Presentation and considerations for relapsed HER2+ metastatic breast cancer with progressing brain metastases.
Mark Pegram, MD: This is a 41-year-old woman who is in good health and presented 3 years ago with a 5.5-cm mass in the right breast. A core biopsy showed infiltrative carcinoma, grade 3, ER [estrogen receptor]–positive, HER2 [human epidermal growth factor receptor 2]–positive. Staging showed multiple hepatic metastases at the time of diagnosis, and a liver biopsy confirmed this. The same histopathology, ER-positive, HER2+ in the liver. She was treated with THP [docetaxel, trastuzumab, pertuzumab]. The docetaxel was stopped after 6 cycles, and an aromatase inhibitor was introduced along with an LHRH agonist, and the patient achieved stable disease at that time.
Twelve months later, she developed disease progression in the liver and was started on T-DM1 [trastuzumab emtansine], achieving a partial response, lasting about 10 months. Then she had a repeat interval restaging that showed liver progression. This time it was accompanied by a 2-fold elevation of her transaminases. The patient was started on trastuzumab deruxtecan at that time, achieving a partial response. Nine months later the patient complained of mild headaches, and a CT showed stable liver disease in terms of her extracranial disease, but her brain MRI showed 2 new lesions; 1 was 2 cm and the other was 1 cm. There was no surrounding peritumoral edema. There was no mass effect or a shift to these lesions, and they were minimally symptomatic indeed.
Joyce O’Shaughnessy, MD: We have a patient who has control of systemic disease, but she does not have control of CNS [central nervous system] at this point. What do you think about her, Mark, in terms of the options for her at this moment?
Mark Pegram, MD: These lesions were felt to be too deep-seated, and because there was more than 1, neurosurgery was not an option, but she did have her case presented at our neuro-oncology tumor board. That left a debate between systemic treatment with a tucatinib triplet or stereotactic radiosurgery. She would have met the eligibility criteria for the HER2CLIMB study, so we treated her with the HER2CLIMB regimen because she had minimal symptoms—nothing that was in an area of concern to our neurosurgeons that would need urgent treatment. Therefore, we elected not to give radiation therapy first either.
Joyce O’Shaughnessy, MD: Show us some of the data, Mark, that go into the triplet and other options that we have for these patients with the brain metastases even before radiation therapy.
Mark Pegram, MD: This is a good case to make the point that there were patients in the HER2CLIMB trial that were eligible for untreated CNS metastases. About half the patients on the study did have brain metastases, and 23% of them had untreated brain metastases and were still eligible for the study. These are the data on the left showing the confirmed intracranial objective response rates, which look similar to the data that Bill showed on the overall response rate in all sites, including the extracranial sites, but these are the confirmed intracranial responses. You could see the response rate is similar to the extracranial response rate, and there’s an example on the right side of a patient who, on tucatinib, had a partial response with this regimen. This is an important point to make, this new treatment is known to practice clinicians that you don’t always have to reflexively move to local therapies with HER2+ breast cancer brain metastases.
These data show the CNS PFS [progression-free survival] also being more favorable in those subjects on the HER2CLIMB regimen that were randomized to tucatinib. On the right-hand side of the slide, you can see the Kaplan-Meier analysis of the patients with active brain metastases who had a significant improvement in overall survival. This is the active metastases group. These are patients that were either untreated or who had progressed despite prior treatment. Despite those relatively high-risk features, these patients did have, in subset analysis, an improvement in overall survival that reached statistical confidence. Those are impressive data for this regimen, the first time in a randomized trial showing robust results, particularly in patients with active brain metastases.
A final point is these data were presented last year at ESMO [European Society for Medical Oncology Congress] and look at new brain lesion-free survival probability. They do suggest that tucatinib, perhaps, has the capacity to delay or prevent the onset of new brain lesions. That’s important because every time there’s a new brain lesion, you are looking at some local intervention that you require at that time, either stereotactic radiation or sometimes even whole-brain radiation. These can have negative impacts in terms of quality of life, particularly in regard to cognitive function. These are exciting data because if we can delay those types of toxicities from radiation therapy, then that should be expected to result and improve quality of life. During that interval, new brain lesions could be delayed.
Joyce O’Shaughnessy, MD: This gives us hope for the adjuvant setting because we’re bringing the tucatinib into combination with the T-DM1 [trastuzumab emtansine] in a KATHERINE-like approach. This will hopefully forestall or prevent the emergence of recurrence with brain metastases. We’d be interested in treating this patient with the tucatinib triplet and putting off the radiation therapy for a while. Let’s say this patient had CLEOPATRA, then she had T-DXd [trastuzumab deruxtecan], then she developed the brain metastases and got the tucatinib triplet. What if you had a patient who developed brain metastases? She was on CLEOPATRA, she developed symptomatic brain metastases, and she went on to the tucatinib triplet and some SRS [stereotactic radiosurgery], etc, but no other disease and the big issue is her brain. Now her disease is progressing on the tucatinib triplet, but she still doesn’t have systemic disease. Of course, we’re going to bring in radiation therapy as we need to bring it in. What other systemic options do we have? In terms this case, we don’t have the level 1 evidence to go beyond the tucatinib triplet for the control of brain metastases. Any experience that you all have had, either not necessarily right after tucatinib but generally with successful treatment of brain metastases, HER2+?
Adam Brufsky, MD: It’s hard. It’s a tough area. I published—not the brain—a case report with 1 of my fellows, an oncologist about 1½ years ago. We had a woman who had progressed through 2 TKIs [tyrosine kinase inhibitors], both lapatinib and neratinib. We got under compassionate use before they were approved. Then we gave her poziotinib under compassionate use, and she responded dramatically for about 6 to 8 months. The question is, and we don’t know the answer to this because it’s a total data-free zone, what do we do? Do we use another TKI? There are a lot of drugs in development that cross the blood-brain barrier, small molecules that maybe will be useful in the future. These are all research tools at this point.
The real question is a lot of people turn to this is to say, “Let’s just use an ADC [antibody-drug conjugate],” because of anecdotal data from T-DM1 [trastuzumab emtansine]. We don’t know enough about how these big molecules get to the blood-brain barrier if at all, to use that as an approach. We use sequential SRS when we can, whole brain when we can. That’s what I do in practice. Neratinib has done the same thing as this last slide that Mark showed. We look at neratinib and tucatinib. There are major differences in their toxicity. Their efficacy is going to be about the same. The trials were done a little differently, so that’s why it comes with the same survival benefit of tucatinib.
We see the same thing in preventing the onset of new metastases. That’s important, both in the metastatic setting and the adjuvant setting. If we had a predictor, some genomic predictor of who can get a brain metastasis up front, in these early-stage patients, those are ones we would direct the TKIs to. That could be a future way that we manage this disease, especially in those patients who have a lot of residual disease after neoadjuvant diseases, like the patient we had before. If we were able to know who would get those brain metastases, those are the people at some point in time we would direct a TKI to. The COMPASS trial is about to start with T-DM1 [trastuzumab emtansine] with or without tucatinib. This could be an important study for us too in the adjuvant setting, with what we’re seeing in the metastatic setting.
Transcript edited for clarity.