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First-Line Combination Therapy in Metastatic Kidney Cancer: Answers and More Questions

By: Lauren Harrison, MS
Posted: Tuesday, April 30, 2019

In an editorial published in The New England Journal of Medicine, Bernard Escudier, MD, of the Institut Gustave Roussy in Villejuif, France, highlighted the results of two recent trials suggesting that combination therapy using PD-L1 or PD-1 inhibitors is superior to sunitinib in treating renal cell carcinoma. These new combinations of avelumab (PD-L1 inhibitor) plus axitinib (VEGF inhibitor) and pembrolizumab (PD-1 inhibitor) plus axitinib are expected to become new standards of care and to be incorporated into future guidelines.

These trials, however, lead to questions that still need answering. The first question centers on the role of axitinib and whether inhibition of PD-1 and PD-L1 coordinates with axitinib. Axitinib was previously shown to be a potent and selective VEGF inhibitor. In the current trials, there was no control of axitinib monotherapy to see what clinical significance axitinib holds on its own.

In addition, it is unclear which of these two combinations will be used. Each trial used axitinib as a control, but the rates of progression-free survival and objective response in the avelumab-plus-axitinib trial compared with the pembrolizumab-plus-axitinib trial were similar. There was a higher percentage of favorable-risk patients in the pembrolizumab trial, reflecting the longer progression-free survival among those receiving sunitinib (11.1 months in this trial vs. 8.4 months in the avelumab trial).

Finally, the results from these trials lead to the question of whether subgroup analysis can help oncologists determine the best combination for an individual patient. Recent data suggest that angiogenesis, the T-cell effector response, interferon-gamma response, and myeloid inflammatory gene-expression signatures may help predict response to inhibitors of VEGF, PD-1, and PD-L1.

Disclosure: The study authors’ disclosure information may be found at nejm.org.



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