Emerging HER2+ Breast Cancer Research Uses Innovative Combinations of Standard Agents

Developments in HER2-positive breast cancer management hinge on an increased understanding of the disease biology that may elucidate ways to best leverage existing therapies in innovative combinations, according to Sara M. Tolaney, MD, MPH.

“We are going to be able to move towards more personalized therapy for patients,” Tolaney said in an interview with OncLive® during the 2024 International Congress on the Future of Breast Cancer® East.

In the interview, Tolaney reflected on the current treatment paradigm for patients with HER2-positive breast cancer and explained how the use of standard agents may be optimized in the future to improve patient outcomes.

Tolaney highlighted the phase 3 CompassHER2 RD trial (NCT04457596), which is evaluating ado-trastuzumab emtansine (T-DM1; Kadcyla) with or without tucatinib (Tukysa) in patients with high-risk HER2-positive breast cancer.¹ Modified invasive disease-free survival (IDFS) serves as the trial’s primary end point, and key secondary end points include breast cancer–free survival, distant recurrence-free survival, and brain metastases–free survival.

She also explained the aim of the phase 3 DESTINY-Breast05 trial (NCT04622319), which is comparing T-DM1 with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in patients with residual invasive breast cancer following neoadjuvant therapy.² This trial’s primary end points are IDFS, and key secondary end points include disease-free survival, overall survival, distant recurrence-free interval, and brain metastases–free interval.

Tolaney is chief of the Division of Breast Oncology and the associate director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: Where does the HER2-positive breast cancer treatment paradigm currently stand?

Tolaney: We’ve seen dramatic changes in our approach to [managing] early-stage, HER2-positive breast cancer over the past 5 to 7 years. Right now, we generally treat patients mostly based on clinical anatomic risk. [If patients] have a big tumor, they get a certain therapy, and we can monitor response and adapt. [If patients have] a smaller tumor, they get less therapy. However, we need to move towards understanding the biology of HER2-positive cancer, so we can give patients the right treatment for the right amount of time. I hope we’ll be able to get there.

What are the standard frontline treatment approaches for patients with HER2-positive breast cancer?

Generally, if a patient comes in with a newly diagnosed HER2-positive cancer, we want to understand what the size of the cancer is. How big is it within the breast? Are there any clinically involved lymph nodes?

If the patient has a tumor that’s super tiny, less than 2 cm, and doesn’t seem to have lymph node involvement, we generally take them to upfront surgery. If they are confirmed to have stage I or II HER2-positive cancer, we offer them paclitaxel plus trastuzumab [Herceptin] or T-DM1. Either choice would be reasonable for a patient with stage I disease. If they come in with a tumor that is bigger than 2 cm or one that has lymph node involvement, we want to give them treatment before surgery. We give preoperative therapy with either docetaxel plus carboplatin, trastuzumab, and pertuzumab [Perjeta; TCHP] or TCHP [plus anthracyclines], although most of us have stopped using anthracyclines and would give TCHP for 6 cycles.

Then, we look to see what their response is at the time of surgery. If they have residual disease, then we give 14 doses of T-DM1, whereas if they’ve had a pathologic complete response [pCR], then usually I just continue the HER2-directed antibodies to complete a year of therapy. [Treatment decisions in] the upfront setting are based on patients’ initial clinical anatomic risk.

How is the use of HER2-directed therapies evolving within this setting?

We initially had trastuzumab, then we got pertuzumab and T-DM1, but there are also other HER2-directed agents. Studies now are trying to assess whether we can add HER2-directed drugs [to standard therapies]. For example, the CompassHER2 RD study is taking patients who have residual disease, who would normally get 14 doses of T-DM1, and randomly assigning them to get T-DM1 with or without tucatinib, a HER2-directed TKI, with the idea being that there seems to be synergy between T-DM1 and tucatinib and that tucatinib gets into the brain. The thought is that maybe [the addition of tucatinib] could help prevent recurrences in the brain.

What research is ongoing in the adjuvant setting for patients with residual disease after surgery?

Several trials are evaluating what to do after surgery. If a patient has residual disease, should we escalate and go beyond T-DM1? The CompassHER2 RD trial is investigating the addition of tucatinib to T-DM1. [Alternatively], DESTINY-Breast-05 is assessing T-DXd compared with T-DM1. There’s also another [phase 3] study called ASTEFANIA [NCT04873362], which is looking to add immunotherapy with atezolizumab [Tecentriq] to T-DM1. Those are trials [enrolling] patients with residual disease.

References

1. 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 August 2, 2024. Accessed August 5, 2024. https://clinicaltrials.gov/study/NCT04457596
2. 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 August 5, 2024. https://clinicaltrials.gov/study/NCT04622319