Antibody-Drug Conjugates Are Carving Out Expanded Roles Throughout Breast Cancer

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Partner | Cancer Centers | <b>Northwestern Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University</b>

William J. Gradishar, MD, discusses the expansion of antibody-drug conjugates across subsets of breast cancer, along with emerging treatment options within each space.

Antibody-drug conjugates (ADCs) illustrate the continued evolution of treatment options across HER2-positive breast cancer, hormone receptor (HR)–positive, HER2-negative breast cancer, and triple-negative breast cancer (TNBC). Following the success of fam-trastuzumab deruxtecan-nxki (Enhertu) in the phase 3 DESTINY-Breast03 trial (NCT03529110), other ADCs are likely to enter the treatment fold in the future, according to William J. Gradishar, MD.

“What we will likely have in the coming years is a series of ADCs that we can use that will extend the duration of therapy and options for patients,” Gradishar said in an interview with OncLive® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

In the interview, Gradishar spoke about the expansion of ADCs across subsets of breast cancer, along with emerging treatment options within each space. Gradishar is the Betsy Bramsen professor of Breast Oncology, a professor of medicine (hematology and oncology) at the Feinberg School of Medicine, and chief of Hematology and Oncology in the Department of Medicine at Northwestern Medicine.

OncLive®: Your presentation focused on HER2-positive breast cancer. What clinical trials have contributed to the updates seen here?

Gradishar: In the HER2-positive space, there have been major advances in the past many years. It seems like every year we get new drugs, and that’s a great thing for [clinicians] and patients [because] it’s improving patient outcomes. I focused on the evolving landscape in metastatic HER2-positive breast cancer and the emergence of ADCs. [This includes] not only ado-trastuzumab emtansine [T-DM1; Kadcyla] but also the emergence of trastuzumab deruxtecan, as well as the results from other trials and new drugs that are still in development.

What this is showing us is that we have a series of drugs to try. Even when a patient develops disease progression on one [treatment], there’s the probability that not only will we have [another agent] to offer [patients] but we have the high probability that they’ll benefit from it.

The DESTINY-Breast03 trial showed that trastuzumab deruxtecan is an excellent drug that can be used after patients progress on a [pertuzumab (Perjeta), trastuzumab (Herceptin), and docetaxel] regimen, so T-DM1 will likely get moved back [in treatment sequencing].

I covered other ADCs that are in development, including the results of the phase 3 TULIP trial [NCT03262935] with vic-trastuzumab duocarmazine, which looked better than alternative options that were used for standard of care.

What options may benefit patients in this population who also present with brain metastases?

The other area that I talked about was new TKIs, focusing on the phase 2 HER2CLIMB trial [NCT02614794] with tucatinib [Tukysa]. [I discussed] the results of the overall trial, which showed a superior outcome for patients getting [tucatinib, trastuzumab, and capecitabine (Xeloda)] compared with trastuzumab and capecitabine [with placebo]. [I specifically addressed] the enhanced benefits seen in patients with brain metastases. This is the first trial that focused on that subset of patients, where it’s shown that including tucatinib had a marked effect on central nervous system [CNS] progression-free survival [PFS] and overall survival [OS] in those patients.

There are anecdotes with other HER2-directed therapies for CNS brain metastases, but [tucatinib] is one of the most compelling stories so far. Trastuzumab deruxtecan is starting to develop some data [in patients with brain metastases], but [data] are clearly the most robust for tucatinib in this setting.

Were there any other treatments you highlighted in HER2-positive breast cancer?

The final thing I talked about was subcutaneous trastuzumab/pertuzumab, which is an option for patients who are getting [intravenous] trastuzumab/pertuzumab. [These 2 treatment administrations] are equally effective [with] no new toxicities. [The subcutaneous administration adds] an element of convenience, both in terms of time in the chair and [length] of infusion. That is a good option for patients.

You also addressed evolving treatment in TNBC. How have ADCs affected this space?

One [area I discussed] was ADCs, in this case, sacituzumab govitecan-hziy [Trodelvy], which is an ADC that targets TROP2. [Previous] data from the phase 3 ASCENT trial [NCT02574455] demonstrated that sacituzumab govitecan was superior to alternative chemotherapy options. The effect was seen regardless of [low, medium, or high] TROP2 expression. Patients who received sacituzumab govitecan had a better outcome, regardless of whether they harbored a BRCA mutation.

Where we must consider our decision making is in patients who are PD-L1 positive. In patients who are PD-L1 positive, we would consider immunotherapy. There are data showing that pembrolizumab [Keytruda] added to chemotherapy improves overall outcomes for patients with a combined positive score greater than 10. Most [clinicians] would proceed with immunotherapy first for a patient with metastatic TNBC. Until it stops working, [immunotherapy] would continue. However, when it does [stop working], a drug such as sacituzumab govitecan could be considered for lines of therapy beyond immunotherapy.

What options are considered for early-stage patients at high risk of disease recurrence?

In patients with early disease, the phase 3 KEYNOTE-522 trial [NCT03036488] demonstrated that neoadjuvant chemotherapy plus pembrolizumab vs chemotherapy alone enhanced not only the pathological complete response rate, but, with long follow-up, event-free survival [EFS]. In the preoperative setting, patients do not need to be PD-L1 positive. Pembrolizumab can be used [regardless of PD-L1 status]. For most patients who fit the criteria for KEYNOTE-522, we would now use a pembrolizumab-based regimen with chemotherapy preoperatively. [Patients with] node-positive tumors bigger than 2 cm are those who we would consider for preoperative therapy.

There are things we’ll have to think about for those patients who have still have residual disease after surgery who get preoperative pembrolizumab. Do you simply give them [adjuvant] pembrolizumab alone, or pembrolizumab with capecitabine? If patients harbor a BRCA mutation, would you add a PARP inhibitor? These are all questions that we don’t have clear answers on, but those are expanding options for patients who remain at risk for disease recurrence.

Could you elaborate on the updates in the adjuvant and metastatic space of HR-positive, HER2-negative breast cancer presented by Ruta Rao, MD, of Rush University Medical Center?

Dr Rao gave us an overview of the role of CDK4/6 inhibitors in the metastatic setting and [shared] emerging data in the adjuvant setting. In the metastatic setting, she covered some of the updates, particularly with ribociclib [Kisqali] and fulvestrant [Faslodex], which clearly demonstrates an OS benefit. All the CDK4/6 inhibitor trials with palbociclib [Ibrance],abemaciclib [Verzenio], or ribociclib, as first- or second-line therapy, all showed an improvement in PFS.

We are starting to see the emergence of an OS benefit, particularly with ribociclib and abemaciclib, and more recently with palbociclib to a smaller degree. There is a consistency in the data. Some might argue that the data with ribociclib are the most compelling, particularly when combined with fulvestrant in the second-line setting, but the general idea is that patients should be getting a CD4/6 inhibitor. They’re all associated with improvements in outcome, and all have manageable [adverse] effect [AE] profiles.

In the adjuvant setting, we’ve had data with palbociclib that did not show an advantage to adding it to [treatment for] high-risk patients, either in those with residual disease or as an adjuvant therapy. We still have data that has not reported from the phase 3 NATALEE trial [NCT03701334] with ribociclib.

The one data set that we have positive data from is the phase 3 monarchE trial [NCT03155997] with abemaciclib, which [examined] patients who are at higher risk. They could have had more than 3 positive nodes, or if they had fewer than 4 positive nodes, then they had to have other [high-risk] features, [regarding] tumor size or proliferation, that would have conferred a greater risk of recurrence. What was demonstrated in that trial, with short follow-up, was that there was a clear benefit with abemaciclib. When the trial data were first presented, a minority of patients had gone through the entire duration of abemaciclib therapy of 2 years. Now with longer follow-up, more of the total pool of patients have completed their abemaciclib therapy. The data still favor the use of abemaciclib. We’ve started using [abemaciclib with endocrine therapy] in patients who fit the criteria for the monarchE trial. It’s been included in the ASCO guidelines and the NCCN guidelines as an option for patients.

What was the main message from the presentation of updates on decision making with molecular assays in early breast cancer, given by Kevin Kalinsky, MD, MS, of the Winship Cancer Institute of Emory University?

Dr Kalinsky, who was the presenter of the phase 3 RxPONDER trial [NCT01272037] when it first was presented, gave an overview of the molecular tools we have to decide prognosis and determine the benefit from chemotherapy. He briefly covered the phase 3 TAILORx trial [NCT00310180], which was conducted in node-negative patients and served as the basis for the RxPONDER trial, which was conducted in higher-risk patients with 1 to 3 positive nodes.

From [RxPONDER], we were able to identify a subset of patients with node-positive disease where we would have almost universally recommended chemotherapy in the past. There is a subset of patients, based not only on their recurrence score but also clinical features and menopausal status, where we can defer chemotherapy and not compromise their overall outcome. Dr Kalinsky discussed the RxPONDER trial and its nuances, particularly as it relates to premenopausal vs postmenopausal women and where we might draw the line on who must get chemotherapy and who would not benefit from it.

That [assay] has been a practice-changing tool that we now employ daily in our practice, just as we did with the TAILORx data for node-negative patients. Dr. Kalinsky put into perspective all the data and nicely reviewed how clinicians would employ this data to make treatment decisions in this setting.

Specifically, how did the TAILORx trial influence the RxPONDER trial?

The TAILORx trial is an older data set at this point. Based on that data, we can identify patients at very low risk of recurrence who don’t require chemotherapy. [As with] RxPONDER, there are many patients with node-negative disease who would have universally gotten chemotherapy [in the past]. Now, because of long-term data from the TAILORx trial, we can feel comfortable avoiding chemotherapy in a significant fraction of patients who would have likely gotten chemotherapy in the past because it does not compromise their outcomes.

How has the overall evolution of treatment affected how you view the treatment landscape?

The IPC webinar and discussions by both myself and my colleagues reflect that we’ve made progress in almost every silo of breast cancer and every strategy we use to reduce risk and to identify patients who can avoid or need specific therapies. [Clinicians] sometimes have to have a longer perspective to understand where we started from, and it’s one of the benefits of being around for a while. Seeing what we were doing 20 years ago was, by some measure, somewhat crude. We have come a long way in terms of dividing breast cancer into subsets, developing therapies for each subset, using molecular tools to identify patients at risk, and [learning] how we can mitigate their risk.

That is different from the landscape I had when I was training, and I suspect in 20 years, what we’re doing now will be viewed as crude. We’ll have something new that makes everything we do today look [antiquated]. Nonetheless, what we heard about in the four talks reflects all the progress that has been made to benefit patients.