ESMO Congress 2026

Lenvatinib is a multi-target tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET and KIT, and its position in hepatocellular carcinoma (HCC) was established by the phase 3 REFLECT trial: among 1,492 enrolled and 954 randomized patients with unresectable HCC in the first-line setting, the lenvatinib arm (n=478) achieved a median survival of 13.6 months, demonstrating non-inferiority to sorafenib (n=476) ^[3]. On this basis, lenvatinib stands alongside atezolizumab plus bevacizumab, sorafenib, regorafenib, cabozantinib and ramucirumab as one of six systemic therapies approved for advanced HCC on phase III evidence ^[1], and it long shared first-line status with sorafenib ^[5], even though median survival in the advanced population remains around one year overall ^[6]. In renal cell carcinoma, lenvatinib is likewise among the agents approved since 2015 with targets beyond VEGFR ^[4].

At ESMO26, the long-term OS results of the phase 3 LEAP-012 study were presented (by Anthony El-Khoueiry and Arndt Vogel): 480 patients with unresectable, non-metastatic HCC were randomized to lenvatinib + pembrolizumab or dual placebo on top of TACE, with dual primary endpoints of PFS and OS. Median OS was 40.4 vs 40.8 months, HR 0.98 (0.76–1.26); median PFS 14.6 vs 10.2 months, HR 0.70 (0.56–0.89); grade ≥3 TRAEs 72.2% vs 32.0%. The study met its PFS primary endpoint but showed no OS benefit, and a median OS of ~40 mo was noted as setting a new benchmark for trial design. In the same meeting, the ChromoKey phase 2 study (presented by Ilya Tsimafeyeu) showed activity of lenvatinib + pembrolizumab in metastatic chromophobe renal cell carcinoma, with specific figures not disclosed in the live post.

LEAP-012 extends lenvatinib's evidence from the advanced first-line setting ^[3] to unresectable, non-metastatic patients treated with TACE — a population whose existing care centers on locoregional approaches such as chemoembolisation ^[2], while systemic therapy evidence has mainly come from advanced patients ^[6]. The PFS benefit (HR 0.70) confirms the antitumor activity of the "local plus systemic" combination, but the OS curves essentially overlap (HR 0.98) with median OS of about 40 months in both arms, far higher than the 13.6 months in REFLECT ^[3]; as the two trials enrolled different populations (LEAP-012 restricted to non-metastatic disease with TACE, REFLECT in the advanced first line), the figures cannot be compared directly, yet the long baseline survival underscores the difficulty of discriminating OS in this population.

Limitations: against a negative OS result, grade ≥3 TRAEs rose from 32.0% to 72.2%, so the benefit-risk balance hinges on the clinical weight of the PFS gain; the live post also provided no subgroup, subsequent-treatment or quality-of-life details, which await full publication.