NGS and Novel Therapies Lends to Prolonged Survival Outcomes in HR+/ HER2– Breast Cancer

Francisco J. Esteva, MD, PhD

Recent advancements in sequencing targeted therapies are reshaping the management of hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, underscoring the critical role of next-generation sequencing (NGS) in personalizing treatment decisions, according to Francisco J. Esteva, MD, PhD.

“[It is important to ensure that] all patients in the metastatic setting are tested not only for estrogen and progesterone receptors [ER; PR] or HER2 [status, but they also must undergo] NGS,” he explained in an interview with OncLive®.

In the interview, Esteva discussed key factors to consider when treating patients with HR-positive, HER2-negative breast cancer, as well as highlighted data from several key trials across breast cancer treatment landscape and their clinical impact.

Esteva currently serves as the interim chief of the Division of Hematology and Oncology and the chief of Breast Medical Oncology at Lenox Hill Hospital where he is the director of Breast Medical Oncology for Northwell Health, in New York, New York.

Check out additional insights that Esteva provided on the topic in another interview with OncLive.

OncLive: What are the key factors to consider when sequencing CDK 4/6 inhibitors for metastatic breast cancer treatment and how may biomarker assessment inform treatment decisions in this setting?

Esteva: The landscape is changing because of the recent approvals of inavolisib [Itovebi] and capivasertib [Truqap]. In patients who develop metastatic breast cancer, it's recommended to do a biopsy to [confirm the presence of] metastatic disease to start with, and then request NGS to look for specific mutations in the tumor.

The most relevant [mutations] for this group of patients are genetic alterations in the PIK3CA kinase pathway, which could include a PIK3CA, AKT, and P10. We also look for ER mutations, [but those] would not be used in the front line setting right now. For patients with no [actionable] mutations, we would use a CDK 4/6 inhibitor like palbociclib [Ibrance], ribociclib [Kisqali[, or abemaciclib [Verznio]. It can be in combination with an aromatase inhibitor [AI], possibly fulvestrant [Faslodex], if the patient is progressing. But for patients with PIK3CA mutations, this is where we have now these new therapies. [This] would be for the first-line [setting, to observe] how this affects the treatment, [before] we move [to] the second-line [setting] with ESR 1 mutations [where] selective estrogen receptor degraders and subsequent therapies [might be more appropriate].

Looking to the phase 3 SOLAR-1 trial (NCT02437318), what key findings were observed here?

SOLAR-1 was a study that looked at alpelisib [Piqray], a PIK3CA inhibitor, compared with placebo, in combination with fulvestrant in postmenopausal women with HR- positive, HER2-negative metastatic breast cancer, who progressed on an AI or had prior AI therapy.

The interesting thing is that they looked at 2 different cohorts: the PIK3CA mutation cohort, and the non-mutant wild type PIK3CA kinase cohort. However, in this study, [particularly in patients] with PIK3CA mutations or alterations, these patients had an improved PFS compared [with] placebo. The main complications in these patients were the high incidence of hyperglycemia, rash and other adverse effects that limited the use of this therapy widely.

Another notable trial is the phase 3 INAVO120 trial (NCT04191499). What would you like your colleagues to know about the outcomes of this study?

Patients [enrolled] on the trial had PIK3CA-mutated HR- positive, HER2-negative, locally, advanced or metastatic breast cancer. The biomarkers were measured either by circulating tumor DNA [ctDNA], by tissue, or ctDNA testing locally. Basically, [patients] were randomized 1:1 to palbociclib and fulvestrant and placebo vs inavolisib, which is a PIK3CA kinase inhibitor.

The study showed a significant improvement in progression-free survival. This [data] was presented at the San Antonio Breast Cancer Symposium, [and then] updated at the ASCO Annual Meeting, and [most recently], has been published in the New England Journal of Medicine. [This treatment approach] prolonged PFS and delayed the initiation of chemotherapy, which is the most important finding in this group of patients.

You can't compare different drugs and different trials, but, for example, the hyperglycemia reported was mostly grade 1 or 2. The same thing for diarrhea, rash, and stomatitis. But [thus far] it seems like it's a tolerable treatment and quite effective for this population in the frontline setting.

Finally, where do the results from the phase 3 CAPItello-291 (NCT04305496) trial fit into the treatment space?

[Patients in the] CAPItello-291 trial, were [in a] similar situation. [These patients had] HR-positive, HER2-negative metastatic disease and were progressing or had received a prior CDK 4/6 inhibitor. [Patients] were randomized to [receive] capivasertib and fulvestrant or fulvestrant and placebo, and they looked at the overall population, as well as patients with AKT pathway alterations, as capivasertib is an inhibitor of AKT.

This study [showed that], patients treated with capivasertib and fulvestrant had a longer PFS, and particularly in the patients with PI3K, AKT, or P10 alterations. Again, the AEs seemed acceptable, most of them being grade 1 or grade 2. The quality of later life was maintained. The blood sugar was not extremely high in patients treated with capivasertib compared [with] placebo. Again, [this] sounds like a tolerable treatment.

How should antibody-drug conjugates be sequenced to maximize benefit in HER2-low breast cancer?

Another area that is of high interest is the use of antibody drug conjugates and how we can sequence them. In patients with low levels of HER2 that we used to consider triple-negative breast cancer now have HER 2-low breast cancer, and those patients can be treated with [fam-trastuzumab deruxtecan-nxki; Enhertu] or [sacituzumab govitecan-hziy; Trodelvy]. It was interesting to see the data on trials, and we need to figure out how to sequence these therapies to get the maximum benefit for these patients.

What is your primary takeaway for your colleagues regarding the role of NGS?

My takeaway is that we need to do NGS, whether it's tissue or blood liquid biopsy, looking at ctDNA in all patients, in particular [those with] HR-positive, HER2-negative metastatic breast cancer to identify patients with PI3K/AKT mutations. This will determine [which agent] patients will receive in the front line setting and which [they will get] in the second line setting. However, after AI therapy, there are studies also looking at frontline therapy with capivasertib.