Novel Treatment Regimens Populate the HR+/HER2– and HER2+ Breast Cancer Armamentariums

The continued investigations of agents such as fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), ado-trastuzumab emtansine (T-DM1; Kadcyla), and ribociclib (Kisqali) in patients with hormone receptor (HR)–positive, HER2–negative and HER2-positive breast cancer have yielded potentially practice-transforming results, according to Yara Abdou, MD. However, adverse effects (AEs) continue to mediate the advances seen with these drugs, and treatment decisions in each line of therapy must center around individual patient needs and risk factors, she emphasized.

At the 2023 ASCO Annual Meeting, findings were presented from the phase 3 CAPItello-291 trial (NCT04305496) of the AKT inhibitor capivasertib plus the oral selective estrogen receptor degrader (SERD) fulvestrant (Faslodex) in patients with HR-positive, HER2-negative advanced breast cancer. In the overall population, which included patients with HR-positive, HER2-negative advanced disease who had relapsed or progressed during or after treatment with an aromatase inhibitor, the median progression-free survival (PFS) was 7.2 months with capivasertib plus fulvestrant vs 3.6 months with fulvestrant plus placebo (hazard ratio, 0.60; 95% CI, 0.51-0.71; P < .001).¹

Additionally, in the HER2-positive arena, findings from the phase 3 DESTINY-Breast03 trial (NCT03529110) continue to confirm the benefit of T-DXd over T-DM1. In this trial, the 12-month PFS rates were 75.8% (95% CI, 69.8%-80.7%) in patients who received T-DXd vs 34.1% (95% CI, 27.7%-40.5%). However, 98.1% of patients in the T-DXd arm experienced treatment-related AEs (TRAEs) compared with 86.6% of those in the T-DM1 arm.²

“We’ve made big leaps in HR-positive breast cancer, especially regarding targeted therapies in the frontline setting. Patients are living for a long time with metastatic disease,” Abdou said in an interview with OncLive^®.

In the interview, Abdou discussed key updates in breast cancer research, including paradigm shifts on the horizon for T-DXd, key data regarding capivasertib in the HR-positive, HER2-negative setting, and the importance of weighing the efficacy benefits of these agents with the risks for serious associated toxicities.

Dr Abdou is an assistant professor of medicine in the Division of Oncology in the Department of Medicine at the University of North Carolina School of Medicine in Chapel Hill.

OncLive: What were your overall perceptions of new data in HR-positive, HER2-negative breast cancer that came out of the 2023 ASCO Annual Meeting?

Abdou: [It was] exciting to see more options for patients, particularly in the adjuvant setting. We already have abemaciclib [Verzenio], 1 of the CDK4/6 inhibitors, approved in that setting through the [phase 3] monarchE study [NCT03155997]. [Findings from the phase 3] NATALEE trial [NCT03701334] were presented at the 2023 ASCO Annual Meeting, supporting potentially a new CDK4/6 inhibitor, ribociclib, in the adjuvant setting. It’s nice to see more options [being evaluated] for patients.

In the metastatic setting, it was nice to see the final analysis of the [phase 3] TROPiCS-02 trial [NCT03901339] confirming the efficacy of sacituzumab govitecan-hziy [Trodelvy], with improvements in PFS and overall survival [vs chemotherapy] while maintaining a similar safety profile. [There were] a lot of exciting data for patients in the early and metastatic settings with HR-positive, HER2-negative breast cancer.

What factors do you consider and prioritize when selecting second-line treatments for patients with HER2-positive disease?

I consider many factors when selecting second-line treatment options for these patients, including efficacy, toxicity profiles, and, most importantly, the ongoing risk of central nervous system [CNS] metastases.

In general, in the absence of a particular toxicity, I tend to use T-DXd for patients in the second-line setting, based on the impressive efficacy data seen in DESTINY-Breast03. I always keep in mind the risk of interstitial lung disease [ILD], which [occurs in approximately 10% to 15% [of patients who receive] T-DXd. If there’s a particular patient [in whom] I’m concerned about ILD, I might choose a different agent in the second-line setting.

The other important factor is CNS metastases. DESTINY-Breast03 included patients with treated CNS metastases, but did not include patients with active metastases, whereas the [phase 2] HER2CLIMB trial [(NCT02614794), which investigated tucatinib [Tukysa] plus trastuzumab [Herceptin] and capecitabine [Xeloda] in patients with HER2-positive metastatic disease,] included patients with active, untreated brain metastases. It’s important to know that these agents work in patients with active brain metastases. Data from the [phase 2] TUXEDO-1 trial [NCT04752059] also indicate that T-DXd is active in patients with active brain metastases, although, the numbers [in that trial] were much smaller. Many oncologists tend to reach for the tucatinib combination in patients with active brain metastases based on the HER2CLIMB data, but both agents have good data in that regard.

How does the safety profile of T-DXd compare with that of T-DM1?

DESTINY-Breast03 showed that they have similar rates of TRAEs. Discontinuation rates are slightly higher with T-DXd compared with T-DM1. Most importantly, the serious toxicity of ILD was higher with T-DXd, at 10.5% vs 1.9% with T-DM1. In real life, nausea, vomiting, and alopecia are bothersome AEs [associated with] T-DXd that affect patients. I tend to communicate that with patients before making a choice for treatment.

How have you begun to utilize T-DXd in the second line?

I use T-DXd in the second-line setting based on the DESTINY-Breast03 data, which made it clear that T-DXd is the winner in the second-line setting compared with T-DM1, with a [median] PFS that was [not reached (95% CI, 18.5-not estimable) vs 6.8 months (95% CI, 5.6-8.2) with T-DM1. I certainly use T-DXd in the second-line setting, taking into consideration the toxicity profiles of both [T-DXd and T-DM1]. In patients with any risk of ILD, I tend to make that choice with caution.

Is there still a role for T-DM1 in HER2-positive breast cancer?

I believe there is a role for T-DM1, probably in the third-line setting or beyond. It’s an effective antibody-drug conjugate and is well tolerated, so it’s an option for patients with metastatic disease. T-DM1 is currently the adjuvant treatment of choice for patients who [have] residual disease after surgery in the early-stage setting.

What does the future hold for T-DXd in patients with HER2-positive disease?

T-DXd is climbing the ladder [of] treatment lines. The [phase 3] DESTINY-Breast09 trial [NCT04784715] is investigating T-DXd in the first-line setting compared with the [phase 3] CLEOPATRA trial [NCT00567190] regimen that’s currently the approved first-line [standard] for [patients with] HER2-positive breast cancer. [This is a] 3-arm trial evaluating T-DXd plus pertuzumab [Perjeta], T-DXd alone, and the CLEOPATRA [regimen].

Other studies are investigating T-DXd in the early setting. The [phase 3] DESTINY-Breast05 [NCT04622319] trial is evaluating T-DXd vs T-DM1 in patients with residual disease after neoadjuvant therapy. The [phase 3] DESTINY-Breast11 trial [NCT05113251] is investigating T-DXd in the neoadjuvant setting.

One of the concerns with T-DXd is that serious 10% to 15% risk of pneumonitis. In the first-line setting, when patients are expected to live for 5 or 6 years, it’s a concern to be thinking about a serious AE, such as pneumonitis. That becomes even more of a concern in the curative-setting population. That’s something we should consider, using effective treatment [and being mindful of] toxicity.

What factors do you consider when choosing third-line treatments for patients with HER2-positive disease?

At this point in patients’ treatment, they’ve had accumulative toxicities from their ongoing therapies. It’s important to weigh toxicity when making decisions on what comes next. Another factor is the ongoing risk of CNS metastases. It’s important, if patients have CNS metastases, to choose a treatment that crosses the blood-brain barrier and can control CNS disease as well. Regarding the toxicity profiles, those will differ from 1 patient to another depending on their history and what prior agents they’ve used. At this point, it’s a patient-centered decision where we get to make that decision together.

What are some of the biggest unmet needs in HR-positive metastatic breast cancer?

One big unmet need is in patients who progress rapidly on these drugs. A subset of patients start targeted therapy and endocrine therapy and rapidly progress through it, and they tend to have a poor prognosis overall. It’s important to understand what’s driving this progression. What’s the mechanism of resistance with endocrine therapy? That remains a big question that we would like to understand more about.

What are the efficacy and safety profiles of capivasertib as seen in the CAPItello-291 trial?

I have not used capivasertib in clinical practice yet. Many of us have not used it yet. Diarrhea and rash seem to be the most common AEs based on [the data from] CAPItello-291. There’s no way to tell [which patients] are more at risk of developing these AEs, so it’s important to educate patients on what to expect.

Overall, the AKT inhibitor has a tolerable safety profile, and it compares favorably with other agents targeting that pathway. For example, the risk of hyperglycemia was much lower [with capivasertib] than what we see with alpelisib [Piqray], an approved PIK3CA inhibitor [for patients with HR-positive, HER2-negative disease]. Also, the risk of dermatitis was much lower [with capivasertib in CAPItello-291] compared with everolimus [Afinitor] in the POLARIS trial [NCT03280303].

How do you sequence CDK4/6 inhibitors across all lines of therapy?

I use CDK4/6 inhibitors in the first-line setting with endocrine therapy for patients with metastatic HR-positive, HER2-negative breast cancer. Once patients progress on that CDK4/6 inhibitor, should we continue the CDK4/6 inhibitor beyond progression in the second-line setting? We’ve seen data from the [phase 2] PACE [NCT03147287] and PALMIRA [NCT03809988] trials showing no benefit with continuing palbociclib [Ibrance] when patients have progressed on palbociclib. This was a bit different than what we saw with the [phase 2] MAINTAIN trial [NCT02632045], [which showed that switching] endocrine therapy backbones and [switching] the CDK4/6 inhibitor to ribociclib [had] a bit of value. We need more data, and we’ll get more data with the postMONARCH trial [NCT05169567], which is a phase 3 trial designed to answer this question.

How do AKT inhibitors compare with PI3K inhibitors?

Post-CDK4/6 inhibition, there’s historically a 2- to 3-month PFS with just standard endocrine therapy, which is a bit disappointing. It seems like targeting [the AKT] pathway after CDK4/6 inhibitor progression [elicits an approximately] 7-month PFS, which is great. It’s interesting that in the CAPItello-291 trial, capivasertib improved PFS compared with fulvestrant alone in the overall population, regardless of alterations in the AKT pathway, whereas alpelisib, the PI3Kα inhibitor approved in this setting, only works in patients with PIK3CA mutations. Also, the AEs were markedly different [between capivasertib and alpelisib]. We see less hyperglycemia with capivasertib and more hyperglycemia with the PI3K inhibitor. There are some differences, and more data will explain those down the line.

How has ongoing research with oral SERDs in breast cancer affected your perception of this class of agents?

Elacestrant [Orserdu] was the first oral SERD approved for patients with metastatic HR-positive, HER2-negative breast cancer with ESR1 mutations who have received prior endocrine therapy. [That approval was] based on [findings from] the [phase 3] EMERALD trial [NCT03778931]. This study paved the way for oral SERDs as monotherapy for patients with metastatic disease. There are many ongoing studies with other oral SERDs that we’re excited to hear about. They’re being studied as monotherapy and in combination with other targeted treatments, such as CDK4/6 inhibitors. We’re also seeing them move to the early-stage setting. Studies are also evaluating oral SERDs in the adjuvant setting. [There is] more to come regarding oral SERDs and advancements in this area.

How do patient preferences and quality of life (QOL) considerations influence your treatment selections?

Patient preferences and QOL are important when I make treatment selections. We as oncologists are experts on breast cancer, [and patients] are experts on their lives, goals, and preferences. I like to think of it as both of us bringing our expertise together and coming up with a plan together that fits their needs and goals for themselves. I prioritize [patient] preferences and QOL factors with every decision I make for their treatments.

References

1. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
2. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022