Impact of Recent Clinical Data on Treatment for HER2+ MBC



Adam Brufsky, MD, PhD: We’re just about at the end here. What I’m going to ask everybody to do, what we always do with these, is to summarize where you think this space is going. I’ll start with Carey.

Carey K. Anders, MD: I think one of the themes at ASCO [the American Society of Clinical Oncology annual meeting] this year was, again, de-escalation. We’re learning more and more about which patients need which therapy. And I think we did learn a lot about what we don’t need to do moving forward. I think the KAITLIN data told us that trastuzumab/pertuzumab in the adjuvant setting is here to stay. I think the metastatic space has really been fantastic. Leaving the San Antonio Breast Cancer Symposium this year, I think I was the most enthusiastic about a space that I’ve been in a really long time, thinking about all the new agents that we have for metastatic HER2-positive breast cancer. It makes it more challenging, but that is certainly a challenge we will all take on because it’s going to improve our patients’ outcomes. The challenge now is going to be in the metastatic setting, determining the sequence, determining the right patient for which treatment, and try to do this in the most logical manner, so that we are able to keep patients stable and living well with their breast cancer for as long as they possibly can in the HER2-positive space.

Adam Brufsky, MD, PhD: Good. Mark?

Mark D. Pegram, MD: I’m excited by the fact that it’s clear now that HER2 ADCs [antibody-drug conjugates] are here to stay. We definitely need more than 1. We need more than 2 because what we’d like to have is a tool chest of ADCs with noncross-resistant payloads so that we could use them in sequence or with different epitopes for the targeting antibody backbone. You could even use them in combination, as long as there is not too much overlapping toxicity.

The other thing that excites me is the tucatinib data from our colleague, here, Dr Murthy. It’s just spectacular data. It’s so nice to finally have a pure HER2 antagonist. That was the holy grail all the way back to the early lapatinib days, recognizing that the other HER2 TKIs [tyrosine kinase inhibitors] that are approved have off-target toxicities due to EGFR [epidermal growth factor receptor] kinase inhibition. There are huge opportunities there, especially in early stage disease, particularly in the extended adjuvant or post-neoadjuvant setting, indeed, a la ExteNET. I think there is a huge opportunity there that I would not want to see lost.

I’m very keen on further antibody engineering, in particular bispecifics. There was a very nice HER2/HER3 bispecific antibody presented at this ASCO that looks very interesting. It binds to subdomain 1 on the HER2 extracellular domains, so it doesn’t bind to pertuzumab or the trastuzumab, so a whole new epitope. On the HER3 molecule, it binds to HER3, and it is tethered confirmation so it can’t bind to ligand. You can’t get HER2/HER3 ligand activated activity at all with that molecule, so it’s very interesting. Zymeworks, Inc has a HER2/HER3 bispecific that’s very potent as a naked antibody in heavily pretreated patients in the phase 1 dose escalation. Very nice and high frequency anecdotal responders, so I think that’s really cool.

Finally, antibody fusions, where you can fuse other therapeutic moieties to the Fc [fragment, crystallizable] domain of a HER2 antibody and give it whatever attribute you want, an I-O [immune-oncology] attribute, for instance. Since we’re doing that now at Stanford Cancer Center with an investigator-initiated trial from a company called Bolt Therapeutics, Inc, it’s a new startup, that’s going to be really interesting to look at the fusions in the future, as well.

Adam Brufsky, MD, PhD: Virginia?

Virginia Kaklamani, MD:It was interesting at ASCO, there were 2 discussions. One is when to escalate, and the other was when to de-escalate treatment. Obviously we’re seeing this more and more in the neoadjuvant and adjuvant setting where we don’t want to overtreat patients. We don’t want to undertreat patients, either. What’s interesting for me in the future is the HER2 low. We have, so far, an ADC that seems to be active in that space. I can’t wait to get more results. HER2 mutations, again, we have a TKI that seems to be doing pretty well. I’m sure others will do pretty well, as well. HER2 becomes more than just the HER2-positive disease. It becomes a lot more inclusive, and that’s what’s exciting.

Adam Brufsky, MD, PhD: Good, and finally, Rashmi.

Rashmi K. Murthy, MD, MBE: Yes, I echo everyone else’s thoughts, but also I would say I think the most exciting parts, for me, since San Antonio Breast Cancer Symposium, has been the approval of all these agents and the expansion of our toolbox for patients in the clinic, which ultimately is going to lead to improved outcomes. It’s been very exciting to be able to think about systemic treatment options now for patients with brain metastases. And I hope that the future would allow us to even think about prevention early on, so to prevent them from having CNS [central nervous system] relapse, whichoftentimes drives their overall prognosis in the setting of metastatic disease. I’m looking forward to more studies and more work to further delve into that.

Adam Brufsky, MD, PhD: Great. Thank all of you in this. It was great, and thanks to our viewing audience for listening to this, and we hope you found this OncLive Peer Exchange® discussion to be useful and informative. Again, thank you very much.

Transcript Edited for Clarity

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