Current Advancements in HER2+ Breast Cancer Management


Erika P. Hamilton, MD: At the San Antonio Breast Cancer Symposium in 2019, it was a big year for HER2+ breast cancer. At the session where tucatinib was presented, we had simultaneous publication in the New England Journal of Medicine; there was actually another HER2 drug that was also simultaneously presented and published in the New England Journal of Medicine as well; this is DS-8201 or otherwise known as trastuzumab deruxtecan. This is an antibody drug conjugate, so not unlike a drug like T-DM1 [trastuzumab emtansine], where chemotherapy is bound to the antibody. This is a little different. It has a different payload. It carriers a different number of molecules on it, but it’s that same mechanism of action. We first became excited about trastuzumab deruxtecan 2 years ago at ASCO [American Society of Clinical Oncology Annual Meeting], when they reported phase I results showing quite an impressive clinical benefit rate of over 90% in a phase I population.

They presented results at this meeting for DESTINY-Breast01. Again, this was a heavily pretreated population of HER2+ patients who had seen a median, or an average, of 6 lines of therapy in the metastatic incurable setting. With that, they saw a quite impressive progression-free survival of over 16 months. They also saw a duration of benefit, so the trial is essentially asking the question: For those patients who did well on it, how long did they do well, how long did the response last? It was 14.8 months. It’s very unusual in this space for heavily pretreated patients to get benefit from 1 drug for over a year.

The advances that we’ve seen this year at San Antonio for HER2 I think trump what we’ve seen in triple-negative probably and HER2+. We’ve certainly finally come to the scene with immunotherapy for triple-negative breast cancer, which has been very exciting to see, both the atezolizumab in the first-line metastatic setting and the recent results of KEYNOTE-522 with pembrolizumab in the neoadjuvant setting. But having both tucatinib and trastuzumab deruxtecan reported at this meeting, again 2 New England Journal of Medicine publications, was really outstanding. It was a huge leap forward for HER2+ disease.

The unmet needs in HER2+ metastatic breast cancer are changing a little bit. One thing is that we have highly effective agents. We have pertuzumab, which is relatively new. We have T-DM1 [trastuzumab emtansine], which is relatively new. These agents are being used more and more in the early-stage setting, so we commonly give a regimen called TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab], a chemotherapy combination with trastuzumab and pertuzumab in the neoadjuvant or before-surgery setting. T-DM1 [trastuzumab emtansine] now, based on the KATHERINE data, is indicated for adjuvant patients who don’t receive a PCR [pathologic complete response] neoadjuvant therapy.

As we think about it, if pertuzumab is being used neoadjuvantly and T-DM1 [trastuzumab emtansine] is being used adjuvantly, for those patients who relapse quickly, they’ve kind of already exhausted what we would traditionally give them in the first and second line. These so-called third-line HER2 regimens are really being effectively moved up for many patients. There’s a huge unmet need for not only brain metastases patients and drugs that can cross the blood-brain barrier to enable those patients to continue to do well but also just new agents in general, as we take our superstar agents and pull them up into the earlier settings.

The HER2 treatment landscape is evolving. Things really started changing with KATHERINE, when we realized that we can define a high-risk population in the early-stage setting with HER2+ patients not by what they initially present as. We used to think about how big the tumor was and if the tumor node was positive. That kind of defined our high-risk subgroup. We looked at trials and drugs like neratinib and pertuzumab in that scenario, based on the initial characteristics, and we saw some benefits, but they were small.

What was different about KATHERINE was we gave our therapy up front and then designed the trial for those patients who did not have a pathologic complete response at the time of surgery, meaning that there was still cancer left in the breast or the lymph nodes under the armpit at that time. Then we allowed those patients either to continue their year of HER2 antibodies or to get T-DM1 [trastuzumab emtansine]. What we saw was an over 10% improvement of disease-free survival in that setting.

We’re getting smarter about learning how to define our HER2 high-risk population and who needs additional therapy versus who doesn’t. I also think that since pertuzumab is being used neoadjuvantly and T-DM1 [trastuzumab emtansine] is being used adjuvantly for those patients who don’t have a pathologic complete response, that we’re moving up some of our traditionally thought of metastatic regimens early line. So it’s very exciting to have new agents in the metastatic setting to use for these patients.

If I had to leave you with 1 pearl, it would be the power of clinical trials. I’ve had tucatinib in my clinic, the Sarah Cannon Research Institute, since 2014, for a population that otherwise really had no standard therapy and where patients did not do well. I think sometimes there’s a hesitancy to use clinical trials, that we think these drugs aren’t proven. I can tell you across the board and particularly in the HER2 arena, there are a lot of exciting drugs out there. I would really encourage providers and patients to look and see whether they might be eligible for clinical trials. I think patients really do well there, and I would love for more people to get the benefits of seeing new agents quicker.

Transcript Edited for Clarity

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