Response-Guided Therapy Is the Next Frontier for Tailoring Therapy in HER2+ Breast Cancer

Response-guided therapies for patients with HER2-positive disease continue to evolve as upcoming clinical trials aim to provide answers on optimal treatments, according to Lisa M. Carey, MD, ScM, FASCO. Carey’s presentation at the 40th Annual Miami Breast Cancer Conference® noted that the standard treatments for this patient population are complex and involve multiple drugs over long courses of time. However, tailored efforts including using risk-adapted strategies based on anatomic risk and response-guided therapies based on pathologic complete response (pCR) rate may represent next wave of advances.¹

“The takeaway [from my presentation] is that…we do a good job in HER2-positive early breast cancer in terms of the medical therapy facilitating less surgery, which is good, and facilitating the thoughtful use of drugs,” Carey said. “We have to build on it even more. We give a lot of therapy to these patients, and we know we’re over treating many of them. The efforts to try and get even more rationality to how we treat HER2-positive breast cancer will be for our patients benefit and many trials are going in that direction.”

Carey highlighted key clinical trials with the potential to impact the future direction of the field, such as the phase 2 CompassHER2-pCR trial (NCT04266249) and the phase 3 CompassHER2 RD trial (NCT04457596). Additionally, she detailed the effect of the response-adapted phase 2 PHERGain trial (NCT03161353) in which patients (n = 285) receiving trastuzumab (Herceptin) and pertuzumab (Perjeta) using 18F-fluorodeoxyglucose-PET experienced a 37.9% pCR (95% CI, 31.6%-44.5%; P < .0001 compared with the historical rate) , suggesting that PET scans can identify responders who may not need chemotherapy.1,2 Carey noted that HER2 expression mattered in the trial and serves as another means of identifying responders.¹

In an interview with OncLive®, Carey, the L. Richardson and Marilyn Jacobs Preyer Distinguished Professor for Breast Cancer Research and deputy director of Clinical Sciences at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, discussed upcoming treatments that could impact standard-of-care practices and the continually evolving role of antibody-drug conjugates (ADCs) role in the treatment paradigm.

OncLive^®: Can you provide an overview of what you covered in your presentation?

I talked about response-guided therapy in HER2-positive breast cancer in the nonmetastatic setting. We already do response-guided therapy in HER2-positive breast cancer. We can minimize surgery through neoadjuvant therapy [and] can tailor the use of more aggressive drugs such as ado-trastuzumab emtansine [Kadcyla; T-DM1] predicated on if [patients] have residual disease. Patients who have pCR can do very well without additional therapy.

We [also] talked about ways in which we’re already moving forward. There are the COMPASS trials. CompassHER2-pCR, if successful, will allow us to take a de-escalated regimen of [docetaxel, trastuzumab, and pertuzumab] THP, [which uses] only 1 chemotherapy drug, and if a patient achieves pCR, even if they started as [with a] larger or node-positive cancer, they don’t have to get more chemotherapy. If that’s successful, that will be another step toward response-guided and tailored therapy. CompassHER2 RD trial is sort of a flip side of [this in that it adds therapy]. In [patients with] high-risk residual disease, we’re adding tucatinib [Tukysa] to T-DM1. We’ll see if that can help with those higher-risk patients who still have a relapse risk of approximately 20%.

One of the standards of care for patients with HER2-positive breast cancer has been to give chemotherapy and/or multiple anti-HER2 drugs for long periods of time. What ongoing approaches are seeking to alter these approaches?

The only group that we don’t already do response-guided therapy [for] is very small node-negative tumors. The rest we give neoadjuvant therapy, and we predicate additional treatment on response to that. The Compass trials are important for the next steps of de-escalating when the cancer is very sensitive and escalating if it’s more resistant and needs more drugs.

We talked a little bit about some of the imaging approaches. There’s a European trial called PHERGain, [where] half of the [patients received] traditional polychemotherapy plus trastuzumab and pertuzumab. The other half [received] trastuzumab and pertuzumab with endocrine therapy if they had hormone receptor–positive [disease] and after 2 cycles they had a PET scan. If the PET showed response to that early marker, patients could continue trastuzumab and pertuzumab alone. If that is a successful trial, that’s a mechanism for using an all-biologic regimen [with] no chemotherapy at all—that would be transformative.

The other things that are coming are [integrated] biomarkers. [For example,] the HER2Dx [assay], looks at immune activation, at intrinsic subtype, and is trying to integrate these features we know are important to how HER2-positive breast cancers respond to therapy.³

Are there any other advancements that you’re hoping to see in response-guided therapy in HER2-positive breast cancer?

The future absolutely is going to be within neoadjuvant therapy, with more adaptive approaches, but those have to be tested in trials. I’m excited that either a combination of biomarkers and response by imaging can give us an early look before surgery so [we] can be more sophisticated than we are right now.

Can you expand on your position presented during the Medical Crossfire^® on sequencing ADCs in hormone receptor–positive metastatic breast cancer?

Debu Tripathy, MD, and I talked about the rapid emergence of ADCs for hormone receptor–positive/HER2-negative metastatic disease. We have 2 drugs that are approved in the pretreated setting, [for those with] endocrine resistant [disease], so the best treatment for these patients upfront is endocrine-based therapy. But when you start to get to chemotherapy the tools we have now include ADCs, specifically fam-trastuzumab deruxtecan-nxki [Enhertu] and sacituzumab govitecan-hziy [Trodelvy]. We talked a little bit about the trials and who would be good patients for these and [the consensus was] pretreated patients.

In the audience, there was a general agreement that most [clinicians] when they get to chemotherapy for these patients, the first thing they give is usually capecitabine because it’s oral and it’s a little bit easier. After that you’ve got trastuzumab deruxtecan, [which] is more tested in that [subsequent] lines [of therapy], and sacituzumab govitecan.

Dr Tripathy and I don’t vary much in what we believe about the use of these drugs [and] we talked mostly about the nuances of how you choose these patients. In terms of ADCs after ADCs, and if chemotherapy is going to be given in this way, we’re going to have to start thinking about the nature of the payload and the resistance mechanisms. You have the antibody target and the drug payload, and you can have sensitivity and resistance [to] either of those. We had a spirited conversation about where we think [ADCs are going] in the future, but it’s an exciting time because most patients end up getting chemotherapy at some point and we want it to be the best chemotherapy, the most efficacious and the least toxic.

Were there any other presentations during the meeting that you wanted to highlight?

There were several talks about new endocrine therapies with the selective estrogen receptor degraders. [There were also] a lot of talks about CDK4/6 inhibitors and what the best [ones] might be. Some poster sessions [focused on] trials such as [the phase 3] HARMONIA [NCT05207709], which is going to do a head-to-head comparison [of ribociclib

(Kisqali) vs palbociclib (Ibrance)] informed by intrinsic subtype. The future [will be] more sophisticated about the molecular biology of breast cancer as opposed to relying entirely on estrogen receptor, progesterone receptor, and HER2 [expression].

References

1. Carey L. Response-guided therapy in HER2-positive breast cancer. Presented at: 40th Annual Miami Breast Cancer Conference; March 2-5, 2023; Miami Beach, FL.
2. Pérez-García JM, Gebhart G, Borrego MR, et al. Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial. Lancet Oncol. 2021;22(6):858-871. doi:10.1016/S1470-2045(21)00122-4
3. Prat A, Guarneri V, Pascual T, et al. Development and validation of the new HER2DX assay for predicting pathological response and survival outcome in early-stage HER2-positive breast cancer. EBioMedicine. 2022;75:103801. doi:10.1016/j.ebiom.2021.103801