Novel Studies Seek to Optimize HER2+ Breast Cancer Management

In the HER2-positive breast cancer field, individual patient responses to earlier lines of therapy may be used as decision-making factors regarding the types and intensity of later lines of treatment, according to Sara M. Tolaney, MD, MPH.

In an interview with OncLive®, Tolaney discussed novel considerations for the use of antibody-drug conjugates (ADCs) in patients with HER2-positive breast cancer, ongoing research in this patient population, and unmet needs for patients with recurrent disease. She shared additional insights about the management of HER2-positive disease in another article.

Tolaney noted the goals of the phase 3 DESTINY-Breast11 trial (NCT05113251), which is investigating fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) alone or in combination with docetaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta) vs standard-of-care (SOC) therapy in patients with HER2-positive early breast cancer. The primary end point of this trial is pathologic complete response (pCR) rate, and key secondary end points include event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival.1

She also highlighted the rationale for the ongoing phase 2 CompassHER2 pCR trial (NCT04266249), which is evaluating the efficacy of paclitaxel, trastuzumab, and pertuzumab in eliminating the need for further adjuvant chemotherapy in patients with stage II to IIIA HER2-positive breast cancer with no evidence of residual disease after neoadjuvant chemotherapy and HER2-directed therapy followed by surgery.2 Three-year recurrence-free survival rate serves as the trial’s primary end point; key secondary end points include 3-year IDFS and EFS rates.

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 in Boston, Massachusetts.

OncLive: How might the role of ADCs continue to evolve for the treatment of patients with HER2-positive breast cancer?

Tolaney: There are new ADCs. We’ve had ado-trastuzumab emtansine [T-DM1; Kadcyla] for the treatment of patients with HER2-positive disease. However, now there’s also T-DXd. This is an agent approved for metastatic HER2-positive breast cancer, but there’s an interest in seeing whether we can move it into the early disease setting.

We know T-DXd is better than T-DM1 for patients with metastatic disease. The thought is: Could [we enroll] a patient with residual disease and randomize them to receive either T-DXd or T-DM1? Would T-DXd be better than T-DM1 in this setting? [The phase 3 DESTINY-Breast05 trial (NCT04622319)] is currently ongoing trying to assess that. Lots of new HER2-directed therapies are moving into this field.

How might findings from ongoing research change treatment standards for patients who achieve pCR with neoadjuvant therapy?

There are trials looking to say that maybe patients don’t need to get quite as much [therapy] if they have a pCR [after neoadjuvant therapy]. In the CompassHER2 pCR study, [patients receive] an abbreviated course of preoperative docetaxel, trastuzumab, and pertuzumab. If patients get a pCR, then they don’t receive any more chemotherapy and they just receive HER2-directed antibodies [in the adjuvant setting]. [This trial is] trying to say that maybe we should be giving less treatment to the patients [who achieve] pCR [with neoadjuvant therapy].

There are trials that are pivoting based on patients’ responses to preoperative therapy. However, there are also trials trying to say maybe we should replace what we’re giving preoperatively because right now, we mostly—at least in the United States—give docetaxel plus carboplatin, trastuzumab, and pertuzumab [TCHP] for 6 cycles. In Europe, a lot of oncologists will [add] anthracycline-containing therapy [to TCHP]. The DESTINY-Breast11 trial is looking to replace that standard preoperative treatment with T-DXd, a HER2-directed antibody. Many ongoing trials are trying to replace or add on to our current SOCs.

What unanswered questions remain regarding the management of recurrent HER2-positive breast cancer?

We do well [when managing] HER2-positive disease with our current therapies. Thankfully, most patients [who receive] chemotherapy and HER2-directed treatment are cured of their cancer. The challenge is that there is a subset of patients who are recurring. We need to figure out why that is.

What are the biomarkers that could help us predict who those patients are going to be, and could they help us adjust our treatments in the early and up-front setting to prevent that recurrence? Also, are there ways we can better adapt therapy rather than just assessing response to preoperative therapy? Can we move toward more novel ways to monitor response in the preoperative setting? Could we use circulating tumor DNA, maybe even in combination with more advanced imaging techniques, such as MRI or PET, early in the preoperative setting? Could that help us figure out how much treatment an individual patient needs? Although we’ve done well, I hope we can do better by trying to find biomarkers or better ways to adapt treatment.

References

Trastuzumab deruxtecan (T-DXd) alone or in sequence with THP, versus standard treatment (ddAC-THP), in HER2-positive early breast cancer. ClinicalTrials.gov. Updated July 24, 2024. Accessed August 5, 2024. https://clinicaltrials.gov/study/NCT05113251

Breast Cancer. EA1181 / CompassHER2 pCR. ECOG-ACRIN. Accessed August 6, 2024. https://ecog-acrin.org/clinical-trials/ea1181-compassher2-pcr-breast-cancer/