Integrating the Latest Data Into Best Practices for Patients With HER2+ Breast Cancer

Nusayba Bagegni, MD

As ongoing clinical trials in the HER2-positive and HER2-low breast cancer spaces aim to introduce novel therapies and expand the use of established regimens, updates from the 2022 San Antonio Breast Cancer Symposium (SABCS) have shined a light on the best treatment standards for patients.

Nusayba Bagegni, MD, highlighted key findings from the meeting, including 10-year follow-up data from the phase 2 APT trial (NCT00542451) examining adjuvant paclitaxel and trastuzumab (Herceptin) and 5-year follow-up data from the phase 2 ATEMPT trial (NCT01853748). In addition to updates Bagegni explained how she manages interstitial lung disease (ILD) in practice, which remains crucial as fam-trastuzumab deruxtecan-nxki (Enhertu) continues to demonstrate efficacy in new populations, such as those with HER2-low disease.

In an interview with OncLive®, during a State of the Science™ on Breast Cancer, Bagegni, an assistant professor of Medicine at the Washington University School of Medicine, detailed ongoing research and possibilities for the treatment landscape in the future, which includes investigating escalating approaches through more research in clinical trials.

What were the most important updates from the 2022 SABCS?

We had a number of great updates from key clinical trials at the 2022 SABCS—we saw some updates in the early-stage setting and also in the metastatic setting.

Specifically in the early-stage setting, we saw the 10-year follow-up data of the APT regimen which is 3 months of adjuvant paclitaxel/trastuzumab followed by 9 months of trastuzumab to finish up 1 year of treatment. We found that patients had excellent outcomes with that regimen, and it’s solidified the standard of care in the stage I setting.

Interestingly, [data] showed we could potentially use biomarkers to help identify the patients who will do well with that regimen, [and] they are perhaps patients who might require additional or alternate therapies. The HER2DX [risk score] data were presented in some of the poster sessions. [It was evaluated for] the APT regimen and in the ATEMPT trial and showed some intriguing data—perhaps we’ll see more of that.

We also saw the 5-year follow-up from the ATEMPT trial. That was purely a stage I, HER2-positive group of patients who received a year of adjuvant T-DM1 [ado-trastuzumab emtansine; Kadcyla] vs 1 year of the APT regimen and we found that patients had excellent outcomes at 5-year follow-up.

The primary end point was to look at toxicity from the original [data and] we did find that clinically significant adverse events [did not occur less frequently] with the ATEMPT regimen. So, we now have the ATEMPT 2.0 trial [NCT04893109] which is looking at an abbreviated course of T-DM1. That’s an ongoing trial that I look forward to seeing the results of.

In the advanced stage setting, we saw quite a bit [of data] with trastuzumab deruxtecan in the DESTINY-Breast trials. We saw how trastuzumab deruxtecan compared with a capecitabine-based regimen in a later line setting [DESTINY-Breast02 (NCT03523585)] and we found improved survival with trastuzumab deruxtecan. Then we saw [an improvement] in a head-to-head trial with T-DM1 in the second-line setting [DESTINY-Breast03 (NCT03529110)] and saw the remarkable HR for [progression-free survival] PFS and a substantial benefit of that regimen. Based on those data, it’s really solidified the trastuzumab deruxtecan in the second-line setting after first line taxane plus trastuzumab/pertuzumab [Perjeta].

Have you had any experience managing ILD with trastuzumab deruxtecan?

Unfortunately, I have had patients who have developed ILD with that regimen. I’ve had patients that have had grade 1 ILD [and these are] essentially patients for whom you’re getting routine scans for, and you find some ground glass opacities [in the lungs]. For those patients we have to interrupt therapy and potentially offer corticosteroids, certainly if they’re symptomatic they should initiate corticosteroids immediately. We have patients who are seen by our pulmonologists [and] we would typically offer pulmonary function testing as well as an infectious evaluation to make sure that there is no other etiology for the findings.

I’ve had patients with grade 1 where I interrupt the therapy, potentially offer corticosteroids, have them seen by pulmonary, and then repeat a chest CT 4 weeks later to reassess and determine if the patient can resume therapy. I have [also] had patients [with] symptomatic grade 2 or higher ILD as well and for those patients, you must interrupt therapy, initiate corticosteroids, rule out other etiologies, and ultimately if [the ILD is deemed] to be related to the trastuzumab deruxtecan, unfortunately, at that stage we recommend that they discontinue therapy.

If they’re responding to treatment, it becomes more of a challenging situation. There needs to be a lot more that’s done to really allow us to understand who’s at risk and who potentially could be re-challenged [with trastuzumab deruxtecan], even if they do have symptomatic or grade 2 or higher ILD. Hopefully [there will be] more to come from this so that we can really be guided further by the data.

Now that trastuzumab deruxtecan has improved outcomes in the HER2-low population, how has your institution transitioned to testing for that in patients?

At this stage, all patients have HER2 testing by [immunohistochemistry] IHC—that’s been routine at our institution and that hasn’t changed. We get the IHC testing and if the IHC is 2+ then we reflex test with [fluorescence in situ hybridization] FISH, but all patients get upfront HER2 testing via IHC. I look forward to seeing data from ongoing trials, including the DESTINY-Breast06 trial [NCT04494425] that looks at an ultra-low [population], so greater than 0 less than 1+ IHC. From initial studies, it seems there might be benefit beyond the 1+/2+ category of HER2 IHC and we need a better way of quantifying HER2 expression.

For patients who have 1+/2+ IHC, we’re offering trastuzumab deruxtecan; if they have 0 IHC and had a prior biopsy that did have HER2-low expression by the current definition, I might consider trastuzumab deruxtecan in that setting as well.

In the early-stage setting how has APT elucidated potential biomarkers of treatment selection?

What’s interesting is from the APT and ATEMPT data, and from the HER2DX signature data, we found that patients who meet certain cut offs [using] that scoring system may potentially have better or worse outcomes on these standard regimens. Depending on the cut off of this signature, patients may potentially have excellent prognosis on that regimen and then patients who have a worse score, might be eligible in the future to be triaged to more aggressive therapy.

There were some interesting data looking at PAM50 subtyping, and patients with luminal B, HER2-positive breast cancer seem to have worse disease-specific outcomes. For those patients we may in the future need to modify how we’re going to approach their regimens as compared with regimens for patients who don’t have luminal B breast cancer.

What data determining escalated approaches?

Escalated regimens in the setting of a high HER2 DXT score, would be something that we would consider in a clinical trial perhaps we can consider a clinical trial for, but currently we're not using that in clinical practice. The data is intriguing to make us wonder if we should potentially use that in a setting of a clinical trial to potentially escalate or deescalate therapy. At this stage I wouldn't recommend [it], we don't have it clinically available, and so we can't use that to help us determine what we would escalate or deescalate to, aside from in the patients who have stage 2 and 3 disease. If [those patients] have residual disease after neoadjuvant therapy, you can escalate those patients to the KATHERINE regimen of adjuvant T-DM1, but in the stage 1 setting we don't really have data to help support that, but perhaps a clinical trial in the future could help provide some more information.

Is there any ongoing or planned research at Washington University that you’d like to highlight?

In HER2-positive breast cancer an area of significant unmet need is [for patients with] brain metastasis. We all have had patients [with] stage 2 or 3 breast cancer [and] they do very well with a neoadjuvant regimen, achieve a complete pathologic response, and then unfortunately within 1 year they may relapse in the brain. [Another possibility is] patients who can do very well in the metastatic setting on maintenance trastuzumab/pertuzumab and then have an intracranial progression.

We do have trials looking at how we can hopefully reduce the incidence of brain metastases and also potentially delay progression within the brain in patients who have had disease. For example, in the early-stage setting at WashU, we’re participating in the COMPASSHER2 RD trial [NCT04457596], in which patients who had prior neoadjuvant therapy and had residual disease at the time of surgery are randomly assigned to receive either the standard of care T-DM1 plus placebo vs T-DM1 plus tucatinib (Tukysa). From [available] data, we haven’t seen that T-DM1 alone has really shifted the bar in terms of lowering CNS relapse and my hope is that we’ll see that with this trial—that’ll be exciting to hopefully reduce the incidence of CNS relapse in the early-stage setting.

In the metastatic setting we have a trial called the BRIDGET trial [NCT05323955]. This is a cooperative group study looking at tucatinib in patients who have only progression within the CNS, but otherwise have stable disease extracranially. The thought is can we maintain the current regimen but add a CNS penetrating agent to help delay onset of new CNS disease and potentially even result in a response. That’s based [on] the HER2CLIMB [NCT02614794] regimen that we’ve seen [elicit] excellent CNS response rates of up to 47.3% in patients who had active brain metastasis.