Newly Approved Agents for HER2+ Breast Cancer

Julie R. Gralow, MD: Let’s sum this up, Mark, by talking about these brand-new agents that are FDA approved in metastatic HER2 [human epidermal growth factor receptor 2]–positive breast cancer, in combination with those that were previously proven. How is the availability of these new agents going to impact the care of our patients with HER2-positive metastatic breast cancer? How are we going to use these?

Mark Pegram, MD: To summarize the data, in conclusion, you know for the DESTINY-01 trastuzumab-deruxtecan trial the median prior lines of therapy for that cohort was 6. Whereas in the HER2CLIMB trial it was about 3. So that’s important if you’re going to be comparing these agents in clinical decision making.

Moreover, the median PFS [progression-free survival] was about 16½ months in the DESTINY-Breast01 trial, compared with almost 8 months in the HER2CLIMB trial in the experimental arm. Again, it’s a testament to the robust activity and extraordinary responses, and durability of response with the DS-8201 trastuzumab-deruxtecan.

The overall response rates are about 61% for the antibody-drug conjugate and about 41% for the HER2CLIMB regimen. The big difference, in my opinion, are the extraordinary data for the patients with brain metastasis that was shown at the ASCO [American Society of Clinical Oncology] 2020 Annual Meeting, by Dr Nancy Lin. Just the fact that you can get an OS [overall survival] signal with the HER2CLIMB tucatinib-based regimen in HER2-positive brain mets [metastases], that carries the data for me. If a patient has brain mets, I’m going to use the tucatinib-based regimen. However, if they do not have known brain metastasis, I will probably use the trastuzumab-deruxtecan antibody-drug conjugate because of its very high response rate and long median PFS.

That summarizes my position in patients who have progressed after prior trastuzumab-pertuzumab, and T-DM1 [trastuzumab emtansine]. What do you think, Julie? Am I right on this notion?

Julie R. Gralow, MD: My thoughts are similar to yours and also our community in general. If they’re brain mets, we prefer tucatinib. But without brain mets, the DESTINY-Breast01 is really impressive. We’re tending to favor the trastuzumab-deruxtecan.

What we’re all struggling with right now is that these drugs are approved after a couple of prior lines of therapy, and we want to use them in an earlier line. Of course, we are eager to start testing them even in the adjuvant setting, especially tucatinib—can we prevent brain mets? I’d rather prevent brain mets than treat brain mets.

Mark Pegram, MD: Agree.

Julie R. Gralow, MD: What are you thinking about where these drugs are likely to go in the future, knowing we don’t have clinical trials data yet?

Mark Pegram, MD: I think it’s fairly straightforward to move up the tucatinib regimen into second line if somebody has already had, let’s say, adjuvant or neoadjuvant pertuzumab-trastuzumab and maybe even postadjuvant T-DM1 [trastuzumab emtansine]. You can move into earlier lines because the FDA label says following 1 prior HER2-targeted regimen for metastatic disease. Whereas the label language for the antibody-drug conjugate actually says for 2 or more prior lines than trastuzumab-deruxtecan is approved.

I think we will be doing some peer-to-peer calls, because as you rightly point out, it’s not that uncommon in 2020 to see patients who have already had dual-antibody therapy, and T-DM1 [trastuzumab emtansine], in the early stage disease setting. Therefore, all these new and exciting approaches are going to have graduate into earlier lines for metastatic disease. Moreover, as you rightly point out, there is a rich opportunity to use these agents in an earlier-stage disease, indeed—particularly, as you mentioned, tucatinib. I’d love to see that in an extended adjuvant setting to perhaps replace neratinib because of its higher therapeutic index, for instance. That would be 1 opportunity.

The antibody-drug conjugate is so impressive in terms of response with response duration, probably activity in the brain indeed based on retrospective subset analysis. That may play a role in early stage disease as well, although we’ll have to be very mindful of the risk of interstitial lung disease, as you mentioned in your remarks.

Julie R. Gralow, MD: Where might you consider neratinib in the metastatic setting?

Mark Pegram, MD: For HER2 kinase mutations, I use it regularly for that indication. Outside that, I could envision maybe somebody who’s had all the agents that we’ve already discussed in this program and still has good performance status and is, let’s say, progressing in the brain and have had whole-brain radiation already. You’re really at a loss for anything other than either best supportive care or even hospice considerations versus continuing therapy. In that setting, maybe. But those patients often are so heavily pretreated and are sick by the time they get to that phase, they may not tolerate the neratinib-capecitabine regimen well. I do worry about that, and I would use it cautiously, if at all, in that situation.

Julie R. Gralow, MD: Do you think you’ll ever prescribe lapatinib again?

Mark Pegram, MD: I can’t really imagine, in a tucatinib progressor, that lapatinib is going to have any activity. The KDs [kinase domains] for tucatinib are superior, even against HER2 compared with lapatinib. I imagine that the mechanisms of resistance would be cross-resistant with 2 HER2 TKIs [tyrosine kinase inhibitors] like that. Lapatinib is going to be the lost stepchild in this situation. I can’t really imagine using it with much enthusiasm following tucatinib.

All right. Our time is up for this program. Thank you, Julie, for your insightful discussion. And thank you to our audience for watching this Targeted Oncology™ presentation on precision medicine. We hope you found this discussion to be useful and informative. Julie, any final remarks?

Julie R. Gralow, MD: Thank you. As always, Mark, you have brought up a lot of great points and made me think. This is helpful, and I know we both want to use this information to get the best comes for our patients.

Transcript edited for clarity.