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Immunotherapy triumphs in kidney cancer: A comparative look

Immunotherapeutic drugs that activate the immune system against cancer have radically changed the treatment for advanced kidney cancer. But how does immunotherapy compare with other advanced therapies?

 

New research provides some clues by comparing a type of immunotherapy with targeted therapy for metastatic kidney cancer.

 

Kidney cancer


Kidney cancer

Kidney cancer is a type of cancer that occurs when the cells in the kidney multiply rapidly and uncontrollably. The most common type is renal cell carcinoma (RCC), which starts in the lining of the tiny tubules inside the kidneys. It does not show any symptoms in the early stage. With time, kidney cancer progresses to the aggressive stage which manifests symptoms; the most common of which is blood in the urine.

 

The most common treatment for kidney cancer is surgical removal. Surgery often results in favorable outcomes if it is done when the cancer is still restricted to the kidney.

 

However, if the treatment is not started in time, cancerous cells break off and spread through the lymphatic system or the bloodstream to other organs like the lungs, liver, bones, and brain [1]. This advanced stage is called metastatic kidney cancer, or metastatic RCC (mRCC).

 

In mRCC, various systemic therapies are used to destroy the spread of cancer cells in various parts of the body. One such therapy is immunotherapy.

 

Immunotherapy revolutionizes treatment of metastatic kidney cancer


Cancer immunotherapy leverages the body's immune system to seek and destroy tumors. Under normal conditions, T-cells (immune cells) detect and destroy the cancer cells. But cancer cells give a false signal to the T-cells that inactivates them.

 

The way cancer cells trick the immune system is surprisingly simple. Cancer cells have a type of protein called programmed cell death ligand 1 (PD-L1). This protein interacts with an off-switch, called programmed cell death 1 (PD-1), located on the surface of T-cells. This interaction stops the T-cells from killing the cancer cells.

 

Checkpoint inhibitors are a type of immunotherapy that works by stopping the interaction between PD-L1 (proteins on cancer cells) and PD-1 (off-switch on T-cells).

 

Anti-PD-L1 drugs like atezolizumab and avelumab instead target PD-L1 proteins on cancer cells. Anti-PD-1 drugs like nivolumab and pembrolizumab bind to PD-1 receptors on T-cells. Both strategies stop a cancer cell from switching off T-cells.

 

With multiple novel therapies available, clinicians face a new question - which option works best?

 

Comparing anti-PD-L1 immunotherapy with targeted therapy


Researchers recently analyzed data from three major clinical trials that compared anti-PD-L1 combinations against sunitinib (a targeted therapy drug) in metastatic kidney cancer [2]. Their goal was to clarify how the two therapeutic options approaches stack up.

 

The trials - IMmotion150, IMmotion151, and JAVELIN Renal 101 - enrolled over 2200 mRCC patients in total [3]–[5]. Participants were randomly assigned to receive either:

 

  • An anti-PD-L1 drug (atezolizumab or avelumab) plus bevacizumab or axitinib

  • Sunitinib – a targeted therapy drug for kidney cancer.

 

After a median follow-up period of around 2 years, the studies found:


  • Overall survival was similar between the anti-PD-L1 and sunitinib groups. However, anti-PD-L1 combinations delayed disease progression more effectively.

  • For patients with any level of PD-L1 expression, anti-PD-L1 regimens improved progression-free survival and response rate compared to sunitinib.

  • In patients with high PD-L1 expression, anti-PD-L1 also enhanced overall survival compared to sunitinib.

 

Why might anti-PD-1 therapy have an edge?


Though anti-PD-L1 combinations showed good efficacy, the researchers speculate that anti-PD-1 drugs may work even better for kidney cancer.

 

Anti-PD-1 drugs directly activate T-cells by blocking the PD-1 receptor. This allows them to fully unleash the immune system regardless of PD-L1 levels on cancer cells. In contrast, anti-PD-L1 drugs only target PD-L1 proteins on cancer cells, not T-cells.

 

Evidence from lung cancer treatment suggests that PD-1 blockade is more potent than targeting PD-L1 alone. Anti-PD-L1 drugs do not affect the PD-1/PD-L2 pathway which also dampens T-cells. Unfortunately, no completed kidney cancer trials directly compare anti-PD-1 and anti-PD-L1 immunotherapy.

 

More research is still needed, but these insights hint that PD-1 inhibitors may have an edge for certain patients. 


Key takeaways


  • Immunotherapy performs better than targeted therapy in advanced kidney cancer.

  • Within immunotherapy, anti-PD-1 drugs may outperform anti-PD-L1 agents for kidney cancer, but more head-to-head data is needed.

  • Ongoing advances and combinations will further improve the prognosis for metastatic kidney cancer.


References


1. M. Bianchi et al., “Distribution of metastatic sites in renal cell carcinoma: a population-based analysis,” Annals of Oncology, vol. 23, no. 4, pp. 973–980, Apr. 2012, doi: 10.1093/annonc/mdr362.

2. B. A. Maiorano, D. Ciardiello, E. Maiello, and G. Roviello, “Comparison of Anti–Programmed Cell Death Ligand 1 Therapy Combinations vs Sunitinib for Metastatic Renal Cell Carcinoma,” JAMA Netw Open, vol. 6, no. 5, p. e2314144, May 2023, doi: 10.1001/jamanetworkopen.2023.14144.

4. R. J. Motzer et al., “Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma,” N Engl J Med, vol. 380, no. 12, pp. 1103–1115, Mar. 2019, doi: 10.1056/NEJMoa1816047.

5. D. F. McDermott et al., “Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma,” Nat Med, vol. 24, no. 6, pp. 749–757, Jun. 2018, doi: 10.1038/s41591-018-0053-3.

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