Case 2: Later-Lines of Treatment in Metastatic Breast Cancer


Key opinion leaders consider later-lines of therapy in metastatic breast cancer with lung and brain involvement.

Joyce O’Shaughnessy, MD: We have 2 datasets. The phase III with tucatinib gives us a lot of information about progression, specifically in the brain, and survival in half of the patients in the trial who did have brain mets [metastasis]. It’s a large brain metastasis experience. We have some small, but interesting data suggesting that the T-DXd in patients who have stable treated brain mets can have a very long duration of benefit from T-DXd [trastuzumab deruxtecan] despite the brain mets but we don’t have randomized data there. Bill, where do you sit today? This patient did well on CLEOPATRA, but now she’s progressing in her lungs, you had a brain MRI, and she’s got asymptomatic mets. How do you think through the choice of going on to tucatinib without SRS [stereotactic radiosurgery] perhaps? That’s something new. We’ve always done SRS for these lesions to get on top of them, but I was looking at the data you just showed and it was only 3% of patients that progress. They had a 47% response rate, others had stable disease, and then a fraction had actual progression of the disease. Is it reasonable to forego SRS for a while and do tucatinib, the triplet?

William Gradishar, MD: It could be a consideration. You could take the other tack too. If somebody clearly has, on whatever systemic therapy they’re on, relatively stable disease and an isolated ditzel on their brain that you happen to detect, that may be somebody that I would not change their systemic therapy for but treat that small volume of disease and hold the tucatinib in reserve. As the volume of disease in the brain goes up, whether the systemic disease is changing or not below the neck, I would be more inclined, based on data we have today, to use a tucatinib-based regimen.

Joyce O’Shaughnessy, MD: For a tiny, little volume disease you’re going to stay on their current systemic therapy, you’re not going to change to the tucatinib regimen unless they had larger volume disease?

William Gradishar, MD: Correct.

Joyce O’Shaughnessy, MD: How about you, Mark, concerning this patient? Now she’s progressing both in lung and asymptomatic brain mets, how do you think through what to talk to her about as some optimal options for her?

Mark Pegram, MD: Bill has covered it well and provided data to back that up, so I don’t have any other options to add in this particular case.

Joyce O’Shaughnessy, MD: You would favor the tucatinib triplet at this time. Would you always give SRS first, Mark, before going on to the tucatinib triplet?

Mark Pegram, MD: Not always. A fraction of the patients enrolled in the pivotal HER2CLIMB study, of the fraction of brain metastasis patients, which was 48% of the total, about 23% of them had untreated brain metastasis. Those patients, as long as their tumors were 2 cm or less, were eligible for the HER2CLIMB trial; so there is response data available for them and overall survival data in the brain mets subpopulation. Even in the active brain metastasis subpopulation, there’s good data showing an overall survival signal in subgroup analysis. It’s compelling information that we should consider tucatinib-based treatment systemically, especially for small, perhaps occult, asymptomatic lesions in particular because then you might be able to forestall the need for localized therapy, such as ionizing radiation. Even in stereotactic form, especially if you use it over and over again cumulatively for multiple lesions over time, can lead to neurocognitive decline as a result of radiation toxicity.

Joyce O’Shaughnessy, MD: How about you, Adam, what would your thinking be when she’s finishing the CLEOPATRA now?

Adam Brufsky, MD, PhD: I don’t have a lot to add here. The key here is that it’s above the neck, she has asymptomatic brain metastasis. You just want to prevent the progression of that to something asymptomatic. SRS can do it, but we like to reserve SRS. If I had a systemic therapy that crossed the blood-brain barrier and prevented not only her systemic disease or control the disease above the neck, it’s pretty straightforward to do that. There’s one thing to be cautious about when you look at the DESTINY data, it’s unrandomized, so you have no idea what typical standard of care would have been with this. Had someone received standard of care, would her brain mets have progressed?

Generally, we’ve done this. A long time ago we did a registry analysis of [CNS] HERs and in that analysis, we found that in women with brain mets, their survival was dominated by her systemic disease in the absence of effective therapy, such as trastuzumab deruxtecan. You couldn’t tell that you couldn’t wait long enough to see if her brain mets were controlled or not because they had progression of her systemic disease below the neck. I’m not sure what to make of this and similar to T-DM1 [ado-trastuzumab emtansine] data, the anecdotal data, about brain mets. Given that the decision for me would be to use these TKIs [tyrosine kinase inhibitors] that in a randomized trial do appear to control the disease above the neck.

Joyce O’Shaughnessy, MD: We’re all on the same page here with asymptomatic mets, we’re going to prioritize the tucatinib triplet for her in the second line, so she’s not going to get T-DM1 and she’s not going to get T-DXd. Now she gets the tucatinib triplet, she does well, she responds, she had already had SRS, and now she’s progressing in her lungs. What would you think about giving her next, Bill, at that point?

William Gradishar, MD: If her systemic disease is the most threatening thing and she has gotten tucatinib, I would give her trastuzumab deruxtecan. I wouldn’t have any hesitation about doing that. That would be my next move.

Joyce O’Shaughnessy, MD: Mark and Adam, anything different you would do?Would you consider T-DM1 if, for example, she hasn’t had that yet?

Adam Brufsky, MD, PhD: She hasn’t had trastuzumab deruxtecan, correct?

Joyce O’Shaughnessy, MD: Right.

Adam Brufsky, MD, PhD: You have a choice. You have something with a survival benefit in a randomized trial, but, on the other hand, no one in that randomized trial, EMILIA, had prior HER2 TKI, so it’s not an analogous situation. I would go with the one with the higher PFS [progression-free survival] and that’s going to be trastuzumab deruxtecan.

Joyce O’Shaughnessy, MD: Interesting. How about you, Mark, would you choose the T-DXd over the T-DM1 or vice versa here?

Mark Pegram, MD: It depends on the severity of the extracranial disease. If it’s asymptomatic and not causing any organ dysfunction, T-DM1 can be a wonderful palliative option. It is less toxic than trastuzumab deruxtecan, so I would feel compelled to have more of a balanced discussion on both options in such a case. But, if somebody is symptomatic or their LFTs [liver function tests] are going up, they’re getting short of breath, or any sort of problem with visceral disease, then I would be compelled to use the most active of the two. Trastuzumab deruxtecan will be proven to be the most active. There is a randomized controlled trial comparing T-DM1 head to head against trastuzumab deruxtecan, so we’ll get that data and finally have level 1 evidence to make that decision when the data become available.

Joyce O’Shaughnessy, MD: Until we have that head to head, then we do have an option to weigh the risks and the benefits.

Transcript edited for clarity.

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