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Medicine Matters oncology

GURU SONPAVDE: Hello. I'm Dr. Guru Sonpavde. I'm the bladder cancer director at the Dana-Farber Cancer Institute in Boston, USA, and we are here to discuss a study we presented at the ESMO Congress meeting that happened recently. And this is a study in which we looked at ctDNA - circulating tumor DNA - pre and post-treatment in patients with metastatic urothelial carcinoma who had received an immune checkpoint inhibitor.

We also had a small parallel cohort of patients who had received platinum-based chemotherapy where we had baseline and post-treatment ctDNA assessment. So this was a modest sized study we had 39 patients with metastatic urothelial customer who had received an immune checkpoint inhibitor where we had baseline and post-treatment ctDNA assessment.

So the key features of the ctDNA assessment were, one, the first time point and the second time point were separated by a median of six months. So this is not really early changes. This is late changes at six months out, median. And also we used a platform that is a very sensitive applicant-based next-generation sequencing platform for ctDNA assessment.

This is a highly sensitive platform, we felt, and this is what we found in this study-- more than 95% of patients had a ctDNA alteration, and that includes also the platinum-based patients, where actually all of the six controlled platinum patients had a ctDNA alteration.

So coming to the findings of the study, number one, the platform was [INAUDIBLE] sensitivity held up, and also I might add that the volume of plasma that we used to detect ctDNA was a small volume of 2 ml plasma in general, so very small volume of plasma. There were early changes of ctDNA that were correlating with either response or progression, so it was generally seen that patients who were responding to the immune checkpoint inhibitor had an extension of a genomic alteration found at baseline while patients who had progressive disease had new alterations emerging close to the time of progression at the second time point.

In general, the alterations found are what we would expect in metastatic urothelial carcinoma patients with p53 alterations, telomerase gene alterations, BRCA1, BRCA2 alterations were also found, and what was seen was that in patients who were progressing at the second time point of ctDNA assessment BRCA1, BRCA2, and PIK3CA mutations seemed to be emerging more often. And that seemed to correlate with progressive disease.

And when we looked at the parallel platinum cohort, these patients did not have this frequent emergence of PIK3CA mutations in particular. So we believe that this is a sensitive platform that could be used to select patients for specific treatments, for example, in a genomic alteration guided trial. And given the sensitivity of this platform and the non-invasive nature, of course, it would be much easier to select patients based on a sensitive ctDNA non-invasive platform for a specific trial than an invasive tumor biopsy.

I might note that there are multiple ctDNA platforms out there, and it's always a challenge to find the ctDNA alteration on a non-invasive platform. So I think the sensitivity of the platform is a big advantage in this respect.

So overall, we were encouraged by this study. We think that this platform would be useful to select patients for specific trials, given the sensitivity, and there were also insights into the biology of the tumor, potentially PIK3CA and BRCA1, BRCA2 alterations are a source of resistance to immune checkpoint inhibitors and could be targeted with specific drugs.