LEAP-014 Trial Shows Lenvatinib Triple Combination Fails to Improve Survival in Metastatic Esophageal Cancer
核心洞察
The phase 3 LEAP-014 trial demonstrated that adding lenvatinib to pembrolizumab plus chemotherapy did not significantly improve overall survival compared to pembrolizumab plus chemotherapy alone in patients with metastatic esophageal squamous cell carcinoma (搜索).
Median overall survival was 17.6 months with the lenvatinib combination versus 15.5 months with the control regimen, failing to reach statistical significance with a hazard ratio of 0.92.
Despite higher response rates in the lenvatinib arm (62.2% vs 54.8%), the addition of lenvatinib increased treatment-related toxicity without meaningful survival benefit.
The addition of lenvatinib to pembrolizumab and chemotherapy failed to demonstrate a statistically significant improvement in overall survival compared to pembrolizumab plus chemotherapy alone as first-line treatment for patients with metastatic esophageal squamous cell carcinoma (搜索) (ESCC (搜索)), according to results from the phase 3 LEAP-014 trial presented at the 2025 ESMO Congress.
The median overall survival in the lenvatinib combination arm was 17.6 months (95% CI, 15.5-19.1) versus 15.5 months (95% CI, 13.5-17.2) in the control arm receiving pembrolizumab plus chemotherapy (HR, 0.92; 95% CI, 0.77-1.10; P = .1852). The 12- and 24-month overall survival rates were 65% and 34% in the investigational arm versus 61% and 32% in the control arm, respectively.
"Lenvatinib plus pembrolizumab and chemotherapy did not significantly improve OS as first-line treatment for [patients with] metastatic ESCC (搜索) vs pembrolizumab plus chemotherapy," stated lead study author Jong-Mu Sun, MD, PhD, of the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine (搜索) in Seoul, Republic of Korea.
Trial Design and Patient Population
The LEAP-014 trial enrolled 850 patients at least 18 years of age with histologically and/or cytologically confirmed locally advanced, unresectable or metastatic ESCC (搜索). Patients were randomly assigned 1:1 to receive either lenvatinib plus pembrolizumab and chemotherapy or pembrolizumab plus chemotherapy alone.
In the investigational arm, patients received 8 mg of oral lenvatinib once daily, plus 400 mg of intravenous pembrolizumab every 6 weeks, combined with either cisplatin plus 5-fluorouracil, paclitaxel plus cisplatin every 3 weeks, or modified FOLFOX6 (搜索) every 2 weeks. This was followed by maintenance therapy with 20 mg of lenvatinib plus 400 mg of pembrolizumab every 6 weeks until progression, unacceptable toxicity, or withdrawal.
The control arm received 400 mg of intravenous pembrolizumab every 6 weeks plus chemotherapy according to local standards. Overall survival served as the primary endpoint, with secondary endpoints including progression-free survival, objective response rate, duration of response, and safety.
Baseline characteristics were well balanced between treatment groups. Within the investigational arm, the median age was 64 years, with 49% of patients above age 65. Most patients were male (78%), Asian (66%), and from East Asia (66%). ECOG performance status was 1 in 64% of cases, and most patients had a PD-L1 (搜索) combined positive score of 10 or greater (66%).
Efficacy Results Across Subgroups
The overall survival results were consistent across prespecified subgroups, including PD-L1 (搜索) status, geographic region, and chemotherapy regimen. In patients with a PD-L1 combined positive score of at least 10, the median overall survival was 18.0 months (95% CI, 16.4-20.4) in the lenvatinib arm versus 15.8 months (95% CI, 13.1-17.4) in the control arm (HR, 0.89; 95% CI, 0.71-1.11).
Progression-free survival showed similar patterns, with a median of 7.2 months (95% CI, 6.8-8.4) in the lenvatinib arm versus 6.9 months (95% CI, 5.8-7.0) in the control arm (HR, 0.89; 95% CI, 0.75-1.04). The 12- and 24-month progression-free survival rates were 31% and 12% in the investigational arm versus 23% and 15% in the control arm, respectively.
The objective response rate was higher in the lenvatinib combination arm at 62.2% (95% CI, 57.4%-66.8%) compared to 54.8% (95% CI, 49.9%-59.6%) in the control arm (delta, 7.3%; 95% CI, 0.7%-13.8%). Complete response rates were 16.3% in the lenvatinib arm versus 19.2% in the control arm.
The median duration of response was 8.1 months in the lenvatinib arm with 17% of patients experiencing a response lasting 24 months or greater, compared to 6.8 months in the control arm where 21% of patients had responses lasting at least 24 months.
Safety Profile and Tolerability
The median duration of treatment exposure was longer in the lenvatinib arm at 7.1 months versus 5.6 months in the control arm. Any-grade adverse events occurred in 99.5% of patients in the investigational arm (grade ≥3, 81.2%; grade 5, 9.7%) compared to 99.3% in the control arm (grade ≥3, 79.1%; grade 5, 11.5%).
Adverse events leading to drug discontinuation occurred in 33.3% of patients in the lenvatinib arm versus 39.0% in the control arm. Treatment-related adverse events occurred in 97.1% of patients in the investigational arm and 96.5% in the control arm.
The most frequent adverse events occurring in at least 15% of patients in either arm included decreased neutrophil count, nausea, hypertension, diarrhea, decreased platelet count, anemia, hypothyroidism, stomatitis, decreased white blood cell count, fatigue, decreased appetite, palmar plantar erythrodysesthesia syndrome, and proteinuria.
Immune-mediated adverse events in the experimental arm included hypothyroidism (33.5% any grade), hyperthyroidism (8.1% any grade), pneumonitis (7.6% any grade, 2.6% grade ≥3), adrenal insufficiency (4.8% any grade, 1.4% grade ≥3), and gastritis (2.9% any grade, 0.2% grade ≥3).
"Safety profiles were generally consistent with the known safety profiles of lenvatinib in combination with pembrolizumab and chemotherapy or the pembrolizumab plus chemotherapy regimen," Sun concluded.
The failure of the LEAP-014 trial to meet its primary endpoint represents a setback for the development of multi-targeted approaches in metastatic esophageal squamous cell carcinoma (搜索), despite the higher response rates observed with the triple combination regimen.