Ongoing Studies With Novel Agents in HER2+ Metastatic Breast Cancer

Transcript:

Andrew Seidman, MD: One of the places I like to go at ASCO [American Society of Clinical Oncology annual meeting] is down that poster corridor, where there are no results at all but just trials and progress because I can be really smart and talk to my colleagues and patients about what we are going to know in a few years. VK, there are some next-generation HER2CLIMB studies, HER2CLIMB-04, HER2CLIMB-05, that have potential to impact the future treatment landscape. Maybe you can tell us about those.

Vijayakrishna Gadi, MD, PhD: HER2CLIMB, if you see those letters together, we are talking about tucatinib and trying to introduce it in some way. One trial that caught my eye was HER2CLIMB-05, and this is an interesting concept because we know that in HER2-positive disease, brain metastases are front loaded, as opposed to a lot of disease where you see them later the process. When we can get the patients off of the chemotherapy and they are on the maintenance monoclonal antibodies, maybe now Phesgo [pertuzumab, trastuzumab, hyaluronidase], can we consider adding tucatinib and seeing if we can forestall the emergence of brain metastases and other disease progression. That’s a great concept. I am excited to see what that looks like. Just as a cautionary tale, we tried combining those drugs with Taxol [paclitaxel] in the I-SPY2 trial with tucatinib, not OK, a lot of toxicities. So that’s why we’re not looking at it in that way.

Andrew Seidman, MD: Paclitaxel, trastuzumab, pertuzumab, and tucatinib?

Vijayakrishna Gadi, MD, PhD: Yes, in I-SPY. It was effective but [nasty]. That’s why we really want to do it in that maintenance phase. Another study, HER2CLIMB-04, is a phase 2 study. Here, if you can’t beat them, join them. So combining tucatinib with trastuzumab deruxtecan and looking at that activity. Adding that extra oomph of CNS [central nervous system] protection with tucatinib with a very effective below the neck agent in deruxtecan.

Andrew Seidman, MD: I mentioned that earlier as something that is being explored in the residual disease population, which is an interesting concept.

Tiffany, maybe you can help bring us home for this section and talk about some of the emerging ADCs [antibody-drug conjugates] that target HER2.

Tiffany Traina, MD: Sure. I hopefully will be on a panel in a couple of years reporting out data from some of these. There were trials in progress at this current meeting that showed compound ARX788, another antibody-drug conjugate targeting HER2 with a different payload, and another tubulin inhibitor. That’s actually in a population now. It’s tough for the new agents that are being explored because they are designed to look at folks who have previously seen drugs like trastuzumab deruxtecan or tucatinib. So it’s going to be a really high bar to show benefit. There is a new TKI [tyrosine kinase inhibitor] that’s reversible and highly selective, I think [its called] DZD1516, that’s also being explored. There are bispecific antibodies, there is work looking at dual IO [immunotherapy] and HER2-targeted agents. A lot is on the horizon.

Andrew Seidman, MD: And HER3.

Tiffany Traina, MD: And HER3 as well, with an ADC to HER3, so a lot to come.

Andrew Seidman, MD: Any thoughts about using serial antibodies targeting different receptors that carry the same payload? Are we kidding ourselves to think that that might be an effective strategy in the future? Any thoughts, or am I treading into the unknown too far?

Tiffany Traina, MD: No. I think while it’s certainly an unknown, we really, as a community, need to study the idea of what’s driving resistance. Is it the target or is it the payload? Maybe the delivery is different if you are able to get in a highly active payload in a different way, to different cells, expressing a different target. I think we need to do these studies and looking at optimal sequencing based on resistance patterns.

Stephanie Graff, MD: I think across the history of cancer biology we have seen that often the mechanism of resistance is an alteration in the receptor. It’s reasonable to think that changing the target is going to be an effective mechanism. HER3 is fascinating because HER3 itself isn’t an active receptor at all, it’s mechanistically dead if you will, and we’re targeting it exclusively for the payload effect. It is fascinating.

Andrew Seidman, MD: Final question. What questions in the last year have been answered in terms of sequencing for HER2-directed therapy? VK?

Vijayakrishna Gadi, MD, PhD: Thanks. You give me the easiest job because I get to go first. I think with the P values we’re looking at, with durability of what we’re seeing, I feel like we know in that second line, trastuzumab deruxtecan makes a lot of sense if we are not dealing with a lot of brain metastases, and tucatinib-based regimens make a lot of sense if we are.

Andrew Seidman, MD: …Stephanie?

Stephanie Graff, MD: I feel like we are still in the race to the middle actually. I feel like we even have trials looking at combining trastuzumab deruxtecan and tucatinib right now for second line, or first line, or in that neoadjuvant, residual disease burden KATHERINE space. I keep wondering if or when that is the penultimate winner, what we’re going to be doing in the metastatic space. So I still think that we have as many questions to answer as we have answers.

Andrew Seidman, MD: Bill, any enlightening comments?

William Gradishar, MD: No, without sports analogies…. What I would say is that we haven’t learned a whole lot about sequencing because I think, if anything, all the data, which are great that have been generated, are going to move the sequence. It’s going to be different a year from now and 2 years from now. So, what we have learned with confidence is it’s going to change.

Andrew Seidman, MD: Tiffany, anything to add?

Tiffany Traina, MD: Tough one. I am going to do what my daughter does and not actually answer the question, but tell you what I was thinking. These antibody-drug conjugates are so powerful that I wonder if we will reach a point where we can get away from the idea of polychemotherapy [and] dual-targeted therapy.

Andrew Seidman, MD: In my lifetime, we would like to say, “Do you remember when we used to give chemotherapy to treat breast cancer?” That would be a nice thing to say.

Transcript edited for clarity.