Advani Spotlights Clinical Trial Implications Across Breast Cancer Subtypes

Pooja Advani, MBBS, MD

In an interview with OncLive^®, Pooja Advani, MBBS, MD, a hematologist/oncologist at the Mayo Clinic Comprehensive Cancer Center in Jacksonville, Florida, expanded on key advancements and the significance of pivotal trials that were presented by her colleagues at a recent OncLive^® State of the Science Summit^™ on breast cancer, which she chaired. This included clinical implications for patients with HER2-low disease based on subgroup data from the phase 3 DESTINY-Breast04 trial (NCT03734029) and the advantages of using liquid biopsy to inform treatment selection and clinical trial enrollment.

“There is so much [research] evolving in breast oncology at a pace that has never been seen before. It’s important to gather this knowledge and bring it to the clinic in real time to impact our patient care,” Advani stated during the interview.

She also dove into the significance of data from the phase 3 NATALEE trial (NCT03701334) for patients in the adjuvant setting, and the current as well as potential role of the AKT inhibitor capivasertib (Truqap) which was approved in combination with fulvestrant (Faslodex) for patients with hormone receptor (HR)–positive, HER2-negative breast cancer. The November 2023 approval was based on data from the phase 3 CAPItello-291 trial (NCT04305496).¹

OncLive: Regarding the first presentation by Rohit Rao, MD, what is the significance of the recent FDA approval of capivasertib and fulvestrant in AKT-altered tumors, and what other roles might this combination have in breast cancer?

Advani: The FDA approved the AKT inhibitor capivasertib in combination with fulvestrant for patients with HR–positive, HER2-negative metastatic or locally advanced disease and 1 or more mutations in the PIK3/AKT/PTEN pathway, as detected by an FDA approved companion test. This regulatory approval is for patients [who experienced] progression after at least 1 endocrine-based regimen in the metastatic setting, which is typically a CDK4/6 inhibitor, or recurrence on or within 12 months of completing adjuvant therapy.

The CAPItello-291 trial was a registrational multicenter trial that enrolled over 700 patients in the metastatic setting. It included the overall population that received the combination of capivasertib and fulvestrant, but also the pathway-altered population, which is essentially patients that have PIK3, AKT, and PTEN alterations. The benefit with the combination was seen in both patient populations, but the regulatory approval right now is for those that have these alterations. This is extremely exciting and provides another option for our patients.

In this study, I was [particularly] excited to hear that the rate of hyperglycemia was much lower than seen with the PIK3CA inhibitor alpelisib [Piqray] in combination with fulvestrant. That is good for our oncology community, because hyperglycemia typically poses a significant challenge in the management of these patients.

Based on Dr Rao’s second presentation, how have recent data from the NATALEE trial shifted the treatment paradigm in the adjuvant setting?

The NATALEE trial expanded the number of patients with high-risk, estrogen receptor–positive, HER2-negative early breast cancer that are eligible to receive CDK4/6 inhibitors in combination with endocrine therapy in order to improve their survival outcomes. The trial included patients with high-risk stage II in addition to stage III [disease]. That was the difference between the NATALEE trial and the [phase 3] monarchE trial [NCT03155997] of abemaciclib [Verzenio]; it expanded the patient population.

The second difference between the 2 studies was that ribociclib [Kisqali] was [administered at] a lower dose than what is used in the metastatic setting—it was 400 mg instead of 600 mg. Finally, ribociclib is given for 3 years as opposed to 2 years of abemaciclib. There are some cardinal differences between the 2 studies. However, the NATALEE trial did meet its primary end point, which is improvement of invasive disease-free survival [iDFS] with the combination of adjuvant ribociclib with a non-steroidal aromatase inhibitor [NSAI] compared with a NSAI alone. It is too early to see any statistically significant OS improvement because most of these patients have not yet completed the protocol-specified 3 years of ribociclib. The adverse effects [AEs] associated with the 3-year course of ribociclib in the adjuvant setting were very similar to what has been seen in the metastatic setting.

What does this mean? First, ribociclib is not yet FDA approved, so it is not available to be deployed clinically right away. One of the questions that was raised is that the absolute benefit between the 2 arms and the absolute benefit for iDFS at the current analysis was 3.3%. Is that clinically meaningful? This translated into a 25% reduction in the risk [of death or progression], which is important. Just like any other medication, the benefit must be weighed against the risks. Approximately 8% of patients in the study experienced grade 3 or higher liver AEs, so that is something to also consider.

If both medications are approved, patients that meet the criteria for monarchE for adjuvant abemaciclib should be prioritized, because the follow-up data from monarchE are longer vs the NATALEE clinical trial. If both were available right now, I would consider ribociclib for patients with high-risk disease who do not meet the criteria for monarchE, and for those that are intolerant to abemaciclib.

Regarding the first presentation by Kostandinos Sideras, MD, PhD, what can be learned about the efficacy and safety of T-DXd in HER2-positive and HER2-low breast cancer from the subgroup analysis of DESTINY Breast-04? How do these align with provider perspectives and ILD concerns?

DESTINY-Breast04 was a landmark clinical trial that consolidated the use of fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd] in HER2-low breast cancer in the metastatic setting. In terms of efficacy, the subgroup analysis [showed] that the progression-free survival benefit was essentially seen in all subgroups that were evaluated. Two specific subgroups that are important to call out. Number 1 is those with brain metastases. The number of patients was small in the study, but it did highlight that T-DXd has activity in patients with brain metastases in the HER2-low setting. Second, the efficacy with T-DXd was seen regardless of whether the tissue sample that determined HER2-low status was archival or a fresh biopsy that was obtained at progression, and whether the source of the tissue was from the primary breast vs the metastatic site.

This has a lot of important clinical implications. Clinicians may be able to use T-DXd without necessarily having to obtain a new tissue biopsy at the time of disease progression if there is prior archival tissue that does confirm that the patient has HER2-low status. When we think about the AEs, we can’t talk about T-DXd without thinking about interstitial lung disease [ILD]. ILD has been seen in the different landmark studies with T-DXd, with an incidence of approximately 10% to 15% for all grades. What I learned from this presentation is that the majority of physicians do not view ILD risk as a major barrier but did acknowledge that the patient’s symptoms would need to be monitored closely. Almost all physicians that were queried in that study were concerned about ILD.

What are some challenges and considerations that clinicians should know when using liquid biopsy in metastatic breast cancer, as per Dr Sideras’s second presentation?

Liquid biopsy is so important when we think about our patients with metastatic disease, specifically those that have HR–positive, HER2-negative disease. Liquid biopsy allows us to detect mutations for which targeted therapies are available. [These consist of] ESR1 mutations where elacestrant [Orserdu] can be used, PIK3CA mutations where a combination of alpelisib and fulvestrant can be used, and the recent regulatory approval of the AKT inhibitor capivasertib in combination with fulvestrant for patients with PIK3, AKT, or PTEN mutations.

Liquid biopsy is also important for planning clinical trial enrollments. There are clinical trials that are biomarker specific, so when certain biomarkers are detected in liquid biopsy, it allows us to refer our patients to clinical trials accordingly. Liquid biopsies are also much easier than obtaining the tissue and it does have better clonal representation.

The biggest question right now is how to use circulating tumor DNA in terms of minimal residual disease [MRD] detection and monitoring. Can we have a test that has good sensitivity, specificity, and predictive value that can be done most likely in a serial or longitudinal fashion to determine patients that have MRD? More importantly, how do we act upon it? That is really the crux of the situation. Even if we detect MRD, [how are we going to use that information] in a manner that will improve patient outcomes?

Reference

FDA approves capivasertib with fulvestrant for breast cancer. News release. FDA. November 16, 2023. Accessed January 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer