Novel Approaches Make Headway in HER2+ Metastatic Breast Cancer

Manali Bhave, MD

HER2-targeted antibodies, antibody-drug conjugates (ADCs), immunotherapy, and TKIs have propelled metastatic HER2-positive breast cancer treatment forward, said Manali Bhave, MD, adding that more research efforts are focused beyond the first- and second-line settings.

The investigational HER2-targeted monoclonal antibody margetuximab was found to improve progression-free survival (PFS) in this patient population, and the PFS benefit was enhanced in CD16A-F allele carriers, according to data from the phase III SOPHIA trial that were presented at the 2019 ASCO Annual Meeting.¹ Furthermore, early-stage research found that the bispecific antibody ZW25 induced a disease control rate of 82% in heavily pretreated patients across various HER2-positive tumor types.²

Moreover, the antibody-drug conjugate (ADC) [fam-] trastuzumab deruxtecan (DS-8201) is also generating excitement in the space. Data from the phase II DESTINY-Breast01 study showed that the agent produced encouraging responses in patients with unresectable and/or metastatic HER2-positive breast cancer who had been previously treated with ado-trastuzumab emtansine (T-DM1; Kadcyla).³

Preclinical research suggests that there may be synergism between immunotherapy and anti-HER2—directed therapies, with response rates ranging from 3% to 15%, said Bhave. As such, several ongoing trials are investigating this approach further. Moreover, the TKI pyrotinib is showing promising single-agent activity in patients previously treated with trastuzumab (Herceptin), and neratinib (Nerlynx) is making headway in the metastatic setting.

“With more phase III trials as well as direct comparisons between our current standard-of-care agents and some of these newer agents, we're going to determine the [optimal] sequence of these agents in the treatment of our patients with metastatic HER2-positive breast cancer,” said Bhave.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Bhave, an assistant professor in the Department of Hematology and Medical Oncology at Winship Cancer Institute, Emory University School of Medicine, highlighted the novel agents under investigation in the treatment of patients with metastatic HER2-positive breast cancer.

OncLive: What is the state of HER2-positive metastatic breast cancer treatment?

Bhave: First-line therapy is based off of the CLEOPATRA trial, which included a taxane chemotherapy along with 2 HER2-directed antibodies, which include trastuzumab and pertuzumab (Perjeta). The second-line treatment is currently with T-DM1, which is an ADC that was shown to have a significant improvement in PFS and overall survival (OS) in patients who had progressed on trastuzumab, as seen in the EMILIA trial. There are no standard-of-care treatment options currently available in the third-line setting or beyond, but there are many novel therapies [under investigation].

What developments have been made with anti-HER2 agents, such as margetuximab or ZW25?

The first drug that has shown some promise in women that were heavily pretreated—including treatment with prior trastuzumab and taxane-based chemotherapy, as well as prior treatment with T-DM1—is margetuximab. It is a monoclonal antibody with an Fc component that has been optimized to enhance immune response and antibody-mediated cytotoxicity. The randomized phase III SOPHIA trial showed that heavily pretreated women had high overall response rates (ORRs) as well as improved PFS [with margetuximab], despite treatment with multiple lines of therapy.

ZW25 is a bispecific HER2-directed antibody that's targeting 2 distinct epitopes of the HER2 domain; it binds at both the trastuzumab domain and the pertuzumab domain. This agent has shown very promising single-agent activity in heavily pretreated patients with metastatic HER2-positive breast cancer. Specifically, [the agent] showed single-agent activity with an ORR of close to 50% or 60%, which had been previously difficult to achieve in this heavily pretreated population.

Shifting to ADCs, what work is being done with [fam-] trastuzumab deruxtecan?

One of the more promising therapies is [fam-] trastuzumab deruxtecan, and it's an ADC with a novel payload, which is a topoisomerase inhibitor. [This agent is] 10 times more potent than irinotecan, which is a standard chemotherapy that's used for multiple other histologies. One of the important aspects of this drug is that [it has] a higher drug—antibody ratio, which is about double that of T-DM1. T-DM1 has a drug–antibody ratio of about 3.5, while [fam-] trastuzumab deruxtecan has a ratio of 7.8. There's also a bystander effect in that the drug is able to permeate past the membrane. As such, it has been used in trials with not only women who have HER2-positive disease, but also those with HER2-low breast cancers.

Originally, when the trial was performed, investigators looked at [the agent in a] heavily pretreated metastatic breast cancer population and they found that there was a significant ORR of about 60%, as well as an improvement in median PFS. Based off of the encouraging data seen in the phase I setting, they've moved into a pivotal phase II trial called DESTINY-Breast01; that actually just confirmed the ORRs and the improvement in PFS.

They then looked into 2 planned phase III trials. The first trial is currently ongoing and is looking at [fam-] trastuzumab deruxtecan in comparison with either a trastuzumab-based regimen or a lapatinib (Tykerb)/capecitabine regimen in heavily pretreated women who have received trastuzumab as well as T-DM1. Their other phase III trial is currently planned to look at the use of this drug in the second-line setting, so women who have progressed on a trastuzumab/taxane regimen. This is randomizing those patients to receive either [fam-] trastuzumab deruxtecan versus T-DM1 and that's going to be in DESTINY-Breast03.

What is the role of immunotherapy in HER2-positive metastatic disease? Are there specific agents that you’re excited about?

There are several combinations of immunotherapy with HER2-directed therapies that have already been done or are ongoing. Preclinical studies have shown that there is some synergism between immunotherapy and anti-HER2 blockade. What has been shown is, with the use of trastuzumab in the preoperative setting, there is a change in the tumor immune profile, and perhaps that might make a combination of HER2-directed therapy and immunotherapy more beneficial in these women.

There has also been evidence showing that there's a higher expression of PD-L1 in both patients with metastatic triple-negative breast cancer as well as those with HER2[-positive] disease. Again, this might also make us believe that immunotherapy in combination with anti-HER2 would be beneficial in this patient population.

Currently, the studies that we have available with immunotherapy and anti-HER2 therapy [reported] response rates that have ranged anywhere from 3% to 15%. As we [investigate] more combinations composed of immunotherapy and anti-HER2—directed therapy, we might see more enhanced responses.

Are there any encouraging TKIs under investigation? What work is being done with pyrotinib?

Pyrotinib is a dual HER2 and EGFR blockade TKI that has shown some very encouraging single-agent activity in the phase I setting in patients who have been previously treated with trastuzumab. We’re seeing ORRs between 60% and 70%. Furthermore, in women who are trastuzumab-naïve, ORRs seem to increase with pyrotinib.

While there was good single-agent activity, a phase II trial looking at pyrotinib in combination with capecitabine versus lapatinib and capecitabine showed an incredible ORR rate of close to 79% or 80% with the pyrotinib combination. [The combination] also showed improved median PFS compared with lapatinib and capecitabine. Interestingly, while many of these patients were heavily pretreated, they were treated with up to 2 lines of therapy, so it's unclear right now whether pyrotinib will soon translate into standard of care in the second-line setting or the third-line setting. No head-to-head comparison has been made between T-DM1 and pyrotinib. Hopefully, at some point, we'll get some of that data as well.

Neratinib is also a TKI with both HER2 properties as well as EGFR properties. While it has already been approved for use in the adjuvant setting, there are ongoing trials exploring its use in the metastatic setting. The trial that comes to mind is the phase III NALA trial, which is looking at women who had ≥2 lines of treatment for metastatic HER2-positive breast cancer and is randomizing them to either receive neratinib in combination with capecitabine versus lapatinib with capecitabine. Even in the third-line or beyond setting, we're seeing ORRs of about 32% as well as enhanced median PFS in comparison with lapatinib/capecitabine. The other exciting component of neratinib is that it is a small molecule TKI; as such, there seems to be a delay in symptomatic central nervous system (CNS) disease in women who receive the neratinib/capecitabine combination versus those who received lapatinib/capecitabine. Therefore, perhaps this can be used in women who have progression of their disease in the CNS. We don't have any other good systemic treatments that cross the blood—brain barrier.

How are these emerging agents fitting into the treatment paradigm? What should your colleagues know in terms of selection and sequencing?

In the foreseeable future, I still believe that taxane and dual HER2-antibody blockade with pertuzumab and trastuzumab will continue to be a first-line regimen. It seems as though, right now, most trials are looking at patients who were previously treated with T-DM1. T-DM1 will likely stay in the second-line setting for these women, but beyond that, we're looking at multiple options, including novel antibodies and TKIs, that will change how we treat these women who have progressed on trastuzumab and T-DM1.

Also, many of the novel TKIs for HER2-positive metastatic disease, are being used in combination with T-DM1 as well, so perhaps we might see the entrance of TKIs a little bit earlier on in the treatment of our patients, either in the second-setting in combination with T-DM1 or separately once there's a head-to-head trial.

References

1. Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: a phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37(suppl 15, abstr 1000). doi: 10.1200/JCO.2019.37.15_suppl.1000.
2. Meric-Bernstam F, Beeram, Mayordomo JI, et al. Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers. J Clin Oncol. 2018;36(suppl 15, abstr 2500). doi: 10.1200/JCO.2018.36.15_suppl.2500.
3. Trastuzumab Deruxtecan Demonstrated Clinically-Meaningful Response in Patients With Refractory HER2-Positive Metastatic Breast Cancer, a Population With High Unmet Need. AstraZeneca. Published May 8, 2019. https://bit.ly/2Q1SuEF. Accessed May 8, 2019.