Rationale for Checkpoint Inhibitors in TNBC

Joyce O’Shaughnessy, MD:Checkpoint inhibitors have proven effective in 10 or 12 different cancers and have FDA approval. The place that they’ve been looking most promising in breast cancer is in triple-negative breast cancer. We’ve had some preliminary phase II-type of data in the metastatic triple-negative population. In the first-line setting, we were getting some intriguing results of response rates in unselected patients of 20% to 26%. In the later-line setting, once women had been treated with multiple lines of chemotherapy, we really weren’t seeing any appreciable benefit.

The really exciting data came when pembrolizumab was utilized in the preoperative setting along with chemotherapy in triple-negative breast cancer patients. This really led to an improvement in the pathologic complete response rate. That was our most important signal—that if you utilize the checkpoint inhibitors earlier in the course of triple-negative breast cancer, you could potentially have a very big impact.

A very important area of research is aimed at taking triple-negative breast cancer in the metastatic setting that is PD-L1—negative, or is the kind of cancer that’s been pretreated, for example, and trying to change that cancer so that it becomes more susceptible to killing by immunotherapy. There are various strategies that people are looking at to do that. For example, one clinical trial that’s going on right now combines the HDAC [histone deacetylase] inhibitor entinostat with atezolizumab. Atezolizumab is a checkpoint inhibitor. In pretreated patients, it’ll help a very small minority of patients. It might be effective in unselected patients regardless of PD-L1 status in about 26% of first-line patients by itself. And so, by utilizing an HDAC inhibitor that can increase neoantigens and DNA repair deficiency, you may be able to make that cancer more amenable to killing by immune checkpoint inhibitors. So this is a big area of research. The HDAC inhibitors are one example, but there are several strategies along this line.

Combining checkpoint inhibitors with chemotherapy is really yielding better effectiveness for patients in other cancers compared to checkpoint inhibitor therapy alone. This has certainly been evaluated in metastatic triple-negative patients. When nab-paclitaxel was put together with atezolizumab first in this kind of safety pilot early phase II experience, the response rates were really quite excellent. They were approaching 50% in the first-line setting, which is much higher than you would expect with nab-paclitaxel alone. So that looked quite interesting. Combining chemotherapies such as nab-paclitaxel may change the microenvironment of the breast cancer. There’s some evidence that it could decrease T-regulatory cells, for example. There may also be some DNA effects of various cytotoxic agents to increase the STING pathway, for example. The cancer cell thinks it’s under viral attack and upregulates PD-L1 and causes the tumor infiltrating lymphocytes to come into the cancer. So chemotherapy can have some very interesting microenvironment or DNA damaging effects. We don’t necessarily fully understand them, but they can prime the cancer for eradiation by immune checkpoint inhibitors.

Transcript edited for clarity.