HER2+ Breast Cancer Treatment Arena May Redefine the Roles of ADCs and Targeted Agents

The expansion of the HER2-positive breast cancer treatment landscape hinges on defined treatment sequencing in the later-line setting and further research investigating the safety and efficacy of antibody-drug conjugates (ADCs) in combination with tucatinib (Tukysa), according to Adrienne G. Waks, MD.

The phase 3 HER2CLIMB-02 trial (NCT03975647) is investigating ado-trastuzumab emtansine (Kadcyla) with or without tucatinib in patients with advanced or metastatic HER2-positive breast cancer. The primary end point of this trial is progression-free survival.1 Similarly, the single-arm phase 2 HER2CLIMB-04 trial (NCT04539938) is evaluating the safety and efficacy of tucatinib plus fam-trastuzumab deruxtecan-nxki (Enhertu) in this patient population, with a primary end point of confirmed overall response rate.²

“While these data won’t be immediately practice changing, they will be interesting and important for understanding if and how that combination of probably our 2 most blockbuster agents in this area can move forward in the years to come,” Waks said of the ongoing HER2CLIMB-04 trial.

Additionally, for patients with brain metastases, the standard of care (SOC) is tucatinib plus trastuzumab (Herceptin) and capecitabine (Xeloda) based on data from the phase 2 HER2CLIMB trial (NCT02614794), in which 48% of enrolled patients had active brain metastases.³ In the final overall survival (OS) analysis of this trial, at a median follow-up of 29.6 months, the median OS was 24.7 months (95% CI, 21.6-28.9) with the tucatinib combination vs 19.2 months (95% CI, 16.4-21.4) with placebo plus trastuzumab and capecitabine (HR, 0.73; 95% CI, 0.59-0.90; P = .004).

In an interview with OncLive®, Waks spotlighted the role of the HER2CLIMB regimen in patients with HER2-positive breast cancer with brain metastases, discussed unmet needs in the fourth- and later-line settings in HER2-positive disease, and explained the basis for the ongoing HER2CLIMB-02 and HER2CLIMB-04 trials within the broader ADC landscape.

Waks is associate director of Clinical Research at Dana-Farber Cancer Institute, as well as an instructor in medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: What does the treatment landscape look like for HER2-positive breast cancer with brain metastases?

Waks: There have not been many changes in first-line therapy in recent years. In the second line, the [phase 3] DESTINY-Breast03 trial [NCT03529110] established the ADC trastuzumab deruxtecan as the SOC in the second line for most patients with HER2-positive metastatic breast cancer.

It’s important to review, compare, and contrast the way patients with brain metastases were treated in the DESTINY-Breast03 trial compared with the HER2CLIMB trial, which looked at a different regimen, capecitabine plus trastuzumab plus tucatinib. The HER2CLIMB trial included a large population of patients, but a large proportion of the patients in that trial had either stable or active brain metastases, with the population with active brain metastases in that trial being particularly interesting, unique, and important. HER2CLIMB showed a persistent benefit in the population with stable brain metastases, the population with active brain metastases, and the overall population.

That contrasts with the DESTINY-Breast03 trial, which investigated trastuzumab deruxtecan in the second line in a large population of patients with metastatic HER2-positive disease and showed enormous benefits. However, only a small proportion of the patients in DESTINY-Breast03 had brain metastases, [16% of patients in the trastuzumab deruxtecan arm and 15% of those in the trastuzumab emtansine arm, and [patients with] active brain metastases were not allowed on that trial.

The bottom line is that, although based on DESTINY-Breast03, trastuzumab deruxtecan is the second-line SOC for most patients with HER2-positive metastatic breast cancer, there’s an important carve-out for patients who have intracranial predominant disease with active brain metastases, where, even in the second line, you might go first for the HER2CLIMB regimen.

What HER2-targeted treatment options are available or under investigation for patients in the fourth-line setting and beyond?

Once you get to the fourth line and beyond in metastatic HER2-positive breast cancer, we have several good options. We have many agents we can use, both targeted and non-targeted. However, we’re in a data-free zone regarding which we should use first, second, third, fourth, and so on.

Those regimens [include] neratinib [Nerlynx] combinations and the margetuximab-cmkb [Margenza] novel anti-HER2 antibody. [Additionally], the abemaciclib [Verzenio]/fulvestrant [Faslodex]/trastuzumab combination was investigated in the [phase 2] monarcHER trial [NCT02675231], [although this was not a registrational trial].

Those options exist in the later-line setting and have a good evidence basis. However, we have no data to tell us in what order we should use them and how they will work after the current standard [therapies we have for] second- and third-line treatment.

How might findings from the ongoing HER2CLIMB-04 and HER2CLIMB-02 trials contribute to the HER2-positive breast cancer treatment paradigm?

HER2CLIMB-04 is an interesting trial. To preface, it’s important to mention the HER2CLIMB-02 trial. HER2CLIMB-02 is a phase 3 randomized trial. HER2CLIMB-04 is not phase 3 and is not randomized, so it’s a bit more hypothesis generating.

HER2CLIMB-02, which is a predecessor trial, is a randomized phase 3 trial of trastuzumab emtansine plus or minus tucatinib in a later-line setting. That trial has completed accrual. It will be interesting to hopefully see those results when they’re available; we’re just waiting for it to read out. Trastuzumab emtansine has moved later regarding where we typically use it in the management of HER2-positive metastatic breast cancer, because now we have the HER2CLIMB regimen and trastuzumab deruxtecan.

HER2CLIMB-02 will help us understand whether we can use trastuzumab emtansine in combination with tucatinib, which is an exciting novel agent with interesting brain metastases activity. If HER2CLIMB-02 reads out as positive and supports the combination regimen of trastuzumab emtansine plus tucatinib, that will change the spot where we use trastuzumab emtansine and potentially the way we use tucatinib for a subpopulation of patients. HER2CLIMB-02 will be interesting and hopefully we’ll see [results] in the months to come.

In a similar vein, HER2CLIMB-04 is not a registrational trial. It’s a phase 2 single-arm trial investigating the combination of trastuzumab deruxtecan and tucatinib. There’s great interest in that combination. Dual targeting of HER2 can be a powerful and effective strategy for patients. Trastuzumab deruxtecan and tucatinib are exciting, relatively recent additions to the tools we have that are effective in HER2-positive metastatic breast cancer. The potential to use them together is attractive [and may] improve outcomes for patients. It’s not a registrational trial, but it will give us important data about the safety and tolerability of the combination, which we’re lacking at this point, and potentially give us an early signal of the efficacy of that combination.

References

1. A study of tucatinib vs. placebo in combination with ado-trastuzumab emtansine (T-DM1) for patients with advanced or metastatic HER2+ breast cancer. ClinicalTrials.gov. Updated July 5, 2023. Accessed July 14, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03975647
2. A study of tucatinib plus trastuzumab deruxtecan in HER2+ breast cancer (HER2CLIMB-04). ClinicalTrials.gov. Updated June 13, 2023. Accessed July 14, 2023. https://clinicaltrials.gov/study/NCT04539938
3. Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33(3):321-329. doi:10.1016/j.annonc.2021.12.005