarlimab received accelerated approval for dMMR recurrent or advanced endometrial cancer that progressed on or after platinum-based therapy 1
• Pembrolizumab received approval for MSI-H/dMMR solid tumors including endometrial cancer that progressed following prior treatment 1
• Pembrolizumab plus lenvatinib received approval for advanced endometrial cancer that is not MSI-H/dMMR after platinum-based chemotherapy 1

Clinical Implications

• For dMMR/MSI-H endometrial cancer, both drugs show robust activity as monotherapy 1
• The RUBY trial suggests dostarlimab plus chemotherapy may be particularly effective in dMMR/MSI-H patients with a substantial PFS benefit 1, 5
• For pMMR/MSS endometrial cancer, pembrolizumab plus lenvatinib has established efficacy 1