Dr. Carey Anders:
Welcome everyone to The ASCO Post Roundtable Series on updates on HER2-positive breast cancer. I'm Dr. Carey Anders, the Medical Director of the Duke Center for Brain and Spine Metastasis, the Interim Division Chief at the Duke Cancer Institute, and a breast medical oncologist. I'm really happy to have joining me today, two of my colleagues, Dr. Erika Hamilton and Sara Hurvitz. And I'll turn it over to Dr. Hamilton to introduce herself followed by Dr. Hurvitz.
Dr. Erika Hamilton:
Hi, I'm Erika Hamilton. I'm a breast medical oncologist. I direct the Breast Cancer Research Program at Sarah Cannon Research Institute at Tennessee Oncology here in Nashville, Tennessee. Happy to join you today.
Dr. Sara Hurvitz:
Hi there. Happy to be here today. I'm Sara Hurvitz, also a medical oncologist at the David Geffen School of Medicine at UCLA.
Dr. Anders:
So today we're going to be discussing the recent updates on HER2-positive breast cancer and integrating the new developments into four patient case studies. Our second installment today will focus on HER2-positive breast cancer with brain metastasis.
So, we'll move into case study two. Our patient is a 46-year-old female with a history of de novo ER/PR-negative, HER2-positive breast cancer that's metastatic to the liver at initial metastatic diagnosis.
She received our traditional THP (docetaxel, trastuzumab, and pertuzumab) for six cycles as per the CLEOPATRA study with resolution of hepatomegaly and radiographic improvement of her liver metastasis. At that point, she transitioned to dual antibody therapy with trastuzumab and pertuzumab for the better part of a year-and-a-half with fantastic quality of life. She's very active as a mother of two school-aged children. She runs her own nonprofit and is also quite artistic.
As she comes in to see you at routine restaging scan, she's found to have progression in the liver and the brain. She receives radiosurgery to two intracranial lesions in the posterior fossa, and then asks about the next best systemic therapy in her particular situation.
I'd like to turn over to Dr. Hamilton to see how she might approach this case and what the discussion would look like with her patient.
Dr. Hamilton:
Thanks so much. Yeah, one thing that I think is important to qualify in this case is that she has systemic progression in addition to the brain metastases. So we also often kind of debate whether we need to change systemic therapy when our progression is brain only, but that's not the case here. She has had radiation now to her brain lesions, but we're trying to pick the next line of therapy.
And certainly, one of these options would be capecitabine, trastuzumab and tucatinib. This regimen was approved based on the HER2CLIMB study.
In that study, at the time that it was done, this was really a so-called third-line trial, where patients had seen trastuzumab, pertuzumab, and T-DM1 (trastuzumab emtansine), which was the standard in the second-line setting, which is a little bit different now. They were randomized to either receive capecitabine with trastuzumab or capecitabine with trastuzumab and tucatinib. What's really unique about tucatinib is that it's a HER2-specific tyrosine kinase inhibitor. So unlike some of our other tyrosine kinase inhibitors, we're very used to seeing rash or diarrheas, very prominent symptoms. This really inhibits HER2 while leaving HER1 or eGFR alone, cutting down on the rates specifically of rash and diarrhea we see.
Now, when we get into talking specifically about brain metastases, this trial was really quite ahead of its time in the fact that it allowed not only patients with stable treated brain metastases, but also patients that had not received treatment for their brain metastases or had received local treatment and subsequently were progressing. So this really was quite a heavily pretreated population in the terms of also having almost 50% of patients that had brain metastases. When we break it down by of those 291 patients that had brain metastases, about 117 of them were treated and stable, and about 174 fell into that bucket that were either untreated or treated and were progressing.
And so, from the updated results of San Antonio this past December in 2021, we again saw the overall survival for patients specifically that had brain metastases coming on to study and really looked quite encouraging from 12.5 months up to 21.6 months with the addition of tucatinib. So an over 9 month benefit by adding tucatinib here. I think this really was quite encouraging for us.
And when we look specifically at progression free survival in the CNS (central nervous system), we also saw a benefit favoring the addition of tucatinib, 4.2 months, up to 9.9 months. So certainly, for our highest risk patients with HER2-positive brain metastases, this is a very compelling option showing overall survival data. Unfortunately, we know up to 50% of our patients with HER2-positive metastatic disease will face brain metastases at some point over their disease course.
Dr. Anders:
Thank you for that fantastic summary. I think another aspect of the HER2CLIMB study that really spoke to me was the second progression improvement, progression free survival, and particularly from the intracranial perspective. So if you take this particular patient who's just been diagnosed with brain metastasis and then continued tucatinib vs placebo in the study, you saw a doubling to second intracranial progression. I think it really speaks to the intracranial activity of this compound.
Dr. Hurvitz, any comments that you have particularly around management of the toxicities associated with the HER2CLIMB regimen?
Dr. Hurvitz:
Well, I think it's interesting because this is a novel therapy in that it is HER2-selective. So we're not seeing the rates of diarrhea that have been seen with other HER2 TKIs that are less selective and inhibit eGFR or HER1. The rate of grade three or greater diarrhea was around 13% in the tucatinib arm. That compared a little bit more than the control arm where patients received trastuzumab and capecitabine is about four percentage points higher than the control arm. When you compare that to data relating to, for example, neratinib with capecitabine, I think this compares very favorably. So you do need to talk to patients about diarrhea, make sure that they have their antimotility agents on hand at home and are in close contact with their clinicians, but it isn't the type of diarrhea that we've experienced with other pan-HER inhibitors.
Dr. Anders:
No, absolutely, and I think some of that additional toxicity we've learned is just part and parcel of being on the compounds longer. So I in my own practice have had situations where we've had to discontinue capecitabine altogether. And my preference in that setting has been to continue the dual HER2 blockade with tucatinib and trastuzumab based on some of our experiences with lapatinib and trastuzumab from prior studies. So really important are some of the nuances of management of this regimen.
For this particular patient, she is part of an online support group of patients with HER2-positive metastatic breast cancer and she's hearing a lot about the antibody drug conjugate trastuzumab deruxtecan. She asks if there is activity of trastuzumab deruxtecan (T-DXd) for both the brain and the body, which is a really interesting question. I think historically we have had concerns that antibodies may not traverse an intact blood-brain barrier, but of course we're in a blood-tumor barrier scenario where we know the blood-brain barrier is not necessarily intact.
So how would you discuss this with her, Dr. Hurvitz, in the clinic with regards to activity of trastuzumab deruxtecan, both for brain and body, and what data do we have to support that discussion?
Dr. Hurvitz:
Well, first of all, I would say that we don't have level one evidence yet that T-DXd has benefits in the brain. Whereas with tucatinib, we have level one evidence from the HER2CLIMB clinical trial.
That said, we are seeing very intriguing data relating to the activity of this agent in patients with brain metastases. In the DESTINY-Breast03 clinical trial, there were some patients who had stable brain metastases at baseline. Not all of them had had prior treatment, but all of them had stable, asymptomatic brain metastases who fell into that category. The progression-free survival differences were in favor of T-DXd regardless of whether patients had brain metastases or not. So those who had brain metastases, the median PFS was 15 months with T-DXd, which compared favorably to T-DM1 at 3 months.
What was a little surprising is that by blinded independent central review of the scans for patients who had measurable disease at baseline in the brain, the patients treated with T-DXd had an intracranial objective response of around 63% or 64%. For those treated with T-DM1, it was around 33% intracranial objective response. Now, this is very exploratory data. Again, we don't yet have really compelling level one evidence that this will hold up, but we are building up a lot of circumstantial evidence that this drug does have activity in the brain. And it's really quite interesting because there are some patients who had complete responses, actually, 10 patients had complete responses in the brain compared to one treated with T-DM1.
So, I'm very intrigued by these data and in a patient like our patient, who's progressing not only in the brain, but in the liver, this is the drug I would consider. I think the data that Erika shared relating to tucatinib right now is probably stronger, so I might go with the tucatinib-based therapy first, but I would not hesitate to pivot to T-DXd if she had another progression event, especially outside of the brain.
Dr. Anders:
Excellent, and really intriguing data, just as you described. I know we're all really looking forward to the DESTINY-Breast12 results, which will be focusing and honing in on the patient population with HER2-positive breast cancer with and without brain metastasis. We'll get some more definitive data in a 500-patient study that'll be focusing not only on intracranial responses, progression free survival, overall survival, but there's also a cohort of patients without brain metastasis to really look at potential delays in diagnosis of brain metastasis. So, I know we're all eagerly awaiting the DESTINY-Breast12 study results.
So, let's change the scenario a little bit. And for this particular patient, she moves on to the HER2CLIMB regimen. She receives tucatinib, capecitabine, and trastuzumab with good tolerance, has a durable progression-free survival, but unfortunately presents on a restaging study with stable extracranial disease. She has three more relatively asymptomatic around one-centimeter lesions in the brain. I want to open up the conversation to how we might approach this patient with progressive brain metastasis after dual antibody therapy with trastuzumab and pertuzumab, along with the tucatinib regiment, and how we might think about trastuzumab deruxtecan in this setting.
Dr. Hamilton, do you want to lead off?
Dr. Hamilton:
Yeah, I would absolutely be thinking about trastuzumab deruxtecan here. We know that these antibody drug conjugates are large. There initially was kind of worry about whether they would penetrate into the brain, but brain metastases themselves, certainly local therapy, such as surgery and radiation, really make the blood brain barrier quite permeable. So I've been very encouraged by the data I've seen from trastuzumab deruxtecan so far.
So, for this particular patient, she had standard taxane with trastuzumab and pertuzumab in the first line. She was treated with capecitabine, trastuzumab and tucatinib in the second line. Since brain metastases are still a prominent feature for her, I would be thinking about trastuzumab deruxtecan at this point.
Dr. Anders:
Absolutely, and I think we are starting to see a collective body of literature around this scenario. All of them, albeit are small studies, 20 patients or less, but focusing on patients with HER2-positive progressive brain metastasis who've been treated with trastuzumab deruxtecan with very respectable response rates and durable responses. Some of those studies have included the TUXEDO-1 study.
We also have seen data from the DEBRAH study then also a case series that was led by Dana-Farber, doing a very nice analysis pre-clinically and also clinically of the impact of trastuzumab deruxtecan and active brain metastasis. So again, sort of the jury is still out until we see the DESTINY-Breast12 data, but I think really encouraging early results. I think, again, I can certainly say I'm seeing nice efficacy in my own clinic in this scenario.
So just some key clinical takeaways from this case. I think it's very common knowledge that brain metastasis are a common consequence of advanced HER2-positive breast cancer. It's something we need to be on the lookout for. And while we don't have definitive evidence to say we need to be getting screening MRIs on all of our patients in this scenario, we definitely need to have a really low threshold to obtain a brain MRI for a patient who has any neurologic symptom, even very slight. Newer therapies are certainly showing excellent responses with concurrent quality of life, including the trastuzumab deruxtecan and the tucatinib, capecitabine, trastuzumab triplet. All very exciting.
I think just as we've had in this conversation, it's really complex to determine which agent to choose and I think that there are a lot of factors that go into that. I don't think there's one right answer. Really, there are many factors that come into play when we're having this discussion with our patients in clinic, based on the evidence. I think some of those factors are what is the status of the brain metastasis diagnosis? Are we in a stable setting? Are we in a progressive post local therapy setting? Are we with new asymptomatic brain metastasis that may not require immediate local therapy? The other is the patient's comorbidity, and of course, the patient's preference. Again, this really is a balanced decision between the physician and the patient at that time. And of course, as we've also discussed, we should incorporate clinical trials when we can.
So, this brings us to the end of case number two. Please see the other segments for further discussion about the latest data in breast cancer, or feel free to visit ASCOPost.com. Thank you.
