Biomarker Search Reveals Unexpected Associations in Treatment of Advanced Kidney Cancer

Scientists are gratified when a clinical trial reveals whether one treatment — often an experimental therapy or drug combination — is superior to another. But researchers then often look more deeply into the data, searching for characteristics of tumors associated with a treatment’s effectiveness, or lack of it. In today’s world of precision medicine, identifying such potentially predictive characteristics — called biomarkers —in a patient’s cancer may help guide therapy for individuals.

Scientists led by Toni Choueiri, MD, director of Dana-Farber’s Lank Center for Genitourinary Oncology, undertook a biomarker search using data from a phase 3 clinical trial called JAVELIN Renal 101. This clinical trial found that previously untreated patients with advanced kidney cancer who were treated with a combination of avelumab plus axitinib had significantly prolonged progression-free survival compared with patients who received sunitinib.

Avelumab is an antibody drug that blocks the PD-L1 checkpoint on tumor cells, and in doing so, unleashes immune defender cells against the cancer. Both axitinib and sunitinib are kinase inhibitors that are designed to starve tumors by choking off their blood supply.

Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber.
Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber.

A surprising discovery

Choueiri and his co-authors parsed the data from the JAVELIN trial to identify tumor characteristics associated with better or worse progression-free survival. They analyzed samples of almost 900 patients who were randomized to receive either the combination treatment or the single-agent, sunitini.

Somewhat to the scientists’ surprise, they found no correlation between progression-free survival and two biomarkers that have been associated with improved survival in other immunotherapy studies. One biomarker was the level in tumors of the PD-L1 immune checkpoint. PD-L1 has been found more abundant in patients whose tumors responded to immunotherapy — but that association was not seen in the JAVELIN study. The other potential biomarkers was the number of mutations present in the tumor known as tumor mutational burden, or TMB. Neither biomarker was associated with better progression-free survival in the kidney cancer patients.

“These observations suggestion that PD-L1 expression may have limited positive predictive value” in immunotherapy for kidney cancer, the researchers say.

So, the scientists searched for other factors in the tumors and their environment that might be associated with the effectiveness of the avelumab-axitinib combination or the sunitinib drug. Possible biomarkers might be certain gene mutations or patterns of gene activity that correlated with the tumors’ response to treatment. Their search identified a group of 26 genes whose activity correlated with improved progression-free survival in the avelumab-axitinib combination patients. They dubbed this set of genes the Renal 101 Immune signature. The investigators found another set of genes whose activity was correlated withy longer progression-free survival in the sunitinib-only patients: they labeled this gene group Renal 101 Angio signature, because the genes were mainly involved in generating new blood vessels.

“These findings may inform personalized therapeutic strategies for patients with advanced kidney cancer and other tumor types,” the investigators concluded.

Based on the findings, it’s possible that knowing whether a patient’s tumor cells have the Renal 101 Immune signature or the Renal 101 Angio signature, oncologists may be able to determine which treatment option has a better chance of success.