In just the first half of the year, new drugs with outstanding efficacy continued to be approved for marketing. For renal cell carcinoma (hereafter renal cancer), the US Food and Drug Administration (FDA) expanded the indications for 2 immunologic drugs. No new drugs for kidney cancer were marketed in China during the same period.
Table 1 New indications for kidney cancer expanded by the FDA
|
Drug type |
Drug name or regimen name |
Indications |
| Immunization drugs | Pabrolizumab + axitinib | First-line treatment of advanced kidney cancer |
| Avelumab + axitinib | First-line treatment of advanced kidney cancer |
Below, we describe the application of these new indications.
Treatment of advanced kidney cancer is tricky, and surgery and radiation therapy cannot cure it. The vast majority of kidney cancers are clear cell carcinomas, for which chemotherapy is also largely ineffective, and targeted agents are now used primarily. 9 targeted agents are now available in the United States for advanced kidney cancer, such as sunitinib and pegaptanib.
Prognosis of advanced kidney cancer is stratified according to risk factors, and usually for low-risk patients who respond well to targeted therapy, half usually survive for more than 30 months. However, 60-70% of patients are clinically intermediate to high-risk and do not respond as well to targeted therapy as low-risk patients, especially high-risk patients, with much shorter survival. After the introduction of immune checkpoint inhibitors in 2015, this new class of drugs is also being used to explore the treatment of advanced kidney cancer.
Last year, the FDA approved a dual-immune drug combination regimen, “navulizumab + ipilimumab,” for the first-line treatment of intermediate-to-high-risk (poorly targeted) advanced kidney cancer.
After that, another immune combination regimen, “atezolizumab + bevacizumab (an anti-angiogenesis-targeted agent),” was shown to be more effective than targeted agents in patients with advanced kidney cancer with PD-L1 expression ≥1% in studies with no PFS is an efficacy assessment metric that represents the time to survival with stable improvement and no progression, which has very positive implications for patients.
It is easy to see from the table above that the regimens with expanded indications for kidney cancer treatment this year are also all immune combination regimens, and all are PD-1/PD-L1 monoclonal antibodies combined with anti-angiogenic targeting agents (axitinib).
What’s better about the new regimen this time?
Pabrolizumab + axitinib benefits all patients with advanced kidney cancer
The approval of pabrolizumab + axitinib was based on the results of the KEYNOTE-426 study. In the study, this combination regimen had a nearly 50% longer overall survival (OS) at 1 year than targeted agents, nearly doubled the objective remission rate (ORR), and achieved a median PFS of 15.5 months.
This is the first regimen to result in a PFS of more than 12 months in all kidney cancer populations. This means that patients can benefit from this treatment regardless of their PD-L1 expression status and risk classification. Other previous immune combination regimens have targeted an overall kidney cancer population that is not at all risk.
Alevumab + axitinib, another new option for patients with advanced kidney cancer with positive PD-L1 expression
Another immune combination approved this year, Alevumab + axitinib, was clinically studied in patients with advanced kidney cancer with PD-L1 expression ≥1%, and this combination prolonged progression-free survival (PFS) by more than 5 months compared to the targeted agent, providing an effective first-line treatment option for these patients. The combination regimen has been shown to extend progression-free survival (PFS) by more than 5 months compared with targeted agents, providing an effective first-line treatment option for these patients.
What are the first-line options for advanced kidney cancer?
With the approval of these two new regimens, there are now many first-line treatments for advanced kidney cancer. So, which of these first-line options is best?
Table 2 First-line regimens for advanced kidney cancer, target population, and efficacy
| Program | Population | Efficacy |
| Targeted agents (sunitinib, etc.) | All advanced kidney cancer | Median PFS time 7.7 to 8.4 months |
| Medium to high risk advanced kidney cancer | Median PFS time of 11.6 months | |
| Pabrolizumab + axitinib | All advanced kidney cancer | Median PFS time of 15.1 months |
| Avelumab + axitinib | Advanced renal cancer, especially advanced renal cancer with PD-L1 expression ≥1% (the statutory indication is not restricted and the guidelines do not limit PD-L1 expression) | Median PFS time of 13.8 months |
Targeted agents have been used as first-line treatment for advanced kidney cancer for nearly 10 years. Starting last year, combination therapy with immunologic agents started to enter the first line, and it is easy to see through this year’s FDA indication expansion that immune combination with targeted (anti-angiogenic) will gradually become mainstream.
But the question is whether all populations are suitable for immune-combination anti-angiogenic targeted agents.
How to choose first-line therapy for advanced kidney cancer at different risks
First, let’s look at patients with different risks of kidney cancer. For patients at intermediate to high risk, a combination of dual immunologic agents, or immunologic agents + targeted (anti-angiogenic), are both more effective than targeted therapy alone.
So, what is the choice for low-risk patients? These patients have a low-risk IMDC score or only have good overall prognosis for lung metastases. For these patients, the Checkmate 214 study clearly demonstrated that the dual immune combination was less effective than targeted agents alone. So, is immunotherapy + targeted (anti-angiogenic) right for them?
All of the above studies confirm that first-line treatment of advanced kidney cancer, even in low-risk populations immune combination with targeted therapy exceeds targeted drug therapy alone, but may not be as dramatic as the benefit in intermediate- and high-risk populations.
Therefore, there is no clear advantage of combining PD-1 monoclonal antibody with CTLA-4 monoclonal antibody immune versus immune in low-risk populations, but there may be an advantage of combining immune versus targeted therapy.
However, the combination regimen has higher economic costs and adverse effects than targeted monotherapy. Therefore, clinical considerations need to be taken into account.
How to choose first-line therapy for advanced kidney cancer with different PD-L1 expression profiles
In the 2 approved regimens for immune combination targeting (anti-angiogenesis) – pablizumab + axitinib, and Avelumab + axitinib – only pablizumab + axitinib benefited all patients, and for Avelumab in combination with axitinib, the higher the PD-L1 expression, the the better the effect.
In addition to PD-L1 expression, more effective biomarkers will be needed in the future to help physicians screen patients for more precise treatment with immune combination regimens.