Research on Current and Emerging HER2-targeted Agents Continues to Advance Breast Cancer Treatment

Cynthia X. Ma, MD, PhD

Recent investigations of HER2-targeted agents have shifted the standard of care (SOC) across breast cancer subtypes and strengthened the current treatment landscape. However, further research is necessary to maximize and expand the use of available therapies, according to Cynthia X. Ma, MD, PhD, co-chair of a State of the Science Summit™ on breast cancer.

“Our presenters provided [not only] the current updates [across breast cancer subtypes], but also what we might be looking forward to in the next few years,”​​ said Ma, who is a professor in the Department of Medicine of the Division of Oncology at the Washington University School of Medicine, St. Louis, Missouri.

These ongoing and future avenues include efforts to de-escalate therapy in HER2-positive breast cancer, improve the sequencing of available CDK4/6 inhibitors, and introduce new biomarker-guided therapies into the armamentarium for both HER2-positive and triple-negative breast cancer (TNBC).

There has also been considerable interest in improving the benefit conferred by antibody-drug conjugates (ADC), particularly fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), after the agent’s establishment as a standard of care in HER2-positive breast cancer. The antitumor activity and tolerability of T-DXd was first shown in the phase 2 DESTINY-Breast01 trial (NCT03248492), and was confirmed by findings from the phase 3 DESTINY-Breast03 trial (NCT03529110).¹ The agent’s most recent FDA approval in HER2-low metastatic breast cancer, based on results from the phase 3 DESTINY-Breast04 trial (NCT03734029), indicates its potential efficacy in other, historically negative, classifications of HER2.²

In an interview with OncLive, Ma provided an overview of key topics discussed by herself and her colleagues, including updates in the treatment of patients with TNBC, recent data on HER2-targeted agents in metastatic and early-stage HER2-positive breast cancer, and the role of CDK4/6 inhibitors and oral selective estrogen receptor degraders (SERDs) in hormone receptor (HR)-positive, HER2-negative disease. Ma also expanded on the investigation of ADCs across breast cancer subtypes, including datopotamab deruxtecan (Dato-Dxd) in TNBC, and T-DXd in HER2-low and HER2-positive breast cancer.

OncLive: What key updates in HER2-positive breast cancer were presented by Nusayba A. Bagegni, MD, at this meeting?

Ma: At this OncLive SOSS for breast cancer, we had a series of lectures by breast cancer oncologists at Washington University School of Medicine. [The event was] chaired by myself and Foluso O. (Bisi) Ademuyiwa, MD, MPH, MSCI. The [program] provided an update on the current landscape of agents that we are using to treat our patients with metastatic breast cancer, whether it’s in TNBC or the HR-positive, [or] HER2-positive [space].

In her lecture, Dr Bagegni went through updates [on] HER2-targeted drugs for metastatic breast cancer as well as early-stage breast cancer. [This included] the [phase 2] ATEMPT 2.0 trial [NCT04893109] that showed excellent long-term outcomes, as well as the [phase 2] APT trial [NCT00542451] for patients with lower-risk, HER2-positive breast cancer who need shorter or de-escalated approaches. She also went through biomarker [assays that] would potentially let us select patients who are more sensitive to HER2-targeted drugs, [such as] HER2DX.

In addition, she went through updates [from] the [phase 3] DESTINY-Breast02 [NCT03523585] and DESTINY-Breast03 studies, [which helped] change the current second-line treatment [for HER2-positive breast cancer] from ado-trastuzumab emtansine [T-DM1] to T-DXd.

[She also highlighted the phase 3] DESTINY-Breast06 trial [(NCT04494425), which] is looking at whether this agent could be the [new] treatment of choice in patients with HER2-low disease compared [with] standard of care chemotherapy. The activity of this agent is impressive, [but first] we have to see how to best define HER2-low disease. We’re looking forward to better scoring methods for immunohistochemistry [IHC] or other assays to tell us how to identify patients who may benefit from this drug.

Unlike research in early HER2-positive breast cancer, which has primarily been focused on potential treatment de-escalation, it seems like continued investigations of T-DXd in early-stage disease aim to utilize an escalated approach. What are your thoughts on this?

[We have] a phase 1 study [NCT05372614] looking at T-DXd in combination with neratinib [Nerlynx] in patients with HER2-altered malignancies. At Washington University, we have had great interest in mutation-guided therapies. We’ve shown that targeting HER2 mutations in breast cancer can be achieved by using a TKI [like] neratinib. This trial was based on laboratory results from Ron Bose, MD, PhD, of Washington University School of Medicine, showing that the combination can be synergistic. Neratinib could help increase the uptake of T-DXd, generating higher efficacy for both agents in these patient populations.

Regarding Katherine Clifton, MD’s presentation on the role of CDK 4/6 inhibitors in the management of HR-positive, HER2-negative breast cancer, what key trials have helped clarify the optimal sequencing of first- and second-line therapeutics?

Dr Clifton went over the phase 3 studies of CDK4/6 inhibitors in combination with hormonal therapy [in the] first and second line. She went through the overall survival [OS] data presented last year for the PALOMA-2 [NCT01740427] and MONARCH 3 [NCT02246621] studies. Additionally, she [discussed] whether continuing [treatment with a] CDK4/6 inhibitor would benefit patients [who have] already progressed on prior CDK4/6 inhibitors. [This discussion involved] results from the negative [phase 2] PACE study [NCT03147287] trial of palbociclib [Ibrance] after [prior] palbociclib and the positive phase 2 MAINTAIN trial [NCT02632045]. [MAINTAIN showed that] switching from a prior CDK4/6 inhibitor to ribociclib [Kisqali] and switching the endocrine therapy from an aromatase inhibitor [AI] to fulvestrant [Faslodex] was beneficial [for patients]. Then she presented the [phase 2] RIGHT Choice trial [NCT03839823] in patients with de novo metastatic, HR-positive, HER2-negative breast cancer with an aggressive clinical course. This [trial] has shown that [patients on] chemotherapy did not [experience] better progression-free survival [compared with] the combination of ribociclib and endocrine therapy.

After that, Dr Clifton presented several case [studies] to illustrate our current approaches [for] managing patients with metastatic breast cancer. After the discussion, we presented management strategies for patients with TNBC.

With both the PALOMA-2 and phase 3 PALLAS (NCT02513394) trials reporting negative data with the addition of palbociclib to standard endocrine therapy, how might clinicians view the agent’s efficacy in comparison with other CDK4/6 inhibitors?

That’s a complicated question. There are certain caveats [in] the PALOMA-2 trial, [such as] the imbalance of follow-up information between the 2 arms. [There are also] differences [between] PALOMA-2 and other trials regarding the percentage of patients who had a disease-free interval less than 12 months. [Additionally], an overall survival benefit wasn’t shown [in this trial]. Although, we cannot say for sure that palbociclib is inferior, we’re using the other 2 CDK4/6 inhibitors more in the clinic.

What were the main highlights from your presentation on the role of oral SERDs in HR-positive, HER2-negative breast cancer, as well as the presentation on updates in TNBC given by your co-chair, Dr Ademuyiwa?

I presented some updates regarding the oral SERDs currently in development. We went over the phase 3 EMERALD study [NCT03778931] that led to the FDA approval of elacestrant [Orserdu] in late January [2023 for] patients with ESR1-mutant, metastatic HR-positive, HER2-negative breast cancer [who] progressed on 1 [prior] endocrine therapy. We also went through some other HER2-targeting strategies such as selective estrogen receptor [ER] covalent antagonists, or SERCAs, and complete ER antagonists, or CERANs. These are in early stages of development. Hopefully, they will be entering the clinic soon.

Dr Ademuyiwa went through current updates regarding the [use of] ADCs. For example, [trials investigating] sacituzumab govitecan-hziy [Trodelvy] in addition to the HER2-targeted drug T-DXd [showed that these agents] improved survival, and both ADCs are now available for patients with metastatic breast cancer. She also discussed other potential ADCs that are being developed. [For example], Dato-DXd is a TROP-2 ADC that [contains] a chemotherapy payload similar to T-DXd. That [agent] has shown promising results in the phase 1/2 BEGONIA trial [NCT03742102] of patients with metastatic TNBC in the first line. That ADC is very promising. Hopefully, the efficacy [of Dato-DXd will] be confirmed in future studies.

What stood out from Andrew Davis, MD’s presentation on HER2-low breast cancer?

First, Dr Davis went through the definition of HER2 low by IHC, the shortcomings of using IHC to define HER2 low, and potential future strategies [to treat patients with HER2-low breast cancer] that are in clinical testing. In addition, he went through the trials [that investigated] targeting HER2-low disease with HER2-targeted ADCs. [Overall, there’s] a lot to look forward to in this area.

Editor’s Note: Dr Ma reports serving in a consultory or advisory role for Novartis, Pfizer, Seattle Genetics, Agendia, AstraZeneca, Biovica, Eisai, Olaris, Sanofi, Inivata; she received research funding from Pfizer and Puma.

References

1. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. FDA. May 4, 2022. Accessed April 5, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed April 5, 2023. https://www.fda.gov/news-events/press-announcements/