Refining First-Line Therapy in Advanced Endometrial Care: LEAP-001 Trial Results  

Endometrial cancer (EC) remains a pressing global health concern, ranking sixth in the most common cancers in women globally and exhibiting rising incidence and mortality rates.

For years, paclitaxel-carboplatin chemotherapy has stood as the first-line standard of care. However, given the success of lenvatinib combined with pembrolizumab in previously treated cases, the ENGOT-en9/LEAP-001 trial sought to explore whether this immunotherapy-based combination could serve as a non-chemotherapy alternative in the first-line setting for patients with advanced or recurrent EC.

Here’s a brief overview of the study.

Design of ENGOT-en9/LEAP-001
This trial was a global, open-label, phase III randomized study involving 842 patients with stage III-IV or recurrent, histologically confirmed and radiographically apparent EC. Participants were randomized 1:1 to receive either:

• Lenvatinib (20 mg daily, oral) + Pembrolizumab (200 mg every three weeks, IV)
• Paclitaxel (175 mg/m²) + Carboplatin (AUC 6), administered every three weeks, up to seven cycles.

Patients were further stratified by mismatch repair (MMR) status. The dual primary endpoints were progression-free survival (PFS) and overall survival (OS), with secondary assessments including objective response rates (ORR), patient-reported outcomes, and safety measures.

Key Efficacy Findings
The study found the following results for each endpoint.

• Progression-Free Survival (PFS):
  • In mismatch repair-proficient (pMMR) patients, median PFS was 9.6 months with lenvatinib plus pembrolizumab versus 10.2 months with chemotherapy (HR 0.99).
  • Among all-comers, median PFS favored lenvatinib/pembrolizumab slightly at 12.5 vs. 10.2 months (HR 0.91).
• Overall Survival (OS):
  • In the pMMR group, median OS was 30.9 months for lenvatinib plus pembrolizumab and 29.4 months for chemotherapy (HR 1.02; noninferiority p=0.24).
  • Among all-comers, median OS was longer for lenvatinib plus pembrolizumab (37.7 vs. 32.1 months; HR 0.93).
• Objective Response Rate (ORR):
  • 51% of the pMMR patients receiving lenvatinib plus pembrolizumab, compared to 55% with chemotherapy.
  • Importantly, median duration of response was longer with lenvatinib plus pembrolizumab in the pMMR population. (16.1 vs. 10.6 months).

Results from Subgroup Analyses
Next, in the subgroup analyses, the following results were found.

• Mismatch Repair-Deficient (dMMR) Tumors:
  • PFS favored lenvatinib/pembrolizumab with an HR of 0.61 (PFS median: 31.8 vs. 9.0 months).
  • OS also trended favorably (HR 0.57).
• Patients Previously Treated with Adjuvant Chemotherapy:
  • In this subgroup,lenvatinib plus pembrolizumab improved PFS and showed favorable OS trends (PFS HR 0.60, OS HR 0.67).

Safety and Patient Experience Findings
Finally, the study found the following regarding safety and patient experience.

• • Grade ≥3 treatment-related adverse events were higher in the lenvatinib plus pembrolizumab arm (79%) compared to chemotherapy (67%).
  • Common severe toxicities (Grade ≥3) included hypertension (43%), diarrhea (8%), and proteinuria (7%)

Implications for Clinical Practice
While LEAP-001 did not meet its primary efficacy endpoints in the broader pMMR or all-comers populations, its findings may have wide-reaching ramifications across many areas of EC management.

The combination of lenvatinib plus pembrolizumab demonstrated meaningful benefit in biologically distinct subgroups, specifically patients with dMMR tumors and those undergoing platinum rechallenge after prior chemotherapy. This reinforces the growing recognition that biomarker-driven and prior treatment history-informed strategies may be more appropriate than one-size-fits-all approaches in advanced EC.

LEAP-001 also highlights the importance of patient selection and trial design aligned with biological rationale. As therapeutic options evolve, eligibility frameworks should too.

In short, while LEAP-001 may not revolutionize first-line treatment in advanced endometrial cancer, it meaningfully refines our understanding of when—and for whom—immunotherapy can provide the most benefit.

Reference:

1. Marth C, Moore RG, Bidziński M, et al. First-Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2025;43(9):1083-1100. doi:10.1200/JCO-24-01326