Ethan Sokol, PhD, Cancer Genomics Research, Foundation Medicine, Inc, Cambridge, MA, discusses results form a study analyzing real-world time-to-treatment-discontinuation for patients with high tumor mutational burden hormone receptor (HR)-positive HER2-negative metastatic breast cancer who were treated with immune checkpoint inhibitors.

This study was presented at the virtual ESMO Congress 2021.

Transcript:

My name is Ethan Sokol. I am a senior scientist at Foundation Medicine on the cancer genomics research team. I've been at Foundation for about four and a half years. I've been very interested in breast cancer research and biomarkers in that sphere.

This year, at ESMO, we presented data on the real-world outcomes of hormone receptor-positive HER2-negative metastatic breast cancer patients with high tumor mutational burden that were treated with immune checkpoint inhibitors.

The KEYNOTE-158 study led to the approval of pembrolizumab, an immune checkpoint inhibitor, in advanced cancers with a TMB, or tumor mutational burden, of greater than 10. However, with this kind of broad basket design, there was limited data about the efficacy of these agents in breast cancer specifically.

We decided to look into this for the largest subtype of breast cancer, hormone receptor-positive HER2-negative disease. Although it has a fairly good prognosis for the early setting, once you end up with advanced or metastatic disease, the prognosis is poor. These patients need additional options.

This study leaned heavily on real-world data that was extracted from a collaboration with Flatiron Health. There's a CGDB, or a clinico-genomic database, of over 82,000 patients across all tumor types, including several thousand breast cancer patients.

We used this real-world data set across over 280 institutions to look at patients who had received checkpoint inhibitors in this real-world setting and who had high TMB to understand what kind of patients have this biomarker, what are the real-world outcomes.

We also combined this with real-world data from the Mayo and Duke clinic. The clinico-genomic database, or the CGDB, is a collaboration between Foundation Medicine and Flatiron Health to collect the treatment and outcomes decisions in a large cohort of over 80,000 patients so we can understand: “how does CGP, comprehensive genomic profiling, inform treatment decisions, outcomes?”

It can allow us to look at rare patient populations and population subsets to really extract information that's not otherwise clinically available. That's sort of what we did in this case; breast cancer is pretty common, but if you overlap breast cancer with high TMB and receiving checkpoint inhibitors, with the approval coming fairly recently for this population, you're talking about a very small cohort of patients.

Only when you have the power of tens of thousands of patients in an overall cohort can you really get enough information to glean insights into these populations. It's not only this study but others where we're trying to extract that real-world clinical outcomes data.

As we've previously reported, high TMB is not an uncommon phenomenon in breast cancer. We see it at approximately 7% prevalence of tumor mutational burden of 10 or higher in breast cancer, with a higher frequency in lobular carcinomas and in the metastatic setting.

When we look at how patients do on checkpoint inhibitors, we see that there's an appreciable population that has at least 6 months on therapy. Within the clinico-genomic database, there were 5 out of 18, or 28% of patients, with at least 6 months on therapy. Within the Mayo-Duke cohort, 4 out of 8 patients, or 50%, had a long time on therapy of six or more months, including several patients with exceptional responses, one who was on therapy for over 3 years.

When we dig into this data a little bit more deeply, we find that the patients that responded trended to have a higher TMB. Of the patients with a TMB of greater than 40, 6 out of those 7 patients had a greater than 6-month time to therapy discontinuation.

With the KEYNOTE-158 approval, that opened up the tool or checkpoint inhibitors, specifically pembrolizumab, to physicians who have patients with a TMB of greater than 10.

What our study shows is that a reasonable fraction of these patients, between 28% and 50% in our real-world data set, will have 6 months time to discontinuation in our study set, which suggests that this tool in the toolbox has utility for treating these patients.

Chumsri S, Sammons S, Alder L, et al. Real-world outcomes of hormone receptor-positive (HR+) HER2-negative (HER2-) metastatic breast cancer (mBC) with high tumor mutational burden (hTMB) treated with immune checkpoint inhibitors (ICI).