What were the design, patient population, interventions, efficacy outcomes (PFS, OS, ORR) and safety findings of the phase III, open‑label, randomized Keynote‑775 trial comparing lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks) versus physician’s choice chemotherapy (paclitaxel, doxorubicin, or carboplatin‑paclitaxel) in adults with advanced or metastatic mismatch‑repair proficient/microsatellite stable endometrial carcinoma who progressed after at least one platinum‑based chemotherapy regimen?

KEYNOTE-775 Trial Summary

KEYNOTE-775 was a landmark phase III trial that established pembrolizumab plus lenvatinib as superior to chemotherapy for previously treated advanced endometrial cancer, demonstrating significant improvements in both progression-free and overall survival in patients with mismatch repair-proficient/microsatellite stable (pMMR/MSS) disease. 1, 2

Trial Design

• Phase III, open-label, randomized, active-controlled trial enrolling 827 patients with advanced or metastatic endometrial carcinoma who had progressed after at least one prior platinum-based chemotherapy regimen 3, 2

• Patients were randomized 1:1 to receive either:

  • Pembrolizumab 200 mg IV every 3 weeks plus lenvatinib 20 mg orally once daily, or
  • Physician's choice chemotherapy: doxorubicin 60 mg/m² IV every 3 weeks OR paclitaxel 80 mg/m² IV weekly (3 weeks on/1 week off) 1, 3, 2

• Stratification factors included ECOG performance status, geographic region, and history of pelvic radiation 3

• Treatment continued until RECIST v1.1-defined disease progression (verified by blinded independent central review), unacceptable toxicity, or for pembrolizumab, a maximum of 24 months 3

• Key exclusion criteria: endometrial sarcoma (including carcinosarcoma), active autoimmune disease, or medical conditions requiring immunosuppression 3

Patient Population

pMMR/MSS Cohort (Primary Analysis Population)

• 697 patients with pMMR disease (determined by VENTANA MMR RxDx Panel test) 1, 3

  • 346 patients received pembrolizumab plus lenvatinib
  • 351 patients received chemotherapy (254 doxorubicin, 97 paclitaxel) 3

• Demographics: median age 65 years (range 30-86); 52% age ≥65 years; 62% White, 22% Asian, 3% Black 3

• Performance status: 60% ECOG PS 0,40% ECOG PS 1 3

• Histologic subtypes: 55% endometrioid, 30% serous, 7% clear cell, 4% mixed, 3% other 3

• Prior therapy: 67% had one prior systemic therapy, 30% had two, 3% had three or more; 37% received only prior neoadjuvant or adjuvant therapy 3

Overall Population

• 827 total patients including 130 patients with mismatch repair-deficient (dMMR) disease 2

Efficacy Outcomes in pMMR/MSS Population

Progression-Free Survival

• Median PFS: 6.6 months (95% CI 5.6-7.4) with pembrolizumab plus lenvatinib versus 3.8 months (95% CI 3.6-5.0) with chemotherapy 1, 3

• Hazard ratio: 0.60 (95% CI 0.50-0.72; p<0.0001) representing a 40% reduction in risk of progression or death 1, 3

Overall Survival

• Median OS: 17.4 months (95% CI 14.2-19.9) with pembrolizumab plus lenvatinib versus 12.0 months (95% CI 10.8-13.3) with chemotherapy 1, 3

• Hazard ratio: 0.68 (95% CI 0.56-0.84; p=0.0001) representing a 32% reduction in risk of death 1, 3

• Updated final analysis confirmed sustained OS benefit with HR 0.70 (95% CI 0.58-0.83) in the pMMR population 4

Objective Response Rate

• ORR: 30% (95% CI 26-36) with pembrolizumab plus lenvatinib versus 15% (95% CI 12-19) with chemotherapy (p<0.0001) 3

  • Complete response rate: 5% versus 3%
  • Partial response rate: 25% versus 13% 3

• Updated analysis showed ORR of 32.4% versus 15.1% in pMMR patients 4

Duration of Response

• Median duration of response: 9.2 months (range 1.6+ to 23.7+) with pembrolizumab plus lenvatinib versus 5.7 months (range 0.0+ to 24.2+) with chemotherapy 3

Efficacy Outcomes in All-Comers Population

• Median PFS: 7.2 months versus 3.8 months (HR 0.56; 95% CI 0.47-0.66; p<0.001) 2

• Median OS: 18.3 months versus 11.4 months (HR 0.62; 95% CI 0.51-0.75; p<0.001) 2

• ORR: 33.8% versus 14.7% 4

• Benefits were observed across all subgroups including histology, prior therapy, and MMR status 4

Safety Profile

Overall Adverse Event Rates

• Grade ≥3 adverse events occurred in 88.9% of patients receiving pembrolizumab plus lenvatinib versus 72.7% receiving chemotherapy 2

• Grade ≥3 treatment-related adverse events occurred in approximately 63-70% of patients on combination therapy 5

Most Common Adverse Events (Any Grade)

• Hypothyroidism, hypertension, fatigue, diarrhea, and musculoskeletal disorders were the most frequent key adverse reactions 6

• Other common events included decreased appetite, nausea, vomiting, stomatitis, weight decrease, proteinuria, and palmar-plantar erythrodysesthesia syndrome 6

Grade 3-4 Adverse Events (≥10% Incidence)

• Hypertension, fatigue, and weight decrease were the most common severe adverse reactions 6

Dose Modifications

• Approximately 65% of patients required lenvatinib dose reductions and 72% needed temporary dose interruptions due to toxicity 5

• Pembrolizumab dose reductions are not recommended; dose holds are used for immune-related adverse events 5

• Lenvatinib dose-reduction steps: 20 mg → 14 mg → 10 mg → 8 mg daily 5

Timing of Adverse Events

• Key adverse reactions first occurred within approximately 3 months of treatment initiation 6

Immune-Related Adverse Events

• Included hypothyroidism, rash, and less commonly colitis, hepatitis, pneumonitis, or nephritis 5

Clinical Implications

• This trial supported FDA regular approval of pembrolizumab plus lenvatinib for advanced endometrial cancer that is pMMR/MSS after prior platinum-based chemotherapy 1

• The combination is indicated only for pMMR/MSS tumors; for dMMR/MSI-H disease, single-agent pembrolizumab or dostarlimab is preferred 5

• No new safety signals were observed in updated analyses, and the safety profile remained manageable with appropriate monitoring and dose modifications 4, 6

• Successful management requires patient education, preventative measures, close monitoring, and judicious use of dose modifications and concomitant medications 6