Results from the PHASE3 LEAP-014 study (NCT04949256) investigating Pembrolizumab (Keytruda) plus Lenvatinib and chemotherapy in participants with Metastatic Esophageal Squamous Cell Carcinoma were posted on 2026-07-20. The trial demonstrated that the triple combination therapy led to a statistically significant improvement in objective response rate (ORR) by 7.3% (p-value 0.0152) compared to pembrolizumab plus chemotherapy.

Background

Pembrolizumab (Keytruda) is an anti-PD-1 therapy. This study investigated its use in combination with Lenvatinib, a multi-kinase inhibitor, and standard chemotherapy (cisplatin, 5-fu, or oxaliplatin) for the first-line treatment of Metastatic Esophageal Squamous Cell Carcinoma.

Trial design

The PHASE3 LEAP-014 study, identified as NCT04949256, enrolled 863 participants with Metastatic Esophageal Squamous Cell Carcinoma. The primary hypothesis was that Pembrolizumab plus Lenvatinib plus chemotherapy would be superior to Pembrolizumab plus chemotherapy with respect to overall survival (OS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR). Participants were randomized to receive either Pembrolizumab plus Lenvatinib plus chemotherapy (cisplatin, 5-fu, or oxaliplatin) or Pembrolizumab plus chemotherapy (cisplatin, 5-fu, or oxaliplatin).

A Part 1 safety run-in was conducted to assess dose-limiting toxicities (DLTs) and adverse events (AEs) for the triple combination therapy.

Key results

In Part 1, the safety run-in for the Pembrolizumab + Lenvatinib + Chemotherapy arm reported 2 participants with dose-limiting toxicities (DLTs), 13 participants with adverse events (AEs), and 7 participants who discontinued study treatment due to an AE.

For Part 2 (Main Study) in all participants, key efficacy outcomes included:

  • Overall Survival (OS): Median OS was 17.6 Months for the Pembrolizumab + Lenvatinib + Chemotherapy arm versus 15.5 Months for the Pembrolizumab + Chemotherapy arm. The Hazard Ratio (HR) was 0.92 (95% Confidence Interval 0.77, 1.1), with a p-value of 0.1852.
  • Progression-free Survival (PFS): Median PFS was 7.2 Months for the Pembrolizumab + Lenvatinib + Chemotherapy arm versus 6.9 Months for the Pembrolizumab + Chemotherapy arm. The Hazard Ratio (HR) was 0.89 (95% Confidence Interval 0.75, 1.04), with a p-value of 0.0753.
  • Objective Response Rate (ORR): The ORR was 62.2 Percentage of participants for the Pembrolizumab + Lenvatinib + Chemotherapy arm compared to 54.8 Percentage of participants for the Pembrolizumab + Chemotherapy arm. The difference was 7.3% (95% Confidence Interval 0.7, 13.8), with a p-value of 0.0152.
  • Duration of Response (DOR): Median DOR was 8.1 Months for the Pembrolizumab + Lenvatinib + Chemotherapy arm versus 6.8 Months for the Pembrolizumab + Chemotherapy arm. The Hazard Ratio (HR) was 0.89 (95% Confidence Interval 0.71, 1.11), with a p-value of 0.149.

In participants with Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10, the median OS for the Pembrolizumab + Lenvatinib + Chemotherapy arm was 18.0 Months. The Hazard Ratio (HR) for OS in this subgroup was 0.85 (95% Confidence Interval 0.69, 1.04), with a p-value of 0.0611.

What this means

The results from the PHASE3 LEAP-014 study indicate that adding Lenvatinib to Pembrolizumab and chemotherapy significantly improved the objective response rate (ORR) in patients with Metastatic Esophageal Squamous Cell Carcinoma. While the primary endpoint of overall survival (OS) did not reach statistical significance, and progression-free survival (PFS) also did not show a statistically significant improvement, the enhanced ORR suggests a greater proportion of patients experienced tumor shrinkage with the triple combination. The safety profile observed in the Part 1 run-in provides initial insights into the tolerability of the regimen.

Source

This information was sourced from ClinicalTrials.gov, documenting the results of trial NCT04949256, which were posted on 2026-07-20. The study details are available on clinicaltrials.gov.