The treatment of metastatic kidney cancer used to be a serious challenge for urologic oncologists, unlike prostate cancer and bladder cancer, which are insensitive to radiotherapy and chemotherapy. Interleukin-2 and interferon alpha were once important in the field of metastatic kidney cancer, with objective response rates of 5-27% according to the literature, but this treatment effect was mild and short-lived in most patients.
To achieve better results, high doses of therapy are often required, with serious toxic side effects that most patients cannot tolerate. Because of this, with the advent of targeted therapies, immunotherapy represented by interleukin-2 and interferon alpha gradually receded from the stage of history.
The emergence of targeted therapy represented by sunitinib can be said to be a milestone in the history of metastatic kidney cancer treatment, which was quickly approved by FDA in the United States and other countries due to its reliable efficacy and safety compared with traditional treatment.
The currently approved targeted drugs for metastatic kidney cancer include sunitinib, sorafenib, pazopanib, axitinib, everolimus, tesilimus and bevacizumab. The drugs currently available in China are mainly sunitinib, sorafenib, everolimus and axitinib. These drugs have been widely used in the first-line and second-line treatment of metastatic kidney cancer.
1.Sunitinib
Sunitinib malate (trade name: Sotan Sutent, Pfizer Inc.) is an oral small molecule multi-target receptor tyrosine kinase inhibitor. It has multiple effects of anti-tumor angiogenesis and inhibition of tumor cell growth. The targets that exert anti-cancer effects include: platelet-derived growth factor receptor PDGFR (PDGFRα and PDGFβ), vascular endothelial growth factor receptor VEGFR (VEGFR1, VEGFR2, VEGFR3), FMS-like complex kinase FLT-3, colony-stimulating factor receptor CSF-1R, stem cell factor receptor c-KIT and neurotrophic factor RET.
It has been recommended as a first-line treatment for advanced kidney cancer in several national and regional medical guidelines for more than a decade, based on extensive clinical evidence. Its antitumor effect is mainly achieved through inhibition of angiogenesis and cell proliferation, and is more effective in clear cell carcinoma and tumors containing clear cell carcinoma components.
In the international multicenter phase III clinical study of sunitinib as a first-line agent for metastatic renal cell carcinoma, a total of 750 patients with metastatic clear cell carcinoma were enrolled and randomized 1:1 to the sunitinib and interferon alpha groups, and all patients had not received prior systemic therapy. The median age of the patients was 60 years, and 90% of the patients had undergone prior nephrectomy.
The median overall survival time was 26.4 months and 21.8 months for the sunitinib and interferon alfa arms, respectively, and was even more impressive when considering the crossover of control patients into the treatment arm late in the trial. Major adverse reactions included neutropenia, thrombocytopenia, diarrhea, hand-foot syndrome, and hypertension, but mostly the adverse reactions were safe and manageable.
The efficacy and safety of sunitinib in patients with brain metastases, poor physical status, and non-clear cell carcinoma were further confirmed in a later, expanded trial. Based on the above studies, most guidelines recommend sunitinib as the first-line treatment for metastatic kidney cancer.
2.Sorafenib
Sorafenib is a multi-kinase inhibitor that inhibits a variety of kinases present both intracellularly and on the cell surface, including RAF kinase, vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor receptor-3 (VEGFR-3), platelet-derived growth factor receptor-β (PDGFR-β), KIT and FLT-3. Sorafenib has dual antitumor effects by.
1. Directly inhibits tumor growth by inhibiting the RAF/MEK/ERK signaling pathway;
2. indirectly inhibit tumor cell growth by blocking tumor neovascularization through inhibition of VEGFR and PDGFR.
In a phase III study of sorafenib versus placebo in patients who had failed immunotherapy or were unsuitable for immunotherapy, the median progression-free time was 5.5 months in the sorafenib group versus 2.8 months in the placebo group, and sorafenib also benefited patients in terms of overall survival. Although sorafenib did not show superior efficacy compared with interferon alfa in a phase II trial of previously untreated metastatic kidney cancer, it has been shown to be more effective than interferon alfa in subsequent trials of sorafenib;
However, in subsequent phase III studies with sorafenib as a control for sotane-resistant patients, sorafenib was not inferior to axitinib and tercirolimus. Sorafenib is recommended as a second-line agent in European guidelines and as a first-line agent in US and domestic guidelines.
3. Axitinib
Axitinib is also a multi-target tyrosine kinase inhibitor, a second-generation oral selective vascular endothelial growth factor receptor inhibitor, which can inhibit VEGFR1, VEGFR2, VEGFR3; and has a weak inhibitory effect on other targets, and has a short half-life.
In an international phase III clinical study of axitinib versus sorafenib in the second-line treatment of metastatic kidney cancer, 723 patients who had failed first-line cytokine therapy or targeted therapy were enrolled, and the median disease-free time was 6.7 months and 4.7 months in the axitinib and sorafenib groups, respectively; in the subgroup treated with first-line In the subgroup treated with cytokines, the median disease free time was 12.1 months and 6.5 months in the axitinib and sorafenib groups, respectively;
In the subgroup treated with targeted therapy as first-line therapy, the time to disease progression was 4.8 months and 3.4 months, respectively; however, the final overall survival analysis did not show a significant difference between the two. In this study, grade 3 or higher side effects were mainly diarrhea (11%), hypertension (16%) and fatigue (11%). Patients experienced varying degrees of nausea, vomiting, and malaise in 32%, 24%, and 21% of cases, respectively. In a phase III clinical study of axitinib versus sorafenib in the first-line treatment of metastatic kidney cancer, the time to progression-free disease obtained with axitinib was very low.
The median disease progression-free time in the axitinib and sorafenib groups was 10.1 months and 6.5 months, respectively, and although the median disease-free time was somewhat longer in the axitinib group, they did not reach a significant difference; this suggests that there is no significant difference in the efficacy of axitinib versus sorafenib as first-line therapy. Based on the above findings, axitinib is recommended as second-line therapy by most guidelines.
4. Everolimus
Everolimus is an oral mTOR receptor blocker whose effectiveness has been established in patients who have failed first-line complexine kinase inhibitor therapy. In the phase III clinical study of this drug, patients enrolled were metastatic kidney cancer patients who had failed prior anti-VEGFR therapy, 46% of whom had previously received only sunitinib, while the remainder had received other second- or even third-line therapy; all patients were randomized to the everolimus + best supportive care (BSC) group versus the placebo + best supportive care group.
The median disease-free time was 4 months and 1.9 months in the treatment and control groups, respectively. In a randomized phase II clinical study of everolimus versus sunitinib in patients with metastatic kidney cancer who had not received prior systemic therapy, the median disease-free time was 7.9 months and 10.7 months in the everolimus and sunitinib groups, respectively, suggesting that sunitinib is more effective than everolimus as first-line therapy. Based on these studies, most guidelines recommend everolimus for second-, third- and fourth-line treatment.