Changes in HER2+ Breast Cancer May Include Tailored Therapy With pCR, Use of T-DXd

Escalating or de-escalating therapy on the basis of pathological complete response (pCR) vs residual disease is most likely going to become standard of care (SOC) in the near future for patients with early-stage HER2-positive breast cancer, according to Adrienne G. Waks, MD.

In an interview with OncLive^®, Waks described potentially tailoring treatment based on pCR and detailed therapies for patients with residual disease that may improve upon the efficacy of ado-trastuzumab emtansine (Kadcyla; T-DM1). Two of the key ongoing trials in this setting are the phase 3 DESTINY-Breast05 trial (NCT04622319) and the phase 3 CompassHER2 RD study (NCT04457596), according to Waks. The former is evaluating fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) vs T-DM1 in patients with residual disease and the latter is examining adding tucatinib (Tukysa) to T-DM1 in this patient population.^1,2

Waks is an associate director of Breast Oncology Clinical Research and a senior physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts. She provided insights on neoadjuvant treatment selection in HER2-positive breast cancer and highlighted the state of abbreviated regimens in an additional interview.

OncLive: How do you tailor treatments for patients with HER2-positive early and metastatic breast cancer?

Waks: For patients with early-stage disease we’re at a point or at least on the cusp of a point where escalating or de-escalating [therapy] on the basis of pCR vs residual disease is most likely going to enter the SOC. We may be able to give patients who have a pCR less therapy in the adjuvant setting and for patients who don’t [have a pCR], we have a lot of exciting new regimens on the horizon [examining] how we might further reduce that risk. Those data are forthcoming, will look exciting, and will probably change practice, but we’re also not quite there yet. There are many potential practice-changing trials that will [read out] in the next 1 to 2 years, but we’re not there yet with the results of those phase 3 trials.

In metastatic breast cancer, we’re about to learn whether we should change our first-line therapy to T-DXd as opposed to the current standard of the phase 3 CLEOPATRA trial [NCT00567190] regimen. For HER2-positive metastatic breast cancer [that] will be the biggest, most impactful result of the next couple of years.

What therapies could help lower risk for patients with residual disease in the adjuvant setting?

The main tool that we have is T-DM1, which has an overall survival advantage, and should be a clear SOC for patients. In the phase 3 KATHERINE trial [NCT01772472] patients benefitted from T-DM1 even if they only had a bit of residual disease or if their residual disease had become HER2-negative at the time of surgery. [Therefore], T-DM1 is the clearly established standard across the board for that population at this point.

There are 2 trials that will tell us if we can add to or do better than T-DM1. The CompassHER2 RD trial is looking at T-DM1 plus or minus tucatinib and if that trial is positive, then we should add tucatinib [to treatment with T-DM1] for some of these patients. We know that HER2 blockade with a doublet is better than HER2 blockade with a single agent in a lot of settings, so there’s a lot of rationale behind adding the HER2 TKI to the antibody-drug conjugate. In addition, we know that tucatinib is especially active in the central nervous system [CNS], which is a place where T-DM1 didn’t look as good in the KATHERINE trial; it reduced recurrences overall, but it did not reduce CNS recurrences. The potential to solve 2 problems with the addition of tucatinib will be good if that trial turns out to be positive.

Then, there’s the DESTINY-Breast05 trial that’s comparing T-DM1 with T-DXd in this setting. T-DXd outperforms T-DM1 very easily in the metastatic setting, and it seems reasonably likely that we’ll see it outperform T-DM1 in the residual disease setting as well, although we don’t know yet. For now, T-DM1 is the clear standard but perhaps in the future, we’ll be either adding tucatinib to it or swapping it out for T-DXd depending on the results of those ongoing trials.

How has T-DXd affected the treatment paradigm for patients with HER2-positive disease?

T-DXd has enormously changed the landscape for patients with metastatic HER2-positive breast cancer, not to mention all the other subtypes of metastatic breast cancer. It’s firmly entrenched in the second-line setting for our patients with HER2-positive metastatic disease. In that setting it has a median progression-free survival of 29.0 months. That timeframe in and of itself has been a huge game changer for patients with this subtype of metastatic breast cancer and it outperformed T-DM1 in that setting. In the future, we’ll see the phase 3 DESTINY-Breast09 trial [NCT04784715] data [which will help determine] whether it’s going to move into the first-line setting, which would be another major paradigm shift for our metastatic population.

References

1. A study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in high-risk HER2-positive participants with residual invasive breast cancer following neoadjuvant therapy (DESTINY-Breast05). ClinicalTrials.gov. Updated June 28, 2024. Accessed July 23, 2024. https://clinicaltrials.gov/study/NCT04622319
2. T-DM1 and tucatinib compared with T-DM1 alone in preventing relapses in people with high risk HER2-positive breast cancer, the CompassHER2 RD trial. ClinicalTrials.gov. Updated May 23, 2024. Accessed July 23, 2024. https://clinicaltrials.gov/study/NCT04457596?term=NCT04457596&rank=1