At the ESMO Congress 2026, Lubomir Bodnar (Siedlce, Poland) presented updated results from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 trial (NCT04634877), evaluating the clinical utility of circulating tumor DNA (ctDNA) in patients with resected, high-risk mismatch repair-deficient (dMMR) endometrial cancer receiving adjuvant pembrolizumab plus standard-of-care treatment.
The updated analysis showed a substantial disease-free survival (DFS) benefit with pembrolizumab in the dMMR subgroup, with a hazard ratio of 0.34, while ctDNA testing demonstrated limited ability to predict disease-specific failure-free survival outcomes.
Methods
KEYNOTE-B21 is a randomized, double-blind phase III trial evaluating pembrolizumab or placebo in combination with standard adjuvant treatment following curative-intent surgery for high-risk endometrial cancer.
Patients were randomized 1:1 to receive pembrolizumab or placebo alongside standard-of-care therapy, including chemotherapy.
The prespecified fourth interim analysis (IA4) further evaluated DFS and disease-specific failure-free survival (DSFS) in the dMMR subgroup.
Circulating tumor DNA was prospectively assessed using the tumor-informed Signatera 16-plex assay in patients with available samples at baseline, following chemotherapy, at the end of treatment, and at week 96.
Exploratory analyses examined associations between ctDNA status, ctDNA clearance, and subsequent DSFS outcomes.
Key Takeaways
The fourth interim analysis demonstrated findings consistent with the earlier interim analysis, favoring pembrolizumab in the dMMR subgroup.
- Disease-free survival: Pembrolizumab plus chemotherapy was associated with improved DFS compared with placebo plus chemotherapy (HR 0.34; 95% CI, 0.17–0.65).
- Disease-specific failure-free survival: The combination also favored pembrolizumab for DSFS (HR 0.25; 95% CI, 0.11–0.54).
- Baseline ctDNA positivity: Approximately 20% of patients had detectable ctDNA following curative-intent surgery, with similar prevalence between treatment groups.
- ctDNA clearance: At the post-chemotherapy assessment, 20% of patients in the pembrolizumab arm had cleared ctDNA compared with 14% in the placebo arm.
- End-of-treatment ctDNA: Clearance was observed in 19% of patients receiving pembrolizumab and 16% receiving placebo.
- Week 96: ctDNA clearance was observed in 17% and 10% of patients in the respective treatment groups.
- Predictive performance: Baseline ctDNA demonstrated high specificity and negative predictive value but low positive predictive value and variable sensitivity for DSFS events.
- Clinical utility: Despite differences in ctDNA clearance, the assay demonstrated only modest predictive value for DSFS, partly because ctDNA positivity and disease-specific events were uncommon.
At baseline, ctDNA positivity was similar between treatment groups, including among patients with endometrioid and nonendometrioid histologies.
At subsequent assessments, the pembrolizumab group consistently demonstrated lower ctDNA positivity, reflecting higher clearance and lower emergence rates.
Conclusion
The updated KEYNOTE-B21 analysis showed that adding pembrolizumab to adjuvant standard-of-care treatment was associated with favorable DFS and disease-specific failure-free survival outcomes in patients with high-risk dMMR endometrial cancer.
The DFS hazard ratio of 0.34 and DSFS hazard ratio of 0.25 reinforce the potential benefit of pembrolizumab in this molecularly defined subgroup, although the original trial did not meet its primary DFS endpoint in the overall intention-to-treat population.
Circulating tumor DNA analyses demonstrated numerically greater clearance with pembrolizumab, but the low prevalence of detectable ctDNA after surgery and limited ability to predict disease-specific events restrict its current clinical utility.
More sensitive ctDNA detection approaches and additional prospective validation are needed before ctDNA-guided treatment decisions can be established in the adjuvant setting for endometrial cancer.
Source: ESMO Congress 2026, Abstract LBA36; ENGOT-en11/GOG-3053/KEYNOTE-B21 (NCT04634877).
