Krop Captures 2021 Breakthroughs in Metastatic HER2+ Breast Cancer

Supplements And Featured Publications, 2021 Year in Review: HER2+ Breast Cancer, Volume 1, Issue 1

Ian E. Krop, MD, PhD, discusses highlights from 2021 in HER2-positive breast cancer and expectations for future research in 2022.

One theme of 2021 in HER2-positive breast cancer that will carry into 2022 is the progress that has been made for patients with brain metastases with agents such as tucatinib (Tukysa) and fam-trastuzumab deruxtecan-nxki (Enhertu), explained Ian E. Krop, MD, PhD, who added that the next step will include the investigation of these agents in the early-stage setting and a careful look into the populations who can benefit from de-escalated therapy.

“We still have to work on patients with brain metastases. The regimen from the HER2CLIMB trial [NCT02614794] with tucatinib showed the possibility of real significant progress. Now, we need to keep building upon that. The other real area [of improvement we need to address] is trying to de-escalate therapy. That’s why there are trials like the compassHER2-pCR study [NCT04266249] and the Decrescendo trial [NCT04675827] in Europe,” said Krop.

In an interview with OncLive®, Krop, an associate professor of medicine, Harvard Medical School, associate chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, medical oncologist and clinical research director, Breast Oncology Center, Dana-Farber Cancer Institute, discussed highlights from 2021 in HER2-positive breast cancer and expectations for future research in 2022.

OncLive®: What was the recurring theme in HER2-positive breast cancer in 2021?

Krop: What we are continuing to see is better and better drugs in the metastatic setting that are pushing the needle in terms of improving efficacy. Progression-free survival [PFS] is getting longer and longer, and that’s really encouraging. We are now getting to the point, and this might be wishful thinking or overly ambitious, where we could even think about trying to look for long-term disease control, even theoretically curing patients with advanced HER2-positive breast cancer by leveraging the highest degree of efficacy with these antibodies, the antibody-drug conjugates [ADCs], and the TKIs, such as tucatinib.

By sequencing these agents together [we could] potentially eradicate all clones of metastatic disease and theoretically cure patients. The amount of progress that has been made in the advanced disease setting is remarkable and reflects on an enormous number of people who are working hard on this area and the number of patients who have been willing to go onto trials. In the metastatic setting, there has been a lot of progress.

Reflecting on the 2021 San Antonio Breast Cancer Symposium, what datasets stood out to you in the HER2-positive realm?

[The 2021] SABCS was perhaps a little slower in the HER2 world than some other meetings because [the large studies] seem to come in bunches, but there were data that Sara Hurvitz, MD, of UCLA, presented––an update of the DESTINY-Breast03 trial [NCT03529110]. This trial was looking at patients with HER2-positive metastatic breast cancer who had previously had a

taxane and HER2-directed therapy. This study was largely looking at a second-line patient population. Patients were randomized to the current standard of care, which is ado-trastuzumab emtansine [TDM-1; Kadcyla] vs trastuzumab deruxtecan.

We had previously seen the initial results from this trial at the 2021 ESMO Congress, which were highly encouraging, showing a remarkable improvement in PFS with trastuzumab deruxtecan vs TDM-1. We know that TDM-1 is an active drug in this population, yet the trastuzumab deruxtecan arm did dramatically better with a hazard ratio of 0.28, which is probably the best hazard ratio we have ever seen in a registrational trial in pretreated patients. So, we knew this trial had shown that trastuzumab deruxtecan looked very effective in the second-line population. The data that Dr Hurvitz presented was an update of that trial and included some more data.

The thing that really stood out [from that dataset] was that the investigators looked at the patients who had brain metastases at baseline, and not only did those patients seem to see that same kind of superiority of trastuzumab deruxtecan over TDM-1 as was seen in the whole population, but there did look to be clear responses in the brain, so intracranial responses with trastuzumab deruxtecan. Those data are fitting with some other data that are emerging, suggesting that trastuzumab deruxtecan can have efficacy in the brain for patients with HER2-positive brain metastases.

That goes along with some other data we have seen with TDM-1 as well, showing that even though these molecules are quite large, and theoretically aren’t supposed to be able to cross the blood-brain barrier, that they still seem to have activity in patients with brain metastases. That’s probably because the blood-brain barrier is broken down when there is a metastasis there. These are very encouraging data because we know that brain metastases are quite common in patients with HER2-positive advanced disease. Knowing that these very effective drugs can have efficacy within the brain is good news for patients, and we are hoping that there will be additional data coming out from these trials and specific trials for patients with brain metastases in the next 1 to 2 years.

What is your hope for research in 2022?

In the next few years, we are hoping that we are going to start seeing the results of some of the trials that were started in 2021 or 2020, which are taking some of these highly effective drugs and using them in the early disease setting.

There are 2 trials going on in patients who have residual disease after neoadjuvant treatment where we are trying to take this population, which we know is at higher risk for recurrence and add other HER2-directed therapy [onto their standard therapy]. There’s a trial adding tucatinib to TDM-1 in that situation. [Other studies are] looking at these highly effective ADCs, such as trastuzumab deruxtecan to see whether that is superior [to TDM-1] in that early disease setting, just like it was in the metastatic setting. There’s a trial looking at trastuzumab deruxtecan in patients with residual disease, as well. I’m hoping that we are going to not only make progress in the metastatic setting. The next real place to make true breakthroughs is in further reducing the risk that patients will develop metastatic disease in the first place, so we don’t have to worry about it [down the line]. Those are the 2 areas of real excitement for this patient population.

Apart from moving some of these highly effective therapies into earlier stages of disease, what would you like to see take a bigger focus in 2022?

We are now curing most patients with early-stage, HER2-positive disease. If you look at the most recent randomized trials in the early disease setting, like APHINITY [NCT01358877] or KAITLIN [NCT01966471], we are seeing disease-free survivals at 3 years of well over 90%, and these are high-risk patient populations, so we are curing most patients right now, even those who present with high-risk disease, so that’s great. That also means we are probably over treating a lot of these patients. Progress has been made looking at the trastuzumab [Herceptin]/paclitaxel regimen, which was shown in the APT trial [NCT00542451] in patients with stage I cancers to be completely sufficient to lead to very good outcomes. This is certainly a less toxic regimen than TCH [docetaxel, carboplatin, and trastuzumab] or AC-TH [doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab]. Now, can we build upon that?

We know the patients who have a pathologic complete response [pCR] to HER2-directed therapy tend to do very well, so the idea is, let’s treat patients with stage II/III disease with neoadjuvant therapy but with less chemotherapy because it’s the HER2-directed therapy that’s doing most of the work. Let’s back off on the chemotherapy and take advantage of the ability and the efficacy of HER2-directed therapies. These trials are looking at treating patients with just 12 weeks of a taxane with trastuzumab and pertuzumab [Perjeta; HP]. Patients who have a pCR won’t get any more chemotherapy and will just continue with the antibodies to try to get by with a much less intensive chemotherapy regimen and ride the backs of these antibodies to cure them. We see that with neoadjuvant taxane/HP, the pCR rates are over 50%. If these studies validate that these patients who are treated this way and have a pCR do well, then for most of our patients with HER2-positive disease, we can get rid of these multi-agent chemotherapy regimens and just use a little bit of chemotherapy with HER2-directed therapy, which will be a real benefit for our patients going forward.