HER2+ Breast Cancer: Special Challenges and Expert Insight - Episode 5

HER2+ BC: Considerations for Sequencing Treatment

Adam M. Brufsky, MD, PhD

Neil M. Iyengar, MD

Vijayakrishna K. Gadi, MD, PhD

Sara A. Hurvitz, MD

A panel of experts weighs in the challenges of optimally sequencing therapy for patients with HER2+ breast cancer.

Adam Brufsky, MD, PhD: Let’s do some polling questions. In what percentage of your patients do you use T-DM1 [trastuzumab emtansine] in the second-line setting: 50%, 60%, 70%, 80%, or greater than 80%?

Let’s see the result. Interesting: Everybody chose 70%. Not 80% or 60%, just 70%.

This is back to the same case. This patient had the THP [docetaxel, trastuzumab, pertuzumab] rechallenged. No one did an MRI of her brain. She has 3 or 4 liver metastases. The largest is like 3 cm. They’re asymptomatic, and her ALTs [alanine aminotransferase] are normal. She started on T-DM1 [trastuzumab emtansine]. The question really has to do with sequencing. We touched on this a little. We can take 10 or 15 minutes and talk about sequencing.

How do you approach this patient? She’s on T-DM1 [trastuzumab emtansine], and most of us would do T-DM1 [trastuzumab emtansine] at this point. Let me take it a little further because this is really the question. At this point, she gets a response to T-DM1 [trastuzumab emtansine] for 6 to 9 months, and her liver lesions regress. But it’s now 9 months later and you do a CT. Her largest liver lesion now was 3 cm. It went down to 2 cm, but now it’s 4 cm, and she has a new lesion in the right lobe of her liver. What do you do for this patient? She’s been through THP [docetaxel, trastuzumab, pertuzumab] and T-DM1 [trastuzumab emtansine]. You’re not doing an MRI of her brain. She’s asymptomatic. What do you give her? What factors go into your choice? I’ll start with Neil.

Neil Iyengar, MD: This is the point at which I would really try to rebiopsy, either tissue or circulating, not just for clinical trial information but to go back to our discussion with regard to her HER2 [human epidermal growth factor receptor 2] status. That would be really important. That said, this is a situation where, in the third-line setting, the decision essentially comes down to using either trastuzumab deruxtecan or the tucatinib-based regimen. In the setting of the conversations we’ve been having with regard to prophylaxis of CNS [central nervous system] metastases or screening, my practice has largely been to use the tucatinib-based regimen. That’s partly because of the systemic activity of that regimen but also because we know from the trastuzumab deruxtecan data that it is quite an active drug, even in late lines of therapy. Without trying to get to all the sequencing issues, I would use a tucatinib-based regimen in the scenario you just painted.

Adam Brufsky, MD, PhD: You would use a tucatinib-based regimen and not trastuzumab deruxtecan. Sara, what are your thoughts?

Sara A. Hurvitz, MD: I would talk to her about both. I’m assuming she doesn’t have brain metastases. I got a little confused.

Adam Brufsky, MD, PhD: It gets to a point where she has brain metastases, but let’s assume she doesn’t.

Sara A. Hurvitz, MD: Both are very reasonable options. Trastuzumab deruxtecan is based on phase 2, single-arm data, but the efficacy in patients in terms of objective response rate is phenomenal. But it has the risk of ILD [interstitial lung disease], which is fatal in up to 3% of patients. That’s not insignificant. It’s worth a discussion with the patient. We don’t have any idea how to properly sequence them. Most patients are going to end up getting both regimens at some point, so it’s not totally clear whether sequencing matters.

Adam Brufsky, MD, PhD: VK, what do you think?

Vijayakrishna Gadi, MD PhD: Like Neil, I’m going with tucatinib. Even though this woman’s disease burden is increasing, I’d want to know if it’s starting to transition to HER2-low, HER2-heterogeneous, etc. Outside those considerations, we have a randomized, controlled phase 3 trial with level 1 evidence with OS [overall survival] data and a positive OS signal. That’s distinctive from a very exciting molecule but with phase 2 data. We see phase 2 data come closer to earth in the phase 3 studies. While there’s a lot of enthusiasm, I’m leaning toward that based on the efficacy. Neil pointed out, and I agree, that this is a drug where the deruxtecan works after 6 and 7 lines of therapy. It’s still available, and we still expect it to work well, even after somebody comes off a tucatinib-like drug. For those reasons, I lift tucatinib into this slot.

Adam Brufsky, MD, PhD: I believe DESTINY-B03 was the trial of trastuzumab and capecitabine vs trastuzumab deruxtecan. Assuming there’s a survival benefit in the experimental arm, would that change your minds? Let me start with Sara. Would that change your mind if both trials have the survival benefit? Would you still reach for the tucatinib first?

Sara A. Hurvitz, MD: I didn’t say I’d reach for it first. I would have the discussion with them. I’m compelled by the phase 3 data supporting tucatinib and the safety. It’s a very reasonable choice. However, we have another agent that’s incredibly active that our patients deserve to know about as we make this decision together. It would be compelling evidence to support it, and I’m looking forward to seeing a larger data set relating to the risk of pneumonitis with trastuzumab deruxtecan. That’s the biggest mark against this drug.

Adam Brufsky, MD, PhD: Neil, assuming there was a survival benefit to DESTINY-B03, would that change your mind? Would you still go with tucatinib?

Neil Iyengar, MD: I agree with what Sara said. We’re going to have to see the data. We’re going to have to see what the OS benefit may be. We’re going to have to see what the rate of ILD is. It’s going to come down to a discussion with the patient. Just as we outlined the risks and benefits of the variety of therapies available to us, this is a conversation we’ll be better equipped to have with the DESTINY-B03 data.

Adam Brufsky, MD, PhD: Got it. I’m going to make it a little more complicated. Let’s say you decide to biopsy her liver because you want to put her on protocol, or you just want to know what’s going on because you want to do next-generation sequencing on her. You decided you don’t want to do the ctDNA [circulating tumor DNA], and it comes back heterogeneous staining. Half the tumor stains 3+, but there are some areas that are 0 in the cores that you get. Would that change your mind? This is getting subtle, but it’s an interesting question. I’ll start with VK. Would that change your mind? You’ve been hinting at HER2-low and wanting to reach for trastuzumab deruxtecan. Would that make you want to do that?

Vijayakrishna Gadi, MD PhD: Yes, this is the exact situation. I know we didn’t randomize patients in this manner, but that’s the group of patients for whom we think a drug like trastuzumab deruxtecan would work. Because we have an audience here, I’ll say that this is a drug that binds HER2 and has 8 molecules of the chemotherapy attached to the trastuzumab. Even after it enters the cell and is released by the lysosomes, etc, and kills that cell in which it enters, it also has the ability to transit the cell membrane and kill the nearest neighbors. Even if you have uneven HER2 expression or low HER2 expression, this is a drug that purports to work in those contexts. For me, reading into the tea leaves a little, if I have this extra information all of a sudden, I’m repositioning deruxtecan for this particular patient based on that.

Adam Brufsky, MD, PhD: Neil, do you have any thoughts on that?

Neil Iyengar, MD: It’s interesting that you said 0 staining in some of them, because in that situation, I don’t know if the bystander effect that VK just elegantly outlined is going to still be valid. In that situation, I may shy away from a therapy that’s predominantly or only HER2 or HER2-low directed and try to incorporate some chemotherapy. I would also like to do next-generation sequencing in this kind of situation, as you pointed out, because in the setting of an ERBB2 point mutation, I might consider neratinib.

Adam Brufsky, MD, PhD: Sara, what do you think?

Sara A. Hurvitz, MD: We don’t have a solid amount of data. We’re waiting for DESTINY-Breast04 in HER2-low to read out. This drug may work in HER2(0), meaning trastuzumab deruxtecan. There is some evidence that it does, but the tucatinib-based regimen has a single-agent chemotherapy, capecitabine, with it that should treat the HER2(0) component of the cancer, so it’s a wash as far as which you use.

Adam Brufsky, MD, PhD: Fair enough.

Transcript edited for clarity.