Kidney cancer is a clinically common cancer, accounting for approximately 4% of new cancers and 2.5% of cancer deaths worldwide. Localized lesions of early-stage kidney cancer can be surgically resected for radical cure, although 25% to 40% of them will still progress to distant metastases. In addition, 20% to 25% of patients have advanced kidney cancer with metastases to other sites at the time of presentation.
During the past 15 years, many advances have been made in the development of drugs for advanced kidney cancer, and new drugs have come to market that offer new treatment options and new hope for improved outcomes, relief, and longer survival.
Targeted therapies
Tyrosine kinase inhibitor (TKI)
TKI works primarily by inhibiting the vascular endothelial growth factor (VEGF) signaling pathway. Since its approval in 2007, TKI has become a mainstream first-line agent for the treatment of advanced metastatic kidney cancer.
As shown in Table 1, the efficacy of sunitinib has improved significantly over previous interferon therapies, with more durable remissions and longer overall survival (26.4 vs 21.8 months). As new TKI drugs are developed and introduced, their clinical characteristics are being optimized.
- Pazopanib has similar efficacy to sunitinib, with improved safety and tolerability and a significantly lower incidence of serious toxicities;
- Cabozantinib showed a substantial improvement in efficacy compared with sunitinib, extending median overall survival by 5 to 6 months (26.6 vs 21.2 months).
Table 1. Comparison of the efficacy of TKI first-line regimens for advanced kidney cancer
| Treatment subgroups of the study | Overall survival | Progression-free survival |
| 2007 US study | ||
| Sunitinib | 26.4 months | 11 months |
| Interferon | 21.8 months | 5 months |
| 2013 U.S. Study | ||
| Pazopanib | 28.3 months | 8.4 months |
| Sunitinib | 29.1 months | 9.5 months |
| 2018 U.S. Study | ||
| Cabozantinib | 26.6 months | 8.6 months |
| Sunitinib | 21.2 months | 5.3 months |
TKI analogs can be used as second-line therapy after failure of first-line cytokine therapy. However, for those who failed first-line TKI regimens, only the benefit of second-line treatment with cabozantinib is supported by clinical evidence. Clinical guidelines recommend that such patients are best treated with a switch to an agent with another anti-cancer mechanism, such as nabritumomab.
Mammalian target of rapamycin (mTOR) inhibitors
At present, the only mTOR inhibitor used in first-line treatment of advanced kidney cancer is temsirolimus, which has improved efficacy compared with interferon regimens, but the clinical evidence is not yet sufficient and remains to be validated.
Everolimus can be used for follow-up after failure of first-line regimens, although it is not effective alone and a combination regimen, such as with lenvatinib, is usually recommended to improve efficacy.
Immunotherapy
Immunotherapy
Traditional cytokine therapy
Cytokines such as interleukin-2 and interferon have been used in the past for the treatment of advanced metastatic kidney cancer. However, due to their poor efficacy and significant toxic side effects, they are now being phased out of the history books.
European and American experts have also tried first-line treatment with a combination of bevacizumab and interferon, but overall patient survival was not prolonged and there was a significant increase in the incidence of serious adverse events.
Immune checkpoint inhibitors
These drugs reignite the tumor-killing effect of the patient’s immune system by blocking the interference of the tumor cell PD-1 system with the body’s immunity. As shown in Table 2, they achieve good efficacy in patients with advanced metastatic kidney cancer, whether as first- or second-line regimens.
Table 2. Results of clinical phase 3 studies of immune checkpoint inhibitors
| Research design | Dosing groupings | Treatment outcome |
| First-line treatment: patients with intermediate and high risk |
|
Overall survival was significantly longer and remission rates showed a significant increase in the combination therapy group. |
| First-line treatment |
|
Not yet completed, overall survival to be reported at follow-up, with significantly better safety and tolerability in the combination arm. |
| Second-line therapy: patients who have failed prior first-line therapy |
|
Median overall survival was significantly longer by 5-6 months in the nabugliumab-treated group; the incidence of toxicities was significantly lower, and patients’ quality of life was significantly improved. |
Future combination therapy strategies
Combinations can help improve outcomes and safety and may become the standard first-line regimen for advanced metastatic kidney cancer in the future. As shown in Table 3, there are multiple new drug combination regimens currently in development.
Table 3. New Drug Combination Regimens in Development
| New drug combination regimens | Mechanism of action |
| Avelumab + axitinib | programmed death-ligand 1, PD-L1) inhibitor + TKI |
| Pimozumab + axitinib | Programmed death-1 (PD-1) inhibitor + TKI |
| Pimozumab + lenvatinib | PD1 + TKI |
| PD1 + TKI ± CTLA-4 antibody | |
| Autologous dendritic cell vaccine + TKI |
Summary
In recent years, new drugs have come to market with a better understanding of the antitumor mechanism, leading to a continuous evolution of treatment options for advanced kidney cancer. From early cytokine therapies to current targeted therapies and immunotherapies, combination regimens will likely become the standard first-line regimen for advanced kidney cancer in the future, further improving clinical outcomes.