Lenvatinib is an oral inhibitor of multiple tyrosine kinase receptors, targeting vascular endothelial growth factor receptor (VEGFR1–3), fibroblast growth factor receptor (FGFR1–4), platelet-derived growth factor receptor α (PDGFR α), KIT-ligand (stem cell factor receptor), and RET (rearranged during transfection), with a distinct in vitro tyrosine kinase inhibitory profile compared to sorafenib ^[1][2][3][4][16,17,18,19].

Clinical evidence of the antitumour activity of lenvatinib was demonstrated in preclinical studies, with inhibition of both VEGF- and FGF-driven angiogenesis, and direct antiproliferative activity on liver cancer cells in vitro and in vivo, depending on the FGF-signalling pathway ^{[5][6][7][8][9]}[20,21,22,23,24].

Following positive preliminary data, the REFLECT trial was conducted by Kudo et al. to compare lenvatinib with sorafenib as first-line treatment for unresectable HCC ^[10][11][25,26] (Table 1).

This was a non-inferiority, multicentre, international, open-label, randomised phase 3 trial in 954 patients ^[12][14]. Patients were performance status (PS) 0–1, CP-A, and BCLC B or C without previous systemic therapy. Patients were randomised 1:1 to lenvatinib or sorafenib (478 to lenvatinib and 476 to sorafenib), stratified by region (Asia-Pacific or Western), macroscopic portal vein invasion and/or extrahepatic spread (yes or no), PS (0 or 1), and body weight (<60 or ≥60 kg). Baseline patient characteristics were similar between the two groups, except for hepatitis C virus (HCV) aetiology (lower in the lenvatinib group) and alpha-foetoprotein (AFP) baseline levels (higher in the lenvatinib group). The study was positive for all primary and secondary outcomes: the median OS was 13.6 months vs. 12.3 months (hazard ratio (HR): 0.92, 95% CI, 0.79–1.06); the PFS was 7.4 months (6.9–8.8) vs. 3.7 months (3.6–4.6) (HR: 0.66 (0.57–0.77); p < 0.0001); the time to progression (TTP) was 8.9 months (7.4–9.2) vs. 3.7 months (3.6–5.4) (HR: 0.63 (0.53–0.73); p < 0.0001); the overall response rate (ORR) according to response evaluation criteria in solid tumours (RECIST) was 24.1% (20.2–27.9) vs. 9.2% (6.6–11.8) (Odds ratio (OR) 3.13 (2.15–4.56); p < 0.0001), and the disease control rate (DCR) was 75.5% (71.7–79.4) vs. 60.5% (56.1–64.9).

Subsequently, several publications confirmed significant improvements in PFS, TTP, and ORR compared to sorafenib in real life conditions reflecting a greater anti-tumoral activity ^{[13][14][15][16][17][18]}[27,28,29,30,31,32].

Lenvatinib had a manageable tolerability profile in the REFLECT study. Most common treatment-emergent adverse events (TEAEs) were hypertension (42%), diarrhoea (39%), decreased appetite (34%), and decreased weight (31%). The overall safety profile was comparable to other TKIs, with similar rates of grade ≥3 TEAEs. TEAEs led to lenvatinib interruption in 40% of cases, a dose reduction in 37%, and drug withdrawal in 9% ^[19][33]. Patients treated with lenvatinib had a higher level of high blood pressure (23% vs. 14% of grades 3–4). The higher response rate and the higher frequency of severe hypertension with lenvatinib may indicate a greater anti-angiogenic effect of this drug. On the other hand, patients treated by lenvatinib exhibited a lower level of palmar-plantar erythrodysaesthesia syndrome (PPES) (3% vs. 11% of grades 3–4). Therefore, in patients with pre-existing skin diseases (outside non-healing ulcers), lenvatinib could be preferred to avoid an additional skin toxicity impacting the quality of life. Similarly, pre-ulcerative diabetic foot might benefit from the absence of the neuropathic-like pain induced by the hand–foot syndrome.

Regarding cost-effectiveness analyses, there was an increase of 0.27 life years (LY), an improvement of 0.23 quality-adjusted LY (QALY), and a decrease in costs for lenvatinib compared with sorafenib ^[20][21][22][34,35,36]. The AE treatment costs were very small and accounted for <1% of the total cost, suggesting that lenvatinib could represent a new long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC.

Preclinical studies demonstrated that inhibition of FGF19 signalling may play a role in the anti-tumour effects of TKIs against HCC. FGF19 is expressed in approximately one-third of HCC tissue samples and is associated with tumour aggressiveness, represented by a poorly differentiated tumour and an unfavourable prognosis ^[23][37].

In a post hoc analysis of the REFLECT study of Finn et al., lenvatinib (and not sorafenib) was associated with an increase in FGF19 and FGF23 levels at four weeks (FGF19: 55.2% vs. 18.3%, p = 0.0140; FGF23: 48.4% vs. 16.4%; p = 0.0022, respectively), suggesting efficient inhibition of the FGF signalling pathway ^[24][38]. In the lenvatinib arm, patients with a complete or partial response had a greater increase in FGF19 and FGF23 from baseline vs. non-responders (FGF19: 55.2% vs. 18.3%, p = 0.0140; FGF23: 48.4% vs. 16.4%; p = 0.0022).

Otherwise, early changes in serum FGF19 and Ang-2 (an angiogenesis regulator that plays a role through TEK tyrosine kinase and endothelium receptor levels during lenvatinib treatment) might predict clinical response and PFS. In a recent study of 74 patients (BCLC stages B and C), including patients previously treated with sorafenib or regorafenib, with a median follow-up of 157 days, significantly increased FGF19 levels and decreased Ang-2 levels were seen in lenvatinib responders compared with non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004; ratio at 8 weeks: 2.19 vs. 1.40, p = 0.0015) ^[25][26][39,40]. In multivariate analysis, the combination of serum FGF19 and Ang-2 was the most independent predictive factor for lenvatinib response (OR: 9.143; p = 0.0012) and PFS (HR: 0.171; p = 0.0240). The ability of FGF19 to predict an early lenvatinib response had a receiver operating characteristic (ROC) curve area of 0.726 at the optimal cut-off value of 1.51 for the FGF19 ratio vs. baseline, and with 68.6% specificity and sensitivity in discriminating the responder group from the non-responder group. Similarly, patients who experienced a greater decrease in Ang-2 levels were observed in the responder group compared with the non-responder group at 2 weeks (Ang-2 level ratio at 2 weeks vs. baseline: 0.709 vs. 0.893, p = 0.0041), 4 weeks (Ang-2 ratio: 0.584 vs. 0.810, p = 0.0002), and 8 weeks (Ang-2 ratio: 0.500 vs. 0.804, p < 0.0001).

2. Lenvatinib as Second-Line Treatment

In patients eligible for second-line therapy, after progression on atezolizumab/bevacizumab, treatment options include TKIs (sorafenib, lenvatinib, regorafenib, and cabozantinib), ramucirumab, and IO (pembrolizumab), according to local approvals. The development of IO as a gold standard at first line has opened new perspectives of the use of TKIs and among them lenvatinib as a second line therapy. In vitro studies of PD-1 inhibitor demonstrated that anti-PD-1 antibodies can remain bound to CD8+ T cells for more than 20 weeks ^[27][61]. The introduction of a TKI, and among them, lenvatinib, could act synergistically with anti-PD-1 antibodies even after the interruption of the immunotherapy. Aoki et al. reported encouraging results of lenvatinib when used after failure of PD-1/PD-L1 antibodies ^[28][62]. The ORR was 55.6%, the DCR was 86.1%, PFS was 10 months, and OS was 15.8 months. The OS since initiation of ICI therapy was 29.8 months, which is much longer than that conferred by lenvatinib alone as first-line therapy ^[29][63]. Yamauchi et al. conducted a study of 40 patients with HCC and reported that lenvatinib achieved a high response rate (81%) in tumours with a high expression of FGFR4 ^[30][64]. In addition, treatment with lenvatinib resulted in longer PFS in patients with a high FGFR4 expression than in those without FGFR4 expression (5.5 vs. 2.7 months, respectively), indicating that lenvatinib shows higher antitumour activity against tumours with high FGFR4 expression. However, there is a positive correlation between β-catenin mutations and FGFR4 expression, and its expression is higher in the population of tumours with WNT/β-catenin-activating mutations, which are found in approximately 20–30% of all HCCs ^{[23][28][30][31]}[37,62,64,65]. Thus, even in patients who did not respond well to previous treatment with atezolizumab plus bevacizumab due to β-catenin activating mutations, subsequent treatment with lenvatinib would still provide better results due to its potent inhibitory effect on FGFR4. A multinational, multicentre, and retrospective study reported clinical outcomes of patients who received subsequent systemic therapies after progression on atezolizumab-bevacizumab ^[32][66]. Of the 49 patients, 19 received lenvatinib. The ORR and DCR were 6.1 and 63.3%, respectively, across all patients. With a median follow-up duration of 11.0 months, PFS and OS were 3.4 months (95 CI 1.8–4.9) and 14.7 months (95% CI 8.1–21.2), respectively. Median PFS with lenvatinib was significantly longer than with sorafenib (6.1 vs. 2.5 months; p = 0.004), although there was no significant difference in median OS (16.6 vs. 11.2 months; p = 0.347). Patients treated with sorafenib had significantly more hand–foot syndromes than those treated with lenvatinib (69.0 vs. 26.3%, p = 0.004), while patients with lenvatinib seemed to have more fatigue and hypertension than those with sorafenib (fatigue; 42.1 vs. 17.2%, p = 0.058, and hypertension; 42.1 vs. 17.2%, p = 0.058). In addition, a retrospective study has recently investigated the potential use of lenvatinib (based on real-life experience and in vitro assessment) as second-line for patients intolerant to sorafenib, and as third-line for patients resistant to regorafenib ^[33][67]. The results suggest that lenvatinib is active and safe as a second/third-line treatment for unresectable HCC. Another study in a few patients treated with at least three different systemic therapies also reported the efficacy of lenvatinib as later treatment, with a tolerable toxicity profile ^[34][68]. Cabozantinib has demonstrated an improved OS and PFS in the phase 3 CELESTIAL study and is now validated for patients progressive after sorafenib ^[35][69]. Only retrospective data are available about the use of cabozantinib after ICI in HCC. In the recent multinational multicentre retrospective study of 49 patients who received subsequent systemic therapy after progression on atezolizumab-bevacizumab, only one received cabozantinib as second line ^[32][66]. There is not enough evidence in the literature to choose from the four available TKIs after failure of atezolizumab and bevacizumab.