Background
KEYNOTE-775 (Study 309) was a phase III open-label randomized trial (n=827) evaluating lenvatinib plus pembrolizumab versus single-agent chemotherapy (physician's choice of doxorubicin or weekly paclitaxel) in patients with advanced endometrial cancer who had received at least one prior platinum-based chemotherapy regimen. It tested combined VEGF inhibition and PD-1 blockade — a strategy informed by the single-arm KEYNOTE-146 — in both pMMR and dMMR disease.
Interventions and follow up
Arm A (chemotherapy): Physician's choice doxorubicin 60 mg/m² q21d or weekly paclitaxel 80 mg/m²
Arm B (lenvatinib + pembrolizumab): Lenvatinib 20 mg PO daily + pembrolizumab 200 mg IV q3w
Primary endpoints: PFS and OS (dual primary; tested hierarchically pMMR then all patients)
Median follow-up: 11.4 months
Arm B (lenvatinib + pembrolizumab): Lenvatinib 20 mg PO daily + pembrolizumab 200 mg IV q3w
Primary endpoints: PFS and OS (dual primary; tested hierarchically pMMR then all patients)
Median follow-up: 11.4 months
Results
pMMR mPFS: 6.6 vs 3.8 months; HR 0.60, 95% CI 0.50–0.72, P<.001
pMMR mOS: 17.4 vs 12.0 months; HR 0.68, 95% CI 0.56–0.84, P<.001
All patients mPFS: 7.2 vs 3.8 months; HR 0.56, 95% CI 0.47–0.66, P<.001
All patients mOS: 18.3 vs 11.4 months; HR 0.62, 95% CI 0.51–0.75, P<.001
ORR: 31.9% vs 14.7% (all patients)
pMMR mOS: 17.4 vs 12.0 months; HR 0.68, 95% CI 0.56–0.84, P<.001
All patients mPFS: 7.2 vs 3.8 months; HR 0.56, 95% CI 0.47–0.66, P<.001
All patients mOS: 18.3 vs 11.4 months; HR 0.62, 95% CI 0.51–0.75, P<.001
ORR: 31.9% vs 14.7% (all patients)
Adverse events
Overall: Grade ≥3 AE 88.9% (lenva/pembro) vs 72.7% (chemo); discontinuation due to AEs 33% vs 20%; lenvatinib dose reductions in 67%
Most common Grade ≥3 (lenva/pembro): hypertension 38%, fatigue 10%, diarrhea 8%, hypothyroidism 1%
Most common Grade ≥3 (lenva/pembro): hypertension 38%, fatigue 10%, diarrhea 8%, hypothyroidism 1%
Conclusions
Lenvatinib plus pembrolizumab significantly improved PFS and OS compared with chemotherapy in previously treated advanced endometrial cancer — including in pMMR (MSS) disease — providing the first regimen with demonstrated OS benefit in the second-line setting and establishing a new standard of care.
Key Limitations
Open-label design; physician's choice chemotherapy comparator (not a fixed control); lenvatinib dose reductions in 67% raise tolerability concerns; no direct comparison with other IO combinations; the dMMR subgroup (n=130) was analyzed exploratorily; benefit in pMMR patients is the most clinically distinctive feature, separating this regimen from IO monotherapy.
Clinical Context
FDA approved lenvatinib plus pembrolizumab for previously treated advanced endometrial cancer (not MSI-H/dMMR) in September 2019 (accelerated) and confirmed in 2021 post-KEYNOTE-775. This remains the key second-line standard for pMMR endometrial cancer, though the introduction of pembrolizumab- and dostarlimab-containing first-line regimens (NRG-GY018, RUBY) will alter sequencing. In pMMR patients progressing after IO-containing first-line therapy, the role of lenvatinib plus pembrolizumab is evolving.