medwireNews: Chromatin conformation loops, especially the POU2F2 loop, may have clinical utility as a biomarker in advanced urothelial cancer, suggest exploratory data from the JAVELIN Bladder 100 trial of maintenance avelumab.
The findings were presented by Thomas Powles, from Barts Cancer Institute in London, UK, at the ESMO Congress 2022 in Paris, France.
He reminded the audience that the phase 3 study previously demonstrated an overall survival (OS) benefit with maintenance avelumab in advanced urothelial cancer patients who have not progressed after first-line chemotherapy.
Powles added that prior biomarker analyses have suggested that tumor mutational burden (TMB) and tumor immune activity (indicated by the JAV-immuno T-effector signature) are associated with this benefit.
But for the current analysis, the researchers focused on circulatory markers of immune checkpoint inhibitor efficacy, specifically chromatin conformation, which “has the potential to identify host immune factors in circulating [white blood cells] that are associated with anti-tumor immune activity.”
Applying the EpiSwitch platform to peripheral blood samples from 496 participants of JAVELIN Bladder 100, collected before they were randomly assigned to receive maintenance avelumab plus best supportive care (BSC) or the latter alone, the team identified a chromatin loop that was strongly associated with low JAV-immuno scores. The loop was found to encompass POU2F2, “a transcription factor with known roles in B cell maturation and participation in T-cell dependent humoral immunity.”
The POU2F2 gene expression in the tumor was also associated with the JAV-immuno signature and with the OS benefit of maintenance avelumab. Specifically, patients with a gene expression score greater than the median, but not those with a score equal to or less than the median, had better outcomes with use of the PD-L1 inhibitor.
There was a similar trend with regard to the POU2F2 loop assessed in blood samples, with absence of the loop – which signifies greater POU2F2 gene expression – associated with maintenance avelumab survival benefit.
The presenter noted that while previous research has shown that patients with low TMB do not appear to derive an OS benefit from maintenance avelumab, the current analysis suggests that absence of the POU2F2 loop may identify a subset who do benefit. Specifically, median OS was 36.99 months with avelumab plus BSC and 13.68 months with BSC alone among participants with TMB at or below the median and the POU2F2 loop absent.
By contrast, among those with low TMB and the POU2F2 loop present, the median OS durations were a comparable 17.77 and 16.07 months with and without avelumab, respectively.
Powles drew attention to several limitations of the analysis, including the fact that the blood samples represent “a single time point in the treatment cycle” and therefore “applicability to other time points [needs to] be investigated.”
He continued: “Bioanalytical validation of the POU2F2 loop is also needed to confirm fitness for clinical applications.”
Nevertheless, Powles believes that “[m]easurement of circulating chromatin loops may be a useful method for evaluating systemic [versus] tumor-specific biomarkers.”
And he concluded: “Ongoing research is assessing the potential use of chromatin loops identified by the EpiSwitch platform to form chromatin conformation signatures that may enrich patients [who] benefit from maintenance avelumab.”
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This independent news story was supported by an educational grant from Pfizer and Merck Healthcare KGaA, Darmstadt, Germany