HER2CLIMB: Brain Metastases Data



Adam Brufsky, MD, PhD: Virginia, what are your first- and second-line standards of care right now for metastatic HER2 [human epidermal growth hormone receptor 2]–breast cancer?

Virginia Kaklamani, MD:Assuming somebody has not just finished TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin]?

Adam Brufsky, MD, PhD: Assume it’s 12 months after these or de novo.

Virginia Kaklamani, MD:The de novo is it would be the CLEOPATRA regimen. A taxane plus HP [trastuzumab, pertuzumab] then second-line would be T-DM1 [trastuzumab emtansine]. We have the T-DM1 versus DS-8201 [fam-trastuzumab deruxtecan-nxki] trial, so I try to put all those patients on that trial. Those are my first 2 lines of therapy in the metastatic setting.

Adam Brufsky, MD, PhD: Basically, it’s THP [paclitaxel, pertuzumab, trastuzumab] followed by T-DM1?

Virginia Kaklamani, MD:Correct.

Adam Brufsky, MD, PhD: Is that the consensus? Anybody have any other nuances that you would do here? Probably not. All right, very good. So we’re all fine with that. All of us who have traveled around the world realize that T-DM1 is not available everywhere. That’s the 1 thing we don’t realize in the United States. You go to the Philippines or somewhere else, they can’t get it. It’s really interesting how people are doing their treatment, at least in my experience. I’m curious about what you guys have heard. You’ve heard they use a lot of capecitabine, trastuzumab. There’s a lot of vinorelbine, trastuzumab—the stuff we used to use 10 years ago. Is that your experience outside the United States, Europe, and the wealthier Asian countries?

Mark D. Pegram, MD: This is where the TOP2 gene amplification story can be useful in those jurisdictions. For instance, if you can’t get another HER2-targeted agent and those patients are still anthracycline naïve, which many are in this era, then 35% of those patients will be TOP2 amplified, and those patients do benefit from single-agent anthracycline.

Adam Brufsky, MD, PhD: Meaning not with trastuzumab, just by itself?

Mark D. Pegram, MD: Just by itself. I remember when it was hard to get trastuzumab in the United States, and it still is in some areas of the world such as in sub-Saharan Africa. At any rate, in those jurisdictions or even now, patients who have already had antibody-based and chemotherapy-based treatments in the neoadjuvant or adjuvant setting or first-line metastatic, even if they’re still anthracycline naïve, that’s still a therapeutic opportunity. Of course, they won’t be able to pay for the FISH [fluorescence in situ hybridization] test. That’s the problem with this jurisdiction.

Adam Brufsky, MD, PhD: There are cheap FISH tests if they really want to do them, but that’s another issue. Now we get to the big mystery of our business. Not so mysterious anymore, but third-line therapy. Carey, I’ll put this to you first. What are we really trying to do in third line and beyond? Is it the brain, is it systemic? We all know how many percentages of people relapse in the brain by third line. Is this 50%? Some high number.

Carey K. Anders, MD: Upward of 50% at that point in time. We will be managing both intracranial and extracranial disease. In our patients who have extracranial disease, we also are hopeful to prevent intracranial recurrence. In that setting the brain metastasis consequences are either on our mind because we’re actively treating disease in the brain or we’re trying to prevent that patient from developing CNS [central nervous system] recurrence.

Adam Brufsky, MD, PhD: We’re really getting to this dilemma. It’s a brain-nonbrain relapse, right? The brain dominant versus the nonbrain dominant. Some interesting stuff has come out of ASCO [American Society of Clinical Oncology Annual Meeting] that’s going to really speak to this. Do you agree that it’s the brain? Is that how you’re thinking of the third line and beyond, as a brain-nonbrain-dominant thing? Mark, what do you think?

Mark D. Pegram, MD: The most impressive brain metastasis data at this ASCO was the data presented by Dr Nancy Lin. In the CNS subset analysis of the HER2CLIMB study, there was a 68% reduction in risk of CNS PFS [progression-free survival] in the tucatinib arm with statistical confidence. Median CNS PFS was 9.9 months in tucatinib versus 4 months in the control. Risk of death overall was reduced by 42% in the tucatinib arm with statistical confidence. Median OS was 18 months versus 12. Overall response rate intracranially was higher in the tucatinib arm. Median duration of response intracranially was higher. Every attribute you look at with any metric of CNS disease activity, tucatinib clearly is superior.

Adam Brufsky, MD, PhD: That’s really dramatic, and the cool thing about the trial is that in the patients with stable brain metastasis, what would you define as stable? They didn’t have all those benefits. That’s the weird thing. It was really only in the progressive patients. In other words, what people were thinking is that the people with stable brain metastasis were dominated by their systemic disease. The people with the progressive brain metastasis were dominated by their CNS disease. Rashmi, can you comment on that? Because we waited for this data. This was our question at San Antonio Breast Cancer Symposium, and you gave it to us finally. You want to comment on that?

Rashmi K. Murthy, MD, MBE: The study enrolled patients, stable as well as progressive or new brain metastases, and about 50% of the study actually had some history of brain metastases. Of that, about 40% actually had what we would consider to be active brain metastases. That’s either new disease that was found on the baseline MRI [magnetic resonance imaging] or progressing disease in a patient who had prior history and treatment of their brain metastases. In looking at the results, it is very important to note that these were not patients who just had a history of brain metastases with stable disease. Of that patient population, 40% had what we would consider to be very high-risk brain disease, new disease, or progressing disease. That also brings up the question with the labeling—the FDA approval and the labeling of tucatinib. Technically, we would be allowed to use this after just 1 line in a metastatic setting. Certainly, we also have the T-DM1, the DS-8201 trials, so a lot of our patients do go on that study. But in a patient who has CNS relapse, it may be important to give some thought for actual use of this tucatinib regimen, especially after the results we saw at ASCO, using it in the second-line setting after the CLEOPATRA regimen, before T-DM1. Although in the HER2CLIMB study, 100% of the patients had received prior T-DM1.

Transcript Edited for Clarity

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