William J. Gradishar, MD: Immunotherapy is obviously something that has been slow in breast cancer. But now all of a sudden we have data with atezolizumab and pembrolizumab suggesting that either in the advanced setting or even in the preoperative setting, the drugs may enhance either the pCR [pathologic complete response] rate, which was something demonstrated in the KEYNOTE trial reported at ESMO [European Society for Medical Oncology Congress 2019] or with atezolizumab plus nab-paclitaxel in the advanced metastatic disease setting. We still have challenges trying to identify the patients who are most likely to benefit from those drugs. Obviously pembrolizumab seems to have a broader sweep of patients who might be candidates, whereas with atezolizumab you had to have a tumor that was PD-L1 [programmed death-ligand 1] positive to really garner the benefits from that combination.

As we go forward, it was often thought historically that triple-negative breast cancer patients alone would most likely benefit from the I/O [immuno-oncology] strategy. But now there’s a lot of interest in combining I/O checkpoint inhibitors with HER2 [human epidermal growth factor receptor 2]—directed therapy and even in the endocrine-responsive subset of breast cancer, trying to make what are viewed as generally cold tumors hotter. In the instance of endocrine therapy, CDK4/6 inhibitors are thought to stimulate tumors to be hotter, so to speak, and they may then become candidates for combination with I/O therapy.

In the HER2 space, we don’t have much in the way of data yet, but there are clinical trials ongoing looking at the combination of HER2-directed therapy with I/O therapy. And my guess is we’ll be seeing data: not only early data at this meeting, but also by ASCO [the American Society of Clinical Oncology Annual Meeting] in 2020 and beyond. Whether that turns into a strategy that we would employ broadly, we just have to wait for the results.

Sara A. Hurvitz, MD: It’s only natural that HER2-targeted therapies are being evaluated in combination with immune checkpoint inhibitors, given that the immune system has been shown to be upregulated. The presence of tumor-infiltrating lymphocytes in HER2-positive tumors has been demonstrated over and over, so the thought is that if you can combine an immune checkpoint inhibitor with a HER2-targeted therapy, you might augment that response and have better outcomes. The data have been lukewarm impressive at this point.

KATE2 was an interesting study. T-DM1 [trastuzumab emtansine] combined with atezolizumab didn’t meet its primary end point, and I think it’s going to be really important to define which patients are most likely to respond by PD-L1—positive status. I do think drugs like margetuximab, which enhance the ADCC [antibody-dependent cellular cytotoxicity] by tightening that bond between the Fc portion and Fc receptor of the person’s immune system, should be combined with immunotherapy to augment that activity. I think we’ll see better results than we even saw with SOPHIA if we can combine margetuximab with I/O.

Ian E. Krop, MD, PhD: So far, the data have been somewhat marginal. There is a relatively small trial called PANACEA that combined trastuzumab with the PD-1 [programmed cell death protein 1] inhibitor pembrolizumab, which did show what I think is proof of concept. Those patients, all of whom have had prior trastuzumab, did show a 15% objective response rate in those who had PD-L1—positive, HER2-positive cancers. Certainly not an overwhelming signal of efficacy, but clearly there were some responses suggesting that at least in a subset of patients, adding a checkpoint inhibitor may be beneficial.

We saw similar types of data in the KATE2 trial, which randomized patients to either T-DM1, with or without a checkpoint inhibitor. And that study did not meet its overall end point of improvement in progression-free survival and the intention-to-treat population, but again, similar to what we saw in PANACEA, in the PD-L1—positive patients it looked like a strong trend toward improvement in progression-free survival and overall survival with the addition of the checkpoint inhibitor to T-DM1.

I think we’re seeing a signal of improved efficacy, but we need to build on that. And there are a number of other studies going on looking at the combination of immunotherapies, particularly PD-1 and PD-L1 inhibitors, with HER2-directed therapy. There is a study going on in the United States that’s looking at a new immune target called 4-1BB, which is another target on immune cells that can stimulate not only T cells to attack tumors but also NK [natural killer] cells, which are the main mediators of ADCC, or antibody-dependent cellular cytotoxicity. There are preclinical data saying that a 4-1BB agonist may be synergistic with trastuzumab to get more ADCC activity, so there is a randomized trial called AVIATOR that’s comparing chemotherapy and trastuzumab with either that regimen plus the PD-L1 inhibitor, avelumab; or chemotherapy, trastuzumab, avelumab, and a new 4-1BB agonist called utomilumab.

So there are a number of interesting ideas being tested right now. But from the available data, it’s hard to say that immunotherapy is an active agent to be used in HER2-positive metastatic disease, but we’re continuing to work hard to try to change that.

Transcript Edited for Clarity