Case 3

Dr. Chau Dang:

That really transitions us nicely into our third case, which is our 55-year-old postmenopausal woman who presented with de novo hormone receptor–positive, HER2-positive metastatic breast cancer to the lungs, liver, and bones.

She presented complaining of months and months of right upper quadrant pain that led to imaging, which found lesions in her liver, of course, found lesions in her breast. We biopsied both the breast and liver, and it was a triple-positive breast cancer. This is a question of how do you treat these patients? There are more patients who are de novo now as far as metastatic disease. In addition to antiresorptive therapy for bone metastasis, what is our current standard first-line systemic treatment option for this patient? Is it THP? That is taxane plus trastuzumab and pertuzumab. Or is it T-DXd? Or is it the HER2CLIMB regimen tucatinib, plus capecitabine and trastuzumab or T-DM1? Dr. Elias, what is your answer?

Dr. Anthony Elias:

Right. I think we’re fairly unanimous in this that THP is currently the standard first line. This is on the basis of both the CLEOPATRA and the MARIANNE trials. The CLEOPATRA randomized patients to TH vs THP. It was placebo-controlled and had an improvement in progression-free survival median from 12.4 months with mono antibody to 18.5 months with combined pertuzumab. It has an overall survival advantage as well with a median overall survival of about 57 months vs 41.

The MARIANNE trial was quite disappointing, in my view, at the time it compared to TH, so it was before pertuzumab was established vs T-DM1 alone vs T-DM1 plus pertuzumab. These arms were all very, very similar. They overlapped considerably and did not show an increased benefit for the use of the antibody-drug conjugate. Now, of course, T-DXd is likely to be much more potent, and I would not be a betting man if I thought that T-DXd might have a chance of becoming first-line therapy.

The issue there is really that one has to pay very close attention to the possibility of developing interstitial lung disease, which can be, in fact, life-threatening or even fatal. Monitoring for that toxicity, which occurs somewhere in the 10% range, is critical. The HER2CLIMB regimen is certainly an active regimen, and it has been tested with most patients in third line but also some patients in second line. And it’s certainly active, and some of the current trials are testing whether the addition of tucatinib to an ADC will, in fact, improve outcomes. I’m looking forward to those types of trials.

Dr. Chau Dang:

Absolutely. Your answer is THP at this moment, but we’re waiting for, I think, the DESTINY-Breast09 to show us whether T-DXd may replace THP in the front-line setting. I would agree there. Shanu, do you agree with the answer THP for now?

Dr. Shanu Modi:

I think it’s really hard to deny that advantage to patients. When you look at the long-term follow-up from the THP CLEOPATRA study, in their final study analysis at 100 months median follow-up. You look at the 8-year landmark point, almost 40% of patients are living with stage IV disease still. Even more impressively, 16% are without any disease progression on the pertuzumab arm. That’s why it remains our gold standard first-line therapy today. It’s a well-tolerated regimen. I think it was a brilliant design to give the chemo upfront for six to eight cycles and then back off and try to maintain these patients on just antibody therapy. It gives them a really high quality of life.

Dr. Chau Dang:

Absolutely, I would agree. She’s hormone receptor–positive. Shanu, when you stop your taxane, do you add endocrine therapy?

Dr. Shanu Modi:

Always. I do.

Dr. Chau Dang:

You always?

Dr. Shanu Modi:

Yeah.

Dr. Chau Dang:

It’s interesting because the CLEOPATRA study did not allow that because of the pure test of pertuzumab, I know, but ASCO guidelines have endorsed that. Shanu?

Dr. Shanu Modi:

And part of that is based on the PERUSE trial, which was a real-world study. They looked at different taxane backbones, but one of the things that patients were allowed to do was to get endocrine therapy in that HP maintenance. It’s obviously not a statistical analysis, but very descriptively you saw that those patients do really well. There may be something to it, although we may not definitively test it in a trial today. I think it’s become a pattern of practice.

Dr. Chau Dang:

Right? Exactly. As we expect, she did extremely well. She had a maximum response around 6 months. The taxane was stopped. PET scan showed no disease, and we stopped the taxane and added letrozole, and she was monitored doing quite well. But at 3 years, she began to have symptoms again, and her systemic staging scan showed she had progression in the lungs and the liver, unfortunately. What would we do next? As far as second-line therapy: Is it now switching to T-DXd, or do we just give back the taxane? Stop the letrozole, give the taxane because she didn’t fail the taxane. Can we just give back the taxane, or do we switch to the HER2CLIMB regimen tucatinib, capecitabine, and trastuzumab? Shanu, what would you do here? Now we’re looking for the best second-line option.

Dr. Shanu Modi:

There’s an art to practicing in patients with stage VI disease. I don’t know that we can be dogmatic because you could make a reasonable case for any one of these. But I think if you really want to look at today where our best data lie, it really is with a switch to T-DXd. I think Anthony alluded to that earlier when talking about the DESTINY-Breast03 trial. In the second-line HER2-positive metastatic space, it’s really been dominated by ADCs up until now. Our preferred second-line therapy following first-line TH or THP has been the ADC T-DM1. That was based on the EMILIA trial, which was largely a second- and third-line study back when it was conducted. At that time, patients who had progressed in first-line therapy with a taxane trastuzumab were randomized to second-line treatment of either capecitabine plus lapatinib, which was standard back then, or this new drug T-DM1. And T-DM1 was far more effective, survival advantage, and it had a favorable safety profile.

It really fulfilled the promise of ADC therapy, and it was our standard for almost 10 years. Then, of course, came along the new generation ADC T-DXd, and it has some properties that really differentiated from T-DM1, and I think allow it to overcome some of the barriers of T-DM1. The big landmark study in HER2-positive metastatic breast cancer today is the DESTINY-Breast03 trial. This is a head-to-head comparison now of these two ADCs: T-DM1 vs T-DXd. A really big study. And I think we’ve all seen those progression-free survival curves. They’re dramatic, and you see such a significant advantage for T-DXd over T-DM1. It’s really hard not to notice the quadrupling of the progression-free survival. We just don’t see that very often. Median PFS with T-DM1 was 7 months. With T-DXd it was almost 29 months.

We’ve also now seen in the follow-up from that study there is a survival advantage. Thankfully, neither arm has reached median OS yet. We’d love that number to be a very high number for both arms, of course. There’s a consistent 8% survival advantage at the 1-year and 2-year follow-up points on the DESTINY-Breast03 already. I think when you combine that with the safety profile, DESTINY-Breast03 really set the bar, and I think referring to the ILD that Anthony mentioned, that’s a real risk with T-DXd. But in that trial, the investigators showed us you can deliver this drug very safely. They had mostly low-grade ILD events. There were no grade 4 events. There were no deaths from ILD on that trial. With vigilance, with awareness, with prompt intervention, you can give it very safely. I think T-DXd is probably one of the most active HER2-targeted therapies today, and I would certainly use that next in this patient. While we await the results of DESTINY-Breast09, as we said, now that’ll be the head-to-head comparison of T-DXd to our current gold standard THP. I think we’re all excited to see that outcome.

Dr. Chau Dang:

Absolutely. I would agree there. Anthony, do you have a different answer or do we all agree here, in the second line?

Dr. Anthony Elias:

No, I’m afraid I think the DESTINY-Breast03 is just a “wow” study in terms of the activity. Certainly, the HER2CLIMB regimen has some data in the second line, but I would say it was more in a special population, and I would use T-DXd. I think it’s important to point out that the antibody is the same as trastuzumab, but the toxin is a Topo-1 inhibitor. Basically, we know that Topo-1 inhibitors as free drugs are active in fourth-line breast cancer. Part of the problem for T-DM1 is all the patients have been exposed to an antitubulin in the form of a taxane. There’s probably some intrinsic resistance that’s already developed, whereas with deruxtecan, the breast cancers have not seen that toxin before. When we’re talking about sequential use of ADCs and so forth, I think we have to really keep in mind both the target of the antibody but also the toxin.

Dr. Chau Dang:

Great. Thank you so much. I’m going to target this question to both of you and starting with Dr. Elias. We’re going to change the scenario a little bit. It’s the same patient, first-line therapy, THP, doing great, transitioned from THP to HP and letrozole. But year 3, she started having headaches that prompted her oncologist to order brain MRI, which unfortunately showed two brain lesions about 2 to 3 mm with edema. Repeat PET imaging showed no evidence of disease, extracranially. She was sent to radiation oncology who recommended to offer SRS to these lesions. She comes back to us, and the next question is what do we do with her systemic therapy? She’s essentially NED extracranially. Do we just continue the HP and letrozole because the treatment didn’t fail her outside of the brain? Or do we switch to the HER2CLIMB regimen, tucatinib plus capecitabine and trastuzumab? Or do we switch to T-DXd? Dr. Elias, what are your thoughts here? We see these patients, and there are certainly options that are reasonable here. What would you do?

Dr. Anthony Elias:

To a certain extent, all three options are not unreasonable, because SRS has a very good track record in taking care of whatever brain lesions you’re looking at. But if you’re looking at the risk of new brain metastasis, then I would switch therapy. In general, in this case, I would treat with either T-DXd or the HER2CLIMB therapy. The HER2CLIMB trial did accrue patients who had brain metastases that were not treated with radiation and showed a fairly significant response. Most of the data for T-DXd is a retrospective type of analysis. Again, I am personally impressed with T-DXd with regard to its overall anti-HER2 breast cancer activity. I usually would use T-DXd and am quite comfortable with the toxicities.

Dr. Chau Dang:

Shanu, how would you approach with this case?

Dr. Shanu Modi:

These cases are challenging. Typically, as Anthony said, we make these decisions in a multidisciplinary team. We get our radiation colleagues involved, our neuro-oncologists involved, and even the neurosurgeon sometimes. Traditionally, for very limited CNS involvement, we have been able to offer these patients SRS and then continue their systemic therapy. If they still have great systemic control of their disease, in some ways, we’re motivated to try to keep them on the same systemic therapy. I think that is a very standard approach used commonly today, and I think that’s very reasonable. You’re right, we are now in an era where we have these really exciting HER2-targeted drugs that are also showing great activity for CNS disease. Both tucatinib and T-DXd on that front have great data. I think perhaps our best data are from the HER2CLIMB trial, where half the patients they enrolled in that study had brain metastases, and a majority or large proportion were with active brain metastases, either treated and progressing or untreated, not that dissimilar to this patient.

They showed that you could see responses. The intracranial response rate was almost 50% with the tucatinib regimen. Those patients who got tucatinib with brain metastases had an absolute survival advantage of 9 months on the tucatinib arm. Those with active brain metastases had almost a 10-month survival advantage on the tucatinib arm. We really saw some of the best data we’ve seen ever for a systemic agent in treating the brain from that study. We are now seeing a growing body of data also for T-DXd. All the DESTINY trials included a small number of patients with brain metastases. Most of them were stable with brain metastases, but we saw a very nice pooled analysis of all these studies at ESMO this past year. The response rate intracranially is almost 45%, whether they’re stable or active brain metastases with T-DXd.

Now, we’ve also seen a number of small studies, the TUXEDO-1 trial, the DEBBRAH trial, and even some institutional experiences have been reported. We’re seeing response rates in the brain for T-DXd ranging from 45% to 75%. We’ve certainly suddenly got options available, systemic options for treating brain metastases. I do think one could make a very rational decision to treat this patient with HER2CLIMB with T-DXd. I may be more tempted in this case specifically to use local therapy and try to preserve some of these treatments for a later time. One of the things that would really help us as oncologists is to have a way understanding which patients are going to continue to have CNS as their main site of progression. We may be more motivated to switch therapy in those cases. There are some interesting ongoing trials right now. The BRIDGET study is a great example of that.

It would be perfect for this patient actually, if we could put her on the BRIDGET trial. It is for patients who are being maintained on their trastuzumab and pertuzumab who develop an isolated brain lesion, and after treatment, they then have tucatinib added to their HP. That would be a perfect study for a patient like this.

Dr. Chau Dang:

Great. With all these drugs available, it’s just such good news to know that we’ve got options that actually cross the blood-brain barrier, so our patients can be treated because more patients are progressing to the brain, not their body. It’s truly an unmet need. Before we close, I’d love to hear Dr. Anthony Elias, your thoughts on HER2-mutated cancers. These cancers are traditionally HER2-negative, and when we profile them, we find HER2 mutations. What do you do? What options do we have for them?

Dr. Anthony Elias:

This is an emerging area, and of course, as you know, the NCCN Guidelines point out specific mutations that are actionable, where we have strong data to say this can drive our treatment decisions. HER2 is still in the disciple arena. HER2 mutations occur only in about 1% to 1.5% of invasive ductal carcinomas. They’re typically acquired. They’re much less common in primary tumors. This would be considered an acquired mutation but particularly prevalent in invasive lobular carcinoma that is metastatic, where you can see a 7% or even 10% mutation rate. They are seen both in HER2-negative, those FISH-negative, IHC-low, as well as HER2-positive tumors treated previously with anti-HER2 therapy. They are felt to be resistance mechanisms. Again, we do have phase II data suggesting neratinib, in particular, is an active agent, with response rates in the 30% to 40% range, and in preclinical testing, tucatinib also has significant activity and is currently in clinical trials in this arena.

I will say that the antibody-drug conjugates also have activity, because most of these tumors are going to be at the very least, HER2-low, or in the case of a HER2-positive tumor that developed this mutation, it’ll be expressing the antigen. Antibody-based therapy does work in these also, although there’s much less clinical information based on the fact that they block the signaling of HER2 by degrading the receptor on the cell surface, so it’s not only the antigen density that’s required. This is an area I do expect that will become a fully fledged actionable mutation in the near future, once we get a little bit more data.

Dr. Chau Dang:

Great. Thanks so much. Well, it’s been wonderful. This brings us to the end of our discussion of three case studies in the management of patients with HER2-positive breast cancer, with a focus on selecting among combinations of monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors in different clinical scenarios. I would like to thank my colleagues, Dr. Elias and Dr. Modi, for participating in this important clinical conversation and for sharing their expertise with us today. Thank you so much.