Future Directions for Metastatic Breast Cancer

Transcript:Joyce O’Shaughnessy, MD: For metastatic breast cancer, we still have a lot of unmet needs. Of course, our most important need is to prevent metastatic breast cancer. We need increasingly curative regimens for the adjuvant and neoadjuvant settings. But in the meantime, until we have those data, there is progress being made in metastatic disease. We need to mobilize the immune system as much as we can in patients with metastatic disease and utilize anti-PD1 or anti-PD-L1 agents. There has been some early promise in a small subset of patients with metastatic breast cancer, triple-negative or ER-positive.

Also, being studied in HER2-positive patients are pembrolizumab and atezolizumab. But we need to understand how to overcome more of the mesenchymal biology—interestingly, there has been a study done of eribulin with pembrolizumab. Will the pembrolizumab work better, for example? Maybe that’s in part why the atezolizumab, the paclitaxel, and nab-paclitaxel look so good, because they may be also overcoming some of that mesenchymal biology. And then, increasing antigenicity proliferation and the immunotherapies may work better—the anti—PD-1/PD-L1 agents. So, that’s promising.

It’s not going to be as easy in metastatic breast cancer as it has been with some of the other cancers, where it has been very, very obvious early on—such as melanoma, for example. We’re going to have to work a little bit harder, I think, to overcome some of this mesenchymal biology and to try to improve the efficacy of the immunotherapy agents.

At ASCO, we will hear about an AKT inhibitor that I think is very, very important. It’s the GDC-0068 agent ipatasertib that has been studied in a randomized phase II trial of paclitaxel with or without ipatasertib in metastatic breast cancer patients. So, let’s really hope, because the PI3 kinase inhibitors in that same scenario have not proven to be efficacious. Let’s hope that the AKT inhibitors are efficacious, and we’ll see whether it’s ER-positive disease or triple negative disease. We’ll keep our fingers crossed on that.

We will be hearing about the PARP inhibitors as well coming out for patients that have germline mutations in BRCA1 or BRCA2. Let’s really hope that these are positive trials because there are a number of other germline DNA repair deficiencies and germline mutations that people inherit. The PARP inhibitors are beneficial for BRCA1 and BRCA2 patients; they may potentially help a whole host of other patients as well.

And the luminal B breast cancers that are the genomically unstable, highly proliferative ER-positive breast cancers, they are benefited by the CDK4/6 inhibitors, but we need triplet-based therapy—we have to build rapid triplets. For example, adding PI3 kinase inhibitors on, such as alpelisib, which is being done now. I’d like to see an anti-HER3 agent, such as MM-121 (seribantumab) from Merrimack, be added in that context because the HER family is probably very important there. Perhaps the HDAC inhibitors may also be important, and that’s being studied on its own. Perhaps all these agents, such as SRC inhibitors, have some combination activity in the metastatic setting. We need to build triplets, I think, to get more durable control of these aggressive ER-positive breast cancers.

And in the HER2-positive space, there are a number of other agents that are anti-HER2 TKIs that can penetrate the brain, which is a very important site of recurrence in the metastatic setting. ONT-380, tucatinib, is a very potent anti-HER2 TKI that penetrates the brain. Abemaciclib is another very important CDK4/6 inhibitor with excellent brain penetration that is being studied in combination with trastuzumab, as well as in patients with HER2-negative brain metastases. There are a wide variety of agents being developed, but I like to think mechanistically—what are the key mechanistic needs that we have? Where are the real lethal breast cancers? What’s going on with those, and how can we prioritize the development of these agents?

Mark Pegram, MD: Right now, we’re enjoying a renaissance, really, of clinical research in metastatic breast cancer ranging a broad array of research topics—from exploiting homologous recombination/DNA repair defects in breast cancer with PARP inhibition, for example, to exploiting the immune system. Finally, we understand the biology of T cells well enough to be able to release checkpoints and exploit their true capabilities. We’re seeing responses in the clinic, and that has led all the way to phase III trials that are ongoing in triple-A breast cancer.

In the steroid receptor-positive space, the introduction of CDK4 and CDK6 inhibition has completely transformed the field. That’s something that wasn’t even on the radar a few short years ago, and now it’s a standard of care—on a fast track. In HER2-positive disease, there’s a huge opportunity with a range of new approaches from new small molecule tyrosine kinase inhibitors that are more selective for HER2 and have fewer off-target effects and, consequently, fewer side effects. They are also more soluble in terms of blood—brain barrier access. So, those molecules are very promising.

We have new, human engineered HER2 antibodies that are more potent in eliciting immune responses than trastuzumab. That’s also in a phase III pivotal trial with the aim to get FDA registration if successful. So, that’s very exciting.

We can also augment the immunity of antibodies by using agonist antibodies to get to CD137. Those trials are in combination now with HER2-targeting agents, and those look most promising.

So, the future is really bright, and it’s across the spectrum of different subtypes of breast cancer now. It’s not just restricted to one area. For triple-negative, ER-positive, and HER2-positive, there are very active research programs ongoing, many of which are now already in pivotal phase III trials. We’ll get answers in the 1 to 2 years and hopefully that will transform the field, and then those molecules can hopefully be used in an early disease setting, resulting in even better outcomes in that setting as well.

Transcript Edited for Clarity