ESMO Breast 2021 | Decision-making in metastatic HER2+ breast cancer

At this “Decision-making in metastatic HER2+ breast cancer” session, I had the pleasure of giving the kick-off talk on treatment approaches for metastatic breast cancer that’s HER2+ in 2021. This is a key arena to keep revisiting because of all the changes. We now have eight drugs that are FDA approved in the HER2+ space, and many, many trials that have been reported and are in the process of being performed. And for the treating oncologist, this is a very complicated space.

I think that the, to my mind, and what I talk about a little bit is there are options that are driven by HER2 and are shared across hormone receptor negative/HER2+ and hormone receptor positive/HER2+, but it’s also completely well-known and established that there are the endocrine approaches can be incorporated with HER2 targeting in addition to the others.

So briefly, in general, particularly for hormone receptor negative HER2+ breast cancer, the standard bearer has been THP or taxane plus trastuzumab and pertuzumab. That is still the case. And that is the case based on a really stunning 16-month overall survival advantage in CLEOPATRA.

The second line therapy at the moment is trastuzumab emtansine, which has been studied in multiple trials and performs extremely well. What has come out recently are the tucatinib based approaches. The HER2CLIMB study demonstrated that tucatinib plus capecitabine plus trastuzumab was extremely active. And, in that study, which deliberately included active brain metastases, it showed really a very, very strong activity in patients, even those with progressive or untreated brain metastases.

And then finally, the most recent newcomer is trastuzumab deruxtecan, or T-DXd, has really been studied primarily in a single arm, large study trial, but with incredible activity. Some concern about interstitial lung disease, which needs to be kind of managed, and so I think where it lives is going to evolve very quickly as subsequent trials, particularly randomized trials, come out.

In the hormone receptor positive/HER2+ space, along with those options, you have a variety of endocrine based options with HER2 targeting added on, such as, you know, AIs plus trastuzumab and pertuzumab. Or later on, any other endocrine therapy plus either small molecules, trastuzumab, or both.

So, we have quite a lot of options and I think we go through all of these and we actually create an algorithm that I think will probably change quickly. 2022 may be a different algorithm, but one that I hope is helpful for treating oncologists around the world.

Among the challenges that we face, you know in the talk I give algorithms as I perceive them now, but these aren’t very straightforward. In truth there’s a very valid question of if you have a patient with CNS dominant disease – and we should all recognize that the brain is a setting of particular challenge and Dr Bachelot actually has a lovely talk on that in this session – should tucatinib and tucatinib based approaches move up, and be used earlier in lines of setting.

I think as tucatinib has come in, you know, it was tested against placebo in the HER2CLIMB study, when added to capecitabine and trastuzumab. What does that mean regarding the activity in a tucatinib-treated patient for other small molecules with activities such as neratinib, which also appears to have some improvement in CNS end points compared to older drugs?

I think the main challenge for those of us who want to use the most active drugs is also, where is T-DXd or trastuzumab deruxtecan going to end up and how are we going to manage the interstitial lung disease problem, which appears to be about 14%? And unfortunately, treatment related deaths, we’re seeing in the DESTINY-01 trial.

So, I think all of these will be sorted out over the upcoming years, but those of us treating patients right now, these are challenges that we have to think through. Personally, the algorithm that I outlined is one that I use in general, but I think there’s a lot of heterogeneity in HER2+ breast cancer and certainly treatment decisions can be made on a case-by-case basis.

On the other hand, so we’ve talked about challenges. There’re also opportunities that I think have become clear. We have so many incredibly effective drugs against HER2+ metastatic breast cancer. And all of us have had the experience of treating patients who do incredibly well for an incredibly long time. It does raise the question of, do we have a curative intent opportunity here, because the drugs are so effective? And actually, Eric Weiner is going to take on that provocative question. And I’m very much looking forward to it.

I’d like to also point out that Alex Pratt is going to give actually a really interesting talk that may show us the way forward regarding the biologic heterogeneity of HER2+ breast cancer and how that may affect some of our treatment decision making in the future. So, stay tuned.