Globally, kidney cancer is a common cancer, accounting for approximately 2% to 3% of all solid tumors. The most important lesion feature of kidney cancer is overexpression of genes related to the vascular endothelial growth factor (VEGF) receptor, which promotes neovascularization. If abundant neovascularization is formed at the lesion site, it can provide sufficient oxygen and nutrition for the cancer cells to divide and proliferate uncontrollably, and it also further enhances the risk of continued spread and metastasis. This shows that effective blocking of VEGF-related mechanisms is important for the treatment of kidney cancer.
Why can lenvatinib treat kidney cancer?
Lenvatinib (also known as levatinib) is a multipotent tyrosine kinase inhibitor (TKI) whose efficacy has been demonstrated in clinical studies in multiple solid tumors.
In addition to targeting the 3 vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), it also blocks the biology of multiple fibroblast growth factor receptors (FGFR1-4), platelet-derived growth factor receptor (PDGFRα), and the proto-oncogenes RET and c-KIT. Thus, lenvatinib comprehensively inhibits the pro-angiogenic mechanism of kidney cancer, mitigating the risk of progression and avoiding the catastrophic consequences of lesion spread and metastasis.
Approval of lenvatinib
Lenvatinib in combination with everolimus has been approved in Europe and the United States as a second-line regimen in advanced kidney cancer for the follow-up of patients who have failed first-line anti-angiogenic agent (or VEGF-targeted drug) therapy.
In mainland China, lenvatinib is available but currently approved only for patients with hepatocellular carcinoma.
How is lenvatinib used to treat kidney cancer?
Current clinical guidelines recommend the combination of lenvatinib and everolimus, with oral lenvatinib 18 mg + everolimus 5 mg once daily.
Everolimus is a mammalian target of rapamycin, mTOR inhibitor that inhibits revascularization by blocking the mTOR signaling pathway and is not yet as effective as lenvatinib when used alone. However, when used in combination with lenvatinib, it can have a synergistic effect, inhibiting angiogenesis more significantly than the 2 drugs alone in combination, and exerting a stronger anticancer effect.
As shown in Table 1, a total of 153 patients were enrolled in an international multicenter clinical phase 2 study, and lenvatinib in combination with everolimus was superior to either lenvatinib or everolimus alone for second-line treatment of advanced kidney cancer, both in terms of symptomatic relief and prolonged survival.
Table 1. Comparison of second-line treatment outcomes in advanced kidney cancer
| Medication grouping | Progression-free survival | Overall survival | Objective remission rate |
| Lenvatinib (18 mg/day) + everolimus (5 mg/day) | 14.6 months | 25.5 months | 43% |
| Lenvatinib (24 mg/day) | 7.4 months | 19.1 months | 27% |
| Everolimus (10 mg/day) | 5.5 months | 15.4 months | 6% |
The most common serious adverse reactions to the lenvatinib + everolimus combination regimen included hypertension, fatigue and weakness, and various GI symptoms such as diarrhea, constipation, nausea, vomiting, abdominal pain, and loss of appetite.
Female patients should be advised to use contraception and are prohibited from breastfeeding while taking the drug.
Summary
The combination of lenvatinib + everolimus has been recognized by medical experts and health authorities worldwide for its efficacy as a second-line treatment option for kidney cancer. With several additional clinical phase 2 or larger phase 3 studies underway or imminent, lenvatinib + everolimus is expected to gain further prominence in the treatment of kidney cancer and may become a first-line option for patients.