Investigational Strategies and the Future of TNBC

Joyce O’Shaughnessy, MD:It appears that we have a new subtype of triple-negative breast cancer in the metastatic setting—the PD-L1 [programmed death-ligand 1]—positive population. We’re going to need to identify those patients reliably. And so, this becomes a pathology challenge because PD-L1 can be ascertained on the tumor cells themselves, on the immune infiltrating cells, or on both. The IMpassion130 study specifically looked at the immune infiltrating cells for PD-L1–positivity, but other checkpoint inhibitors have developed PD-L1–positivity on the tumor cells, or on the immune infiltrating cells, or a composite score of both. As oncologists, it will be a challenge for us to request PD-L1 staining, which was done in clinical trials and proved the effectiveness of these agents. It will also be challenging for pathologists to utilize the right PD-L1 antibodies, depending on the agent that’s in question, and read and interpret the PD-L1–positivity based on tumor cells, immune cells, or both. I think that’s going to be the easiest—to read out both. Then the oncologist can utilize the information, as was done in the clinical trials, which led to the approval of the checkpoint inhibitors.

So there are challenges ahead, but, fortunately, this has been going on in 10 or 12 other cancers for quite a number of years. We’ll be able to learn a lot from our colleagues.

The nab-paclitaxel and atezolizumab regimen is a very exciting advance, and I’m sure it will become the standard of care for the PD-L1—positive population. Then the question is, where do we go from here? We await the results of data with gemcitabine-carboplatin plus a checkpoint inhibitor—in this case, pembrolizumab—to see whether getting a DNA damaging agent such as carboplatin together with a checkpoint inhibitor will make another advance. And then, of course, targeted therapies. We expect to look more at interrupting key driving pathways in triple-negative breast cancer that may make the cells refractory to checkpoint inhibitors, such as interrupting the AKT pathway. Combining ipatasertib with atezolizumab and nab-paclitaxel, for example, is very important and is an exciting triplet that’s being evaluated.

Another example of great interest to me that is being done at the University of Kansas combines an HDAC [histone deacetylase] inhibitor, romidepsin, with nivolumab along with cisplatin to try to increase the immunogenicity of these cancers, bringing in the DNA damaging agents along with the checkpoint inhibitor in metastatic triple negative breast cancer.

And then, very importantly is getting into the curative setting and getting into that preoperative setting. We await results of the KEYNOTE-522 trial that combines preoperative chemotherapy with pembrolizumab in the curative setting to see if the pathologic complete response rates will be higher and if the disease-free survival improves. So that’s incredibly important.

Transcript edited for clarity.