Improved Patient Selection Will Pave the Way for ADC Optimization in HER2-Low and -Ultralow Breast Cancer

Erika P. Hamilton, MD

Findings from the phase 3 DESTINY-Breast06 trial (NCT04494425) reinforce the expanding role of HER2-targeted antibody-drug conjugates (ADCs) for treating patients with hormone receptor (HR)–positive, HER2-low or -ultralow metastatic breast cancer, prompting a reevaluation of criteria for identifying candidates for HER2-targeted therapy, according to Erika P. Hamilton, MD.

“We stand at a place for HR-positive disease where [the majority] of patients are going to have some HER2 expression. At some point we have to ask ourselves, ‘Who isn’t appropriate for this therapy?” Hamilton said in an interview with OncLive^®.

At the 2024 ASCO Annual Meeting, results from DESTINY-Breast06 showed that patients with hormone receptor (HR)–positive, HER2-low or -ultralow breast cancer who were naive to chemotherapy in the metastatic setting experienced a significant improvement in progression-free survival (PFS) with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) vs physician’s choice of chemotherapy. In the HER2-low population, patients treated T-DXd (n = 359) achieved a median PFS of 13.2 months per blinded independent central review assessment vs 8.1 months for those treated with chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; P <.0001).

PFS benefit was also observed with T-DXd among patients with HER2-ultralow disease (HR, 0.78; 95% CI, 0.50-1.21), and in the intention-to-treat population comprising patients with both HER2-low and -ultralow disease (HR, 0.63; 95% CI, 0.53-0.75; P <.0001). This finding is particularly important as it broadens the potential patient population that could benefit from T-DXd, challenging previous assumptions about the necessary HER2 expression levels for effective treatment, Hamilton noted.

In the interview, Hamilton discussed the implications of the DESTINY-Breast06 trial in HER2-low and -ultralow breast cancer; the limitations of using immunohistochemistry (IHC) staining to identify HER2-low or -ultralow breast cancer; unanswered questions about sequencing ADCs for select patients; and key considerations for managing associated adverse effects (AE).

Hamilton is the director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute in Nashville, Tennessee.

OncLive: What are some of the key implications of data from the DESTINY-Breast06 trial for the HER2-low breast cancer paradigm, and how has this study differed from prior research in HER2-low disease?

Hamilton: There were 2 main differences in DESTINY-Breast06 compared with DESTINY-Breast04 [NCT03734029], which was our other [phase 3] trial that looked at HER2-low breast cancer. The first was that [DESTINY-Breast06 included patients receiving] first-line cytotoxic therapy, so it didn’t require [exposure to] a previous cytotoxic [regimen] like DESTINY-Breast04 did. The second was the inclusion of a patient population called HER2-ultralow. That’s [defined as] an IHC result of 0 with less than 10% staining.

When we looked at the HER2-low [population], median PFS, which was the primary end point was 13.2 months [with T-DXd] vs 8.1 months [with chemotherapy]. When we specifically look at that group of patients who were HER2-ultralow, the results were similar, with a median PFS of 13.2 months vs 8.3 months. My takeaways are that we can go even lower [in our threshold for HER2 expression] for T-DXd in terms of activity, [because] it’s clearly beating chemotherapy in these patients. The second is that this is a drug that’s likely much more reasonable to use earlier. We don’t necessarily need to use intervening cytotoxics before we use it. It is important to note, though, that this does come after endocrine therapies, so 85% of patients had received at least 2 prior lines of endocrine therapy. We should exhaust our endocrine therapies before we move to antibody-drug conjugates, which I see as a chemotherapy substitute.

How has T-DXd’s development differed from that of other ADCs?

The data there are compelling in terms of the [improvement in median PFS with T-DXd]. Our drug development for T-DXd was driven by the fact that it was [targeting] HER2. For our other TROP2- and HER3-targeting ADCs, we really aren’t testing for that marker. We were pigeonholed a bit by thinking we understood HER2 when we started in high [HER2-expressing tumors], went to HER2-low [tumors], and now [are evaluating HER2-targeted agents in this] HER2-ultralow [category].

What are some of the challenges and limitations of using IHC to identify HER2-low or -zero breast cancer?

IHC was designed to identify patients with HER2-positive [breast cancer]. It was never designed to pick out 1+ or 2+ expression, and certainly not IHC 0 with less than 10% staining. The challenge is pathology concordance. When we look at different samples picking out this HER2-low disease, if you move around the tumor sample, there’s going to be some heterogeneity. We certainly know that there’s heterogeneity from one lesion to another. At the 2023 ASCO Annual Meeting, there was a fantastic presentation [showing] that if we biopsy a patient 4 or 5 times, we’re guaranteed to get a HER2-low result. It gets back to this question of, ‘Do we need to be doing all these repeat biopsies?’ Or is this a drug that, with what we know about HER2 heterogeneity, most patients should have an option of receiving at some point?’

What unmet needs in HER2-low or -ultralow disease still need to be addressed through further research?

That question gets at ADCs in general. Post-T-DXd is a great [setting in which] to think about what we’re going to be doing next. I certainly think that there’s room for another HER2-directed ADC. What we’re learning about these ADCs is that they may hone the molecule to the right place where the cancer cells are, but then it really behaves like chemotherapy, so one can imagine that we could be using these agents sequentially. What we’re seeing in terms of ADCs, though, is that the benefit with the second ADC is not as great as the first. Part of this shouldn’t be surprising, because for each line of therapy, PFS does tend to drop quite substantially. [We should really be] looking at both the target as well as the payload and looking at what ADCs may come next.

As novel ADCs continue to emerge, how will you navigate the increasingly complicated question of ADC sequencing in breast cancer?

Unfortunately, I don’t think we have a great tool to tell us who is appropriate for that second ADC or not. Right now, we know that ADCs beat chemotherapy. The question is whether, with a shorter PFS, that second ADC is still going to beat chemotherapy. My guess is yes. Whether we talk about intervening therapy, or whether we make sure that we have an ADC with a different target and a different payload, these are all hot topics right now.

What should community oncologists know about the safety profile of ADCs, and what advice do you have regarding how to approach toxicity management?

I caution [my colleagues] to not think of all ADCs as a class in terms of adverse effects [AEs]; they’re quite unique drugs. Sacituzumab govitecan-hziy [Trodelvy] has a very different AE profile, with low counts and diarrhea compared with T-DXd where we must worry about nausea and then the possibility of interstitial lung disease [ILD]. There was concern when T-DXd was first coming out about fatal cases of ILD and their frequency. We know that 10% to 15% of patients who receive T-DXd will experience some grade of ILD. Luckily, with increased monitoring and recommendations, we’ve been able to all but eliminate those fatal cases.

The biggest AE day-to-day for T-DXd is nausea. We have to remember that when these trials were going on, mandatory anti-emetics were not required. At least a 2, if not a 3-drug anti-emetic prophylactic regimen is now recommended by the National Comprehensive Cancer Center, ESMO, and ASCO guidelines [for administration] upfront, before anyone has any symptoms. For my patients, this works quite well in the clinic. It’s very rare that patients experience any significant nausea after this regimen, and if they do, I find that olanzapine at night works well for those patients.

What is your main message for colleagues regarding the evolving treatment paradigm in HR-positive breast cancer?

It’s important [to emphasize], particularly for community physicians who may not have the opportunity to use ADCs, that these drugs are effective. We now have 3 ADCs approved in breast cancer. We all need to become familiar with using these, whether we’re talking about sacituzumab govitecan, ado-trastuzumab emtansine (Kadcyla), or T-DXd. Overall, this is an exciting time for breast cancer.

Reference

Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000