Tucatinib Retains its Role in HER2+ Metastatic Breast Cancer, Prompting Questions of T-DXd’s Potential Takeover in the First Line

The presence of controlled systemic disease and intracranial-predominant disease in need of response are good indicators to select the phase 2 HER2CLIMB (NCT02614794) regimen of tucatinib (Tukysa) plus trastuzumab (Herceptin) and capecitabine (Xeloda) vs fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) as second-line therapy for patients with metastatic HER2-positive breast cancer and central nervous system (CNS) metastases, according to Adrienne G. Waks, MD.

As T-DXd continues to demonstrate impressive efficacy, another question surrounding the antibody-drug conjugate is its role in the frontline setting, which is yet to be determined, although data from the phase 3 DESTINY-Breast09 trial (NCT04784715) will help to elucidate its role.1

In an interview with OncLive®, Waks, an associate director of Breast Oncology Clinical Research and a senior physician at Dana-Farber Cancer Institute, shed light on how she selects treatments for patients with HER2-positive breast cancer and for those with brain metastases. Waks is also an assistant professor of medicine at Harvard Medical School, in Boston, Massachusetts.

Waks provided insights on neoadjuvant treatment selection in HER2-positive breast cancer and highlighted the state of abbreviated regimens in an additional interview.

OncLive: Why is the HER2CLIMB regimen an attractive one for patients with HER2-positive breast cancer and brain metastases?

Waks: This is a common question [and] an interesting and important one. We know that brain metastases in breast cancer are prevalent in patients who have HER2-positive metastatic breast cancer. This comes up all the time in clinic. The HER2CLIMB regimen of tucatinib, capecitabine, and trastuzumab looks particularly good and [was] carefully investigated in a population of patients with brain metastases.

In the HER2CLIMB trial population, which was 612 patients, approximately half had brain metastases which is unprecedented in other metastatic breast cancer trials. [Because of that] we got to see the regimen’s [efficacy in patients with brain metastases]. The objective response rate [ORR] in the CNS was 20.0% without tucatinib [and] 47.3% with tucatinib, [showing a] more than doubling of the ORR in the CNS. We saw an overall survival benefit of 9.1 months from 12.5 months [with placebo plus trastuzumab and capecitabine] to 21.6 months in patients who received the tucatinib triplet—those were unprecedented data for patients with brain metastases.

How do you choose between the HER2CLIMB regimen and T-DXd for patients with brain metastases?

When I’m looking for second-line therapy for a patient with HER2-positive metastatic disease, if they have intracranial-predominant disease, need a response in the brain, and have systemic disease outside of the CNS [that] is not causing many problems, then I favor the HER2CLIMB regimen over T-DXd because it has such good data for CNS control.

There are also good data, but not as robust, for T-DXd in terms of its efficacy in both stable and active brain metastases; there are small cohorts that have shown it has activity. Although I don’t think the data are quite as robust as the HER2CLIMB data, T-DXd is also an active agent and it’s incredibly active outside the CNS. For a patient where I’m looking for a second-line therapy, and at the same time as having CNS disease they are having a lot of issues with systemic disease, I would probably then choose T-DXd because its systemic control in the second-line setting is unparalleled and I could feel confident that the CNS benefit is going to be there too.

What key takeaways would you like to share with colleagues on treating patients with HER2-positive disease?

An important question that’s going to arise in HER2-positive metastatic breast cancer in the coming years is [on what to do] if we move T-DXd into the first line; if DESTINY-Breast09 is a positive trial and we replace the phase 3 CLEOPATRA trial [NCT00567190] regimen of docetaxel plus trastuzumab and pertuzumab [Perjeta], which is the current standard, with T-DXd in the first-line setting, we’re going to be left needing data to help us understand how long [to treat patients with] T-DXd. Right now, with the CLEOPATRA regimen we use approximately 4 to 6 months of chemotherapy, and then we drop the chemotherapy and continue with HER2-directed therapy, which is much less toxic and better for quality of life—that [treatment] is great for our patients who we know can get durable benefit out of that approach and lead a life without too many adverse effects.

[The way the] DESTINY-Breast09 [trial was designed] T-DXd [was intended to be continued] until progression [rather than administered up front in] that first 4 to 6 months and then [continued in] a maintenance phase. If that trial is positive [T-DXd will be continued] indefinitely for as long as the patient is benefiting and has acceptable adverse effects. That’s a very different paradigm because T-DXd is a very effective, but also toxic drug and I anticipate patients will stay on first-line therapy for a long time with that potentially toxic regimen.

The key question that’s going to follow if those are positive data, is how we can study doing more of an induction and then maintenance approach with T-DXd in the first-line setting; can we do a certain number of cycles, 6 months of T-DXd, but then transition to trastuzumab and pertuzumab which is part of the CLEOPATRA regimen that we’re also used to. We’re going to need those efficacy, safety, and feasibility data because that’s going to be important for patients—we don’t want to keep them on a toxic therapy long term if we could give them a break after induction.

Reference

1. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). ClinicalTrials.gov. Updated June 13, 2024. Accessed July 23, 2024. https://clinicaltrials.gov/study/NCT04784715