Lenvatinib-Based Regimens Show Higher Adverse Event Rates in LEAP-009

Final safety results from the phase 2 LEAP-009 trial (NCT04428151) showed higher rates of grade 3 to 5 adverse events (AEs), treatment discontinuations, and deaths due to AEs among patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) receiving lenvatinib (Lenvima) plus pembrolizumab (Keytruda) or lenvatinib alone vs standard of care (SOC). The findings were presented at the 2026 European Society for Medical Oncology (ESMO) Congress.¹

The analysis included more than 16 months of additional follow-up beyond the previously published results. In that analysis, median overall survival (OS) was 8.4 months with lenvatinib plus pembrolizumab vs 11.3 months with SOC (HR, 1.48; 95% CI, 1.11-1.97). Median OS with lenvatinib monotherapy was 10.6 months. The combination did not improve OS vs SOC, highlighting the importance of considering safety alongside efficacy in this previously treated population.²

LEAP-009 Trial Design and Patient Characteristics

The trial enrolled adults with recurrent or metastatic HNSCC whose disease progressed within 12 weeks of their most recent treatment after receiving at least 2 doses of anti–PD-(L)1 therapy during or after platinum-containing chemotherapy. Patients were randomly assigned in a 3:3:2 ratio to receive lenvatinib plus pembrolizumab, investigator’s choice of SOC chemotherapy or cetuximab (Erbitux), or lenvatinib monotherapy.

The combination arm received oral lenvatinib at 20 mg once daily plus intravenous pembrolizumab at 200 mg every 3 weeks for up to 35 cycles. Patients receiving lenvatinib alone received 24 mg orally once daily. The end-of-trial safety analysis included 404 patients who received at least 1 dose of treatment: 155 in the combination arm, 153 in the SOC arm, and 96 in the lenvatinib monotherapy arm. Median follow-up was 32.5 months in the combination arm, 32.2 months with SOC, and 31.0 months with lenvatinib monotherapy.¹

Severe Adverse Events and Treatment Discontinuations

Grade 3 to 5 AEs of any cause occurred in 114 patients (73.5%) receiving lenvatinib plus pembrolizumab, 95 (62.1%) receiving SOC, and 70 (72.9%) receiving lenvatinib alone. Hypertension was the most common grade 3 to 5 AE in the lenvatinib-containing arms, affecting 18.1% of patients receiving the combination and 20.8% receiving lenvatinib monotherapy. In the SOC arm, anemia was the most common grade 3 to 5 AE, occurring in 15.0% of patients.¹

Serious AEs occurred in 61.9% of patients receiving lenvatinib plus pembrolizumab, compared with 41.8% of those receiving SOC and 56.3% of those receiving lenvatinib alone. AEs led to discontinuation of any study drug in 49 patients (31.6%) in the combination arm, 19 (12.4%) in the SOC arm, and 22 (22.9%) in the lenvatinib monotherapy arm. Treatment-related grade 3 to 5 AEs were reported in 80 patients (51.6%) receiving the combination, 63 (41.2%) receiving SOC, and 51 (53.1%) receiving lenvatinib alone.¹

AEs leading to death occurred in 27 patients (17.4%) in the combination arm, compared with 9 patients (5.9%) receiving SOC and 9 (9.4%) receiving lenvatinib monotherapy. Treatment-related AEs leading to death were reported in 8 patients (5.2%) receiving lenvatinib plus pembrolizumab, 1 (0.7%) receiving SOC, and 3 (3.1%) receiving lenvatinib alone.¹

Immune-Mediated Adverse Events

Immune-mediated AEs or infusion reactions occurred in 45.8% of patients receiving lenvatinib plus pembrolizumab, 13.7% receiving SOC, and 42.7% receiving lenvatinib monotherapy. Hypothyroidism was the most frequently reported event in this category, occurring in 40.0%, 8.5%, and 34.4% of patients, respectively.¹

The investigators concluded that the final safety findings were consistent with the known safety profiles of the regimens, although grade 3 to 5 treatment-related AEs, treatment discontinuations, and deaths due to AEs were more frequent with lenvatinib-containing regimens than with SOC.¹

Findings from the separate phase 3 LEAP-010 trial in first-line HNSCC also showed that adding lenvatinib to pembrolizumab improved response and progression-free survival but did not improve OS.³ The LEAP-009 results add further safety data for lenvatinib-based treatment in patients whose disease progressed after prior platinum-based chemotherapy and anti–PD-(L)1 therapy.

REFERENCES

1. Kim HR, Oliva Bernal M, Salas S, et al. End-of-trial safety results of the phase 2 LEAP-009 trial of lenvatinib plus pembrolizumab for recurrent/metastatic head and neck squamous cell carcinoma. Presented at: ESMO Congress 2026; October 23-266, 2026; Madrid, Spain. Abstract1555P.

2. Kim HR, Oliva M, Salas S, et al. Lenvatinib plus pembrolizumab versus standard of care in recurrent/metastatic head and neck squamous cell carcinoma: randomized, phase 2 LEAP-009 trial. Eur J Cancer. 2026;243:116824. doi:10.1016/j.ejca.2026.116824.

3. Licitra L, Tahara M, Harrington K, et al. Pembrolizumab with or without lenvatinib as first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma: pPhase III LEAP-010 sStudy. J Clin Oncol. doi:10.1200/JCO-25-00570