Komal Jhaveri, MD, FACP: Yes, absolutely. We can handle all the questions as we get to the metastatic and hopefully, we can do all of it. Moving on to the sequencing of a HER2-positive metastatic patient, why don't we start with this case? We have a 41-year-old woman who's otherwise very healthy and presented 2 years ago with a 5.5-cm mass in her right breast. Core biopsy from this mass showed an invasive ductal carcinoma that was grade three with ER/PR–negative and HER2-positive. She had staging study given that this was a large tumor stage III disease, and that showed multiple liver metastases, which confirms her ER/PR HER2 status to be ER negative, PR negative, and HER2 positive. And subsequently, very appropriately based on what we've learned from the CLEOPATRA study [NCT00567190], where we've seen a significant and unprecedented both progression-free and overall survival benefit, this woman was offered a taxane with HP, which is trastuzumab and pertuzumab. The docetaxel was stopped after six cycles. She achieved a partial response. She continued her maintenance HP. And while on HP, [she] had imaging done at 18 months, at which point there was disease progression seen in the liver, including elevation in the liver enzymes, which are 2 times the upper limit of normal. My first question to you here, Adam, would be, would you recommend to do a brain MRI in this scenario after course line progression in this woman?

Adam Brufsky, MD, PhD: It's a great question. I'll preface that question by saying there was a support group about 15 years ago that pushed for brain MRIs early. And after much consternation with a neuro-oncologist and some of the medical oncologists, we decided not to recommend MRIs because we really didn't have any therapy. Well, now we do. And thus, at progression, I will order a brain MRI, yes. And I'm sure you guys probably do that as well. I would order a brain MRI here.

Komal Jhaveri, MD, FACP: Yes. I have been finding a low threshold to figure out why I should order a brain MRI. Of course, we have so much data now where we've had screening MRIs as part of clinical trials that led to us understanding the benefit of certain drugs. And we'll talk about tucatinib and the HER2CLIMB [trial] data [NCT02614794] as well. But given our current guidelines where we're otherwise not really necessarily making a huge change in the survivals outside of being able to offer these therapies or consider these therapies when patients are asymptomatic, I've not necessarily been doing that unanimously. I think it's still a clinical trial question. And fortunately, both my site and I think there's a trial ongoing even at the Dana-Farber [Cancer Institute] that is looking at this specifically, and hopefully, we'll have some better data so that we can really offer it to all if that proved out to be really beneficial for all.

Adam Brufsky, MD, PhD: Yes. It's a great question. I think that I go both ways. I said it were a brain MRI, but I have a very low threshold. A foot drop, headache, anything like that. Visual changes, which 5 times out of 10 or 9 times out of 10 are basically maybe just dry eyes or something like that. But I will have a low threshold to order a brain MRI.

Komal Jhaveri, MD, FACP: Exactly. I feel like we've become more and more vigilant to ask our patients or probe to certain symptoms to make sure that we're not missing an opportunity to order something, especially if they have something low grade that they haven't reported on their own, so I agree with you. Let's move on. And thus, now let's make this case hypothetical in some ways, right? We can talk about different ways because we'll have both kinds of patients in clinic. This patient really insisted on having a brain scan and we did a brain MRI and there was no evidence of any brain metastasis. All we have is liver metastases. With that information and the elevated liver enzymes, what do you offer her to be the next therapy of your choice?

Adam Brufsky, MD, PhD: If she had no brain metastasis, based on [the] DESTINY-Breast03 [trial (NCT03529110)], she [would] get trastuzumab deruxtecan, no doubt with the survival benefit and the PFS [progression-free survival] benefit of about 27 months in the setting vs TDM-1, which you're going to show us in a minute as about 7.2 months. I think if she had brain metastases is very interesting. I think I would give her based on HER2CLIMB. I would give her tucatinib, capecitabine, and trastuzumab. Although a lot of us may do CyberKnife on those 2 lesions first. And then, it's dealer's choice. It can give you either one. I think a lot of us still would give it tucatinib triplet, because I think as you're going to say, you may or may not say they had a secondary endpoint in HER2CLIMB, which was metastasis after metastasis. If you had progression, [then] you were allowed to stay on it once the progression was treated to look for new metastasis. And I feel pretty strongly about what the TKIs [tyrosine kinase inhibitors] are doing is actually preventing micrometastatic disease from becoming symptomatic micrometastatic disease. And thus, I probably would still use tucatinib-based regimen second-line [therapy]. But as you're probably going to talk about in DESTINY-03, I think it was a small number, maybe 60 patients or something out of the total DESTINY-03 cohort. You had a 60% response rate from T-DXd [trastuzumab deruxtecan]. And hence, it's something that I've now started to think about. I was a big skeptic. I have to admit, I didn't think these big molecules would get into the CNS [central nervous system], but apparently, there's enough disruption on the blood-brain barrier to allow that to happen. I think for me, I think again, to summarize, if they had metastasis on the brain MRI, probably give tucatinib triplet or I'd radiate them and think about T-DXd. But if they had no brain metastasis, I'd give T-DXd in the cell.

Komal Jhaveri, MD, FACP: Right. Thank you for walking us through that thought process of yours. And I like the way you put it that it's dealer's choice and I completely agree, and I think many people can justify it many different ways. The good news is we have those options and we can think about it for a given patient right in front of us and talk them through with our patient population maybe, the toxicity profile for the patient, maybe a clinical scenario that they're presenting with and together make a patient-physician making process. Hence, we do have those various options. The way I think about [it] in these patients also, is that if their systemic burden is really driving their tumor progression, I do think about trastuzumab deruxtecan, and we'll talk through the data to know why. And when it's more driven by say, active brain metastases, I think about the tucatinib regimen over T-DXd. Although we now have started hearing about the TUXEDO-1 trial [NCT04752059] and the DEBBRAH trial [NCT04420598] that are evaluating trastuzumab deruxtecan even in patients with active brain metastases, where in very small number of patients we've started to see benefit. Thus, I think we are going to have great options for both scenarios with both these molecules which is great news for our patients.

Adam Brufsky, MD, PhD: Totally agree.

Transcript edited for clarity.