A prior analysis of data from The Cancer Genome Atlas (TCGA) demonstrated that high EphrinB2 gene expression was associated with poor survival in patients with muscle-invasive bladder cancer. At the American Society of Clinical Oncology (ASCO) annual meeting, researchers reported new findings showing that EphrinB2 expression in patients with metastatic urothelial carcinoma was linked with lower response to PD-1/L1 immune checkpoint inhibitor monotherapy.
In this exclusive MedPage Today video, investigator Sarmad Sadeghi, MD, of the Keck School of Medicine of the University of Southern California in Los Angeles, explained the significance of the results.
Following is a transcript of his remarks:
We reported a clinical trial of a drug [soluble EphB4-human serum albumin (sEphB4-HSA)] that targets EphrinB2. This drug was used in combination with pembrolizumab [Keytruda] for previously treated patients with the diagnosis of metastatic urothelial carcinoma.
This study enrolled 70 patients. This was a multicenter study. And we found that the average response — the response rate for this study — was [37%] among all patients. And if patients express EphrinB2 on their tumors, the response rate went up as high as 52%. This was very surprising. The expectation for response rate in pembrolizumab is about 20%. So the entire population did better, and the population that expressed EphrinB2 did much better.
Based on TCGA data, we knew that EphrinB2 is a negative prognostic marker for overall survival. So the question here was, “Do these patients do better just because they’re getting immunotherapy?” And we didn’t have the data to answer that question. Now we do.
In collaboration with Dana-Farber and University of Colorado, we surveyed 120 patients, we collected tissue and stained it for EphrinB2. These patients had to have had prior chemotherapy and had to have received immunotherapy, monotherapy basically. And we found that [for] the entire population — 120 patients — the response rate was 20%, exactly as we expected. But if they expressed EphrinB2, the response rate was 12%. And if they did not express EphrinB2 on the tumor, the response rate was 33%.
So this confirms the hypothesis that EphrinB2 continues to be a negative prognostic marker, and inhibiting it improves patient outcomes and improves the outcomes of treatment with immunotherapy.
It does a few things for us. I think this is not one of the common markers that we look at when, for instance, we do a Caris profile or a Tempus profile. But it is available in RNA information in those studies. And I think if patients express high levels of EphrinB2, we can say that we don’t expect the average response to immunotherapy at 20%. We think there may be resistance to immunotherapy.
I think we can also say that inhibiting it — as was shown in the clinical trial that we presented — is a promising therapeutic approach for patients with bladder cancer and perhaps other cancers. So these have to be verified with larger studies, prospective studies, but they are hypothesis-generating and they are, I think to some extent, informing us of future directions for clinical trials.
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