Newly Defined Breast Cancer Targets Expand TNBC Treatment Options

Advances with chemoimmunotherapy combinations, PARP inhibitors, and antibody-drug conjugates (ADCs) are creating an increasingly specified treatment landscape for patients with triple-negative breast cancer (TNBC), including those with HER2-low disease, according to Kevin Kalinsky, MD, MS.

“This is a great time for us to talk about some of the advances we’re making, including in medical oncology, with some of the new drugs that have been approved, even in the past couple of weeks,” Kalinsky said in an interview with OncLive^® during the 40th Annual Miami Breast Cancer Conference^®.

In the interview, Kalinsky discussed the evolution of genetic sequencing in TNBC, the significance of breast cancer tumor board discussions for informing further research and optimizing patient care, and how future directions in breast cancer treatment are building off the current benefits of drugs classes like ADCs.

The phase 3 DESTINY-Breast04 trial (NCT03734029), which evaluated the ADC fam-trastuzumab deruxtecan-nxki (Enhertu) vs physician’s choice of chemotherapy in 494 patients with previously treated hormone receptor (HR)–positive, HER2-low advanced breast cancer, also included a cohort of 63 patients with HR-negative, HER2-low disease. Treatment with the agent led to a median progression-free survival (PFS) of 10.1 months (95% CI, 9.5-11.5) in the HR-positive population and 8.5 months (95% CI, 4.3-11.7) in the HR-negative population. Kalinsky explained how these findings have guided treatment sequencing in patients with HER2-low disease.¹

He also highlighted the benefits of another ADC, sacituzumab govitecan-hziy (Trodelvy), in patients with metastatic TNBC. The phase 3 ASCENT trial (NCT02574455) investigated sacituzumab govitecan in this population and showed that the agent provided a median PFS of 5.6 months (95% CI, 4.3-6.3) vs 1.7 months (95% CI, 1.5-2.6) with single-agent chemotherapy, supporting sacituzumab govitecan as a standard of care in these patients.²

Kalinsky is an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as the Louisa and Rand Glenn Family Chair in Breast Cancer Research, the director of the Glenn Family Breast Center, and the director of Breast Medical Oncology at Winship Cancer Institute of Emory University in Atlanta, Georgia.

OncLive^®: How has treatment sequencing for metastatic TNBC evolved with the addition of new agents and therapies?

Kalinsky: For patients with metastatic TNBC, we have seen some advances. For patients who have PD-L1–positive tumors, which is about 40% of the population, we give chemotherapy and immunotherapy, specifically pembrolizumab [Keytruda]. We also have sacituzumab govitecan, an ADC, for patients who have TNBC, [as well as] chemotherapy options. If patients have germline BRCA mutations, there are PARP inhibitors.

The biggest advance for patients with metastatic TNBC has been the addition of trastuzumab deruxtecan for patients with HER2-low metastatic breast cancer. That’s defined right now as [tumors that are immunohistochemistry] 1+ or 2+ and have non-amplified [HER2] genes. There was a smaller subgroup of patients [with TNBC] in the DESTINY-Breast 04 study that [was included in] the approval of trastuzumab deruxtecan for patients with HER2-low breast cancer.

[In my presentation, I discussed] how to best sequence the ADCs. Given that sacituzumab govitecan was approved and showed an overall survival benefit, specifically in patients with TNBC, that tends to be the preferred initial ADC [for that population]. [I also talked about] the limitations [regarding] the absence of data we have right now about sequencing ADCs.

How do you approach sequencing strategies based on patient characteristics?

When we have a patient with newly metastatic [disease], 1 of the most important [up-front processes] is checking for PD-L1 status. That is done based upon available tissue. This can be done [with] the metastatic tissue, and if that’s not available, then we reflex to looking at primary tissue. We do not do this in lymph nodes. In the primary setting, we do this in the breast tissue. [We categorize patients based on] the combined positive score. If patients have a score of 10% or greater, about 40% of patients, we give frontline pembrolizumab.

We should [also] do germline testing to make sure patients don’t have a BRCA mutation or a PALB2 mutation. For instance, if patients have a germline BRCA mutation, we may think about giving them a PARP inhibitor based upon [findings from] the large, randomized trials.

What is the importance of discussing future genetic testing directions in a molecular tumor board?

The molecular tumor board is a new addition to Miami Breast. This reflects where the field is going, that [it is becoming] increasingly complicated [regarding] next-generation sequencing [NGS], germline testing, and how to best incorporate these into the clinic for our patients with metastatic disease. [On January 27, 2023, the FDA approved] elacestrant [Orserdu] for patients who have ESR1 mutations. We have agents targeting the PI3K/AKT/mTOR pathway. This demonstrates that we’re increasingly moving toward precision medicine. That’s reflected in the fact that we had this molecular tumor board [at the meeting] to talk about genomic assays, NGS, and germline testing.

What unmet needs remain across the breast cancer treatment landscape, and what research is seeking to address some of these?

Based upon the tumor subtype, there are different unmet needs. For patients with TNBC, there’s been an advance even in the early-stage setting, with immunotherapy. However, for our patients with metastatic disease, there remains an unmet need for new targets and new drugs. We’ve made advances, including with the ADCs, but we need to do more for our patients. Patients who have received neoadjuvant chemotherapy, and potentially immunotherapy as well, who have residual disease are at higher risk [for recurrence]. Identifying new ways of decreasing recurrence, like with ADCs, in this area, will hopefully move the field forward.

For our patients with HER2-positive breast cancer, we have agents that target the central nervous system [CNS]. That’s been a nice advance. Hopefully, we’ll be using these agents earlier to also help prevent CNS tropism.

For patients with HR-positive, HER2-negative breast cancer, in the metastatic setting, there’s a huge unmet need for targets and drugs beyond [those used to treat] endocrine-sensitive disease. Once patients have endocrine-resistant disease, that can be hard to treat.

For patients with early-stage breast cancer, 1 of the most common questions that we get is: How do I know I’m not at risk for recurrence? This is where the potential role of circulating tumor DNA may come in prognostically and predictably. Ongoing studies are hoping to answer that question and have the potential to move the field forward for that subtype of breast cancer, and potentially other subtypes, as well.

In your view, what were the most important aspects of the 40th Annual Miami Breast Cancer Conference?

Miami Breast is an attractive symposium and conference for many different disciplines. The talks are [given] by surgeons, radiation oncologists, and medical oncologists. It’s a multidisciplinary meeting. That makes it unique. It is also patient centered. We discuss cases and how will we manage these patients. It’s a practical conference. It reflects how quickly the field is changing. This sort of meeting is important, so we can keep up to date and best treat our patients.

References

1. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
2. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384:1529-1541. doi:10.1056/NEJMoa2028485