Overview of the management of HER2-low breast cancer patients

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Published: 3 Feb 2023
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Prof Hope Rugo - University of California San Francisco, San Francisco, USA

Prof Hope Rugo speaks to ecancer about the management of HER2-low breast cancer patients.

HER2 detection tests can only tell if a patient is HER positive or negative but they don't detect the range of HER2 expression in a patient which Prof Rugo says is important to know when choosing the best treatment option for the patient.

Prof Rugo explains that there are new protein assays that can help detect the expression much better and that is something to look forward to in the near future.

She further talks about all the studies regarding ultra-low HER2-positive breast cancer and how they can be practice-changing.

We also talked about some of the other issues that are facing us and we had a special session where we talked about HER2-low and how we define HER2-low. That’s really important – there’s a lot of controversies around that. We see this hugely variable expression of HER2; the tests were not designed to really detect the difference between 0 and 1+, or 1+ and 2+ for that matter. Really it was designed to detect HER2 positivity versus negativity. So, there are new techniques that are being developed to try and look at protein expression more reliably and it will be fascinating to see how those come about.

Also, there is a study looking at patients who have ultra-low HER2 positive disease. So not 0 but not 1+ by ASCO/CAP guidelines but somewhere in between. DESTINY-Breast06, that also will be very interesting although it’s an exploratory endpoint. 

There were many, many studies presented at San Antonio that we reviewed in our panel to try and really think about how we should be dealing with HER2-low at present. Should we use HER2-low being positive in any tumour sample at any time as our indicator for eligibility for treatment with T-DXd? So, if you had a positive tumour five years ago but all of your biopsies in the metastatic setting are negative, 1+ then, 0 now, does it matter? Could you use the archival tumour result? It’s hard to know. 

Data that was presented by Aleix Prat at San Antonio looking at the tumour samples that were submitted for DESTINY-Breast04 found that patients seemed to benefit regardless of whether their HER2-low positivity was found in the archival sample or in the metastatic tumour sample and regardless of the origin. But I think we really need to do more work to understand that. It is possible that if you have liver metastases that are your dominant site of disease and that is really 0 that you are less likely to benefit from T-DXd. I have a handful of patients that have had zero response and I think going back and really understanding the biology of those cancers will be really important moving forward as well as how long ago that HER-low status works to predict response.

We talked about some of the other antibody-drug conjugates that are in the wings and I think the most important third antibody-drug conjugate is datopotamab deruxtecan. It uses deruxtecan, the topoisomerase inhibitor, similar to T-DXd, and we call this Dato-DXd because it’s a long name, but it’s a TROP2 directed antibody different from sacituzumab. It’s also given once every three weeks as opposed to being given day 1 and day 8 like sacituzumab govitecan. The agent itself has been tested in a number of different settings but the most important is the phase I TROPION, Pan-TROPION, trial where it has been tested in both HER2 negative triple negative, essentially, disease and hormone receptor positive disease. The results in the triple negative group were fairly striking with very nice response rates that were very durable. Responses are a little lower in hormone receptor positive disease but also quite durable. What’s fascinating is that you see nausea, like you see with T-DXd, but the one toxicity we don’t see with T-DXd is stomatitis. So really interesting. We’ve been using a steroid mouthwash in our neoadjuvant I-SPY trial with remarkable control of the stomatitis. We still do see patients with stomatitis and, interestingly, if they have stomatitis when they get Dato-DXd and they go on to other therapies, sometimes the stomatitis is very slow to resolve. So that’s going to be something we’ll have to focus on as well.

These data from the Pan-TROPION trial led to two phase III trials in the second or third line setting. In hormone receptor positive disease the TROPION-1 trial which already has completed accrual looking at Dato-DXd versus chemo of physician’s choice, and in the first-line metastatic triple negative setting in a trial that’s currently accruing, again with a similar comparison. 

There is also interest in whether or not antibody-drug conjugates can be combined with immunotherapy and a number of studies have looked at single-arm trials. The BEGONIA trial looked at Dato-DXd and durvalumab, a checkpoint inhibitor, in patients with triple negative disease in the first line setting and they also looked at T-DXd with durvalumab in patients who had HER2-low triple negative disease in the first line setting. Both of these combinations resulted in really remarkable  responses, quite high, and they were extremely durable. Very similar toxicities, maybe a little enhancement because of the immune toxicity. There was, for example, pneumonitis seen with the Dato-DXd durvalumab combination where you don’t see it with Dato-DXd alone. But overall the results were quite encouraging. We just don’t know if durvalumab added anything but that will be explored in additional studies.

Then sacituzumab is being combined with pembrolizumab in the post-neoadjuvant setting and in a first line exploratory trial out of Dana-Farber in both triple negative and hormone receptor positive disease and in a randomised phase III trial in the first line triple negative setting where patients have PD-L1 positive disease. 

A lot of trials going on and a lot of discussion about HER2-low and how we define it. One big question comes up about how we sequence antibody drug conjugates: if you use T-DXd first will sacituzumab be effective next? And the reverse, for example, in triple negative disease and what order we should be using these agents in. Here in Egypt and the Middle East a big discussion was can these agents replace sequential endocrine therapy which we believe no, these are chemotherapy agents, they have chemotherapy toxicities and we should be giving them after you’ve had response and then progression to sequential single agent or endocrine therapy combined with a targeted agent, really following the international guidelines. For the moment, these agents are only approved in the second line setting. 

There was data recently presented and published by myself and then with an updated overall survival analysis of using sacituzumab govitecan in hormone receptor positive disease in patients who had received a median of three lines of prior chemotherapy, so very heavily pre-treated. Similar to the EMBRACE trial that looked at eribulin and, of course, about 50% of patients with the treatment of physician’s choice received eribulin in the TROPICS-02 trial versus sacituzumab. We showed an improvement in progression free and overall survival as well. So this further increases the question about sequencing of antibody drug conjugates. T-DXd is approved, of course, in HER2-low disease regardless of receptor, sacituzumab in triple negative disease and sacituzumab for hormone receptor positive disease should have a ruling by the FDA in February of 2023.