Emerging Data Help Steer CDK4/6 Inhibitor Choice in HR+/HER2– Breast Cancer

Karen S. Anderson, MD, PhD

The CDK4/6 inhibitors ribociclib (Kisqali), abemaciclib (Verzenio), and palbociclib (Ibrance) are approved by the FDA for the treatment of patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer. Although the 3 agents have not been compared in head-to-head trials, emerging long-term survival data have helped direct some treatment choices with these agents for this patient population, according to Karen S. Anderson, MD, PhD.

“What [these data] are telling us is that all CDK4/6 inhibitors are not the same. These emerging data are going to start to affect [treatment decisions] as we move forward into the adjuvant setting,” Anderson said following an OncLive® State of the Science Summit™ on breast cancer, which she co-chaired.

In an interview with OncLive^®, Anderson expanded on the emerging data and role for CDK4/6 inhibitors in the treatment of patients with HR-positive, HER2-negative breast cancer. She also discussed the growing use of antibody-drug conjugates (ADCs) across the breast cancer spectrum, updates in triple-negative breast cancer (TNBC), and ongoing research at the Mayo Clinic Comprehensive Cancer Center. Anderson is a medical oncologist at Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

OncLive^®: Shakeela Bahadur, MD, of Banner MD Anderson Cancer Center, discussed the role of CDK4/6 inhibitors in the treatment of patients with HR-positive breast cancer. How are emerging data continuing to shape the use of these agents in this space?

Anderson: Dr Bahadur presented a summary of research on HR-positive breast cancer and some of the advances in clinical studies associated with that [subtype]. In that field, one of the main exciting and evolving themes is around the role of CDK4/6 inhibitors. We’ve been using CDK4/6 inhibitors for patients with metastatic disease for a number of years. More recently, abemaciclib [was approved] in the high-risk adjuvant setting based on [data from] the [phase 3] monarchE trial [NCT03155997].

There have been some updates [with CDK4/6 inhibitors]. In the metastatic setting, we’re starting to see overall survival [OS] data. In particular, there have been some differences in OS data with palbociclib in the metastatic setting from the [phase 3] PALOMA-3 trial [NCT01942135] vs the ribociclib data from the [phase 3] MONALEESA-2 [NCT01958021] and MONALEESA-3 [NCT02422615] studies. Ribociclib is consistently showing OS advantages in those studies, whereas palbociclib has not been showing as much [of an OS benefit].

One thing that is facing many clinicians is, “What should we be thinking about for the first choice [of CDK4/6 inhibitor] for patients with newly diagnosed metastatic disease?” Based on the most mature data that we have, it is starting to look as though the choice is ribociclib—when we can obtain it—for first- or second-line therapy for up-front metastatic disease. For patients who are already on therapies, such as palbociclib, and are doing very well, it is a hard call to think about switching [treatment]. However, these are conversations that we routinely have with our patients.

The survival data for abemaciclib are still preliminary, and we will be looking for those updated data soon. The early preliminary data also suggest that abemaciclib may have an OS benefit, but we need to see the final reports.

How have CDK4/6 inhibitors affected treatment in the adjuvant setting for patients with HR-positive, HER2-negative breast cancer?

Currently, the latest changes that have happened in the adjuvant setting [include] the FDA restrictions on the use of adjuvant abemaciclib, based on the monarchE trial and the requirements for Ki-67 testing. [The requirement for] elevated Ki-67 in high-risk [patients] in the adjuvant setting has been dropped. The ongoing data are demonstrating benefit from adjuvant CDK4/6 inhibition with abemaciclib in [patients with] high-risk, node-positive HR-positive, HER2-negative breast cancer. I believe we will see a tremendous amount of increased evaluation and interest in adjuvant CDK4/6 inhibitors, especially as the monarchE data mature and we continue to see evidence of benefit for [abemaciclib].

The adjuvant ribociclib data are still pending from the [phase 3] NATALEE trial [NCT03701334], and we will see where that goes. However, adjuvant palbociclib did not appear to have any benefit [in adjuvant setting], even in a subset analyses, in women with early-stage, high-risk [HR-positive, HER2-negative] breast cancer [in the phase 3 PALLAS trial (NCT02513394)].

For [patients with] HR-positive, HER2-negative breast cancer, [CDK4/6 inhibitors] are changing breast cancer care. Future studies starting to look at different combinations of CDK4/6 inhibitors with other medications outside of endocrine therapy will also be very exciting.

Lida A. Mina, MD, of the Mayo Clinic Comprehensive Cancer Center, discussed emerging ADCs in patients with HER2-positive or -low breast cancer. As different ADCs continue to emerge, how could sequencing be approached in these populations?

Dr Mina gave a wonderful overview of ADCs, reviewing a bit about the biology and the biochemistry of how they work. ADCs have started to have an increasing role in our management of breast cancer, certainly in patients with advanced disease. We have had sacituzumab govitecan-hziy [Trodelvy] for several years now for use in second- and third-line therapy for [patients with] metastatic TNBC. However, more recently, the [phase 3] DESTINY-Breast04 [NCT03734029] study has shown the benefits of fam-trastuzumab deruxtecan-nxki [Enhertu] for patients with HER2-low tumors that are HR positive or HR negative.

The role of trastuzumab deruxtecan in identifying the HER2-low population has led us to research more about the detection of HER2-low tumors. [HER2 low] represents perhaps a little over 50% of our patient population; however, the problem is that HER2 low is difficult to assess, and there is a lot of variability in this testing. We are still trying to evaluate which patients may benefit from trastuzumab deruxtecan.

In addition, for patients with HR-positive disease, the [phase 3] TROPiCS-02 study [NCT03901339] of sacituzumab govitecan also demonstrated that these Trop-2–targeted ADCs have potential benefit [in this patient population], in addition to patients with HR-negative breast cancer.

How we should be sequencing these ADCs, [as well as] what some of these new emerging targets are going to be, is currently being evaluated. As breast cancer medical oncologists, we are using a lot more of these ADCs in a broader setting. For example, we’ve been using them in HER2-positive breast cancer for a number of years, but we are now starting to expand across the spectrum of breast cancer. That is exciting for our patients to have a whole host of new medications and potential targets. [ADCs] have started to move the use of chemotherapy, at least in [patients with] HR-positive, HER2-negative breast cancer, further down the list in terms of prioritization of therapeutic approaches.

Felipe Batalini, MD, of the Mayo Clinic Comprehensive Cancer Center, discussed novel targets in breast cancer. Could PARP inhibitors potentially have an expanded role in additional subgroups of breast cancer?

Dr Batalini has been studying a number of different novel targets in breast cancer and, in particular, targets in the context of patients who have defects in homologous recombination or DNA repair defects. Dr Batalini provided a summary about emerging and novel targets in breast cancer, [including] the evaluation of PARP inhibitors and the expanded evaluation of these agents. Should we be using [PARP inhibitors] for patients with somatic BRCA1/2 alterations? Should we be thinking about PARP inhibitors for patients with other germline repair defects in DNA damage repair? There are ongoing studies that are currently looking at [these questions].

We’ve seen an effect from the use of olaparib [Lynparza] from the [phase 3] OlympiA study [NCT02032823] in the adjuvant setting, showing reduced recurrence rates in high-risk patients with germline BRCA1/2 variants. Looking at the use of olaparib in [other] settings, the question becomes whether there are potentially more patients who could benefit from these therapies, and how can we think about combining them with other therapies?

What other emerging therapies should be noted when discussing novel targets in breast cancer?

Dr Batalini also touched on other specific emerging therapies that have come out recently. One is the use of elacestrant [Orserdu], which was recently approved for patients with ESR1 mutations in metastatic HR-positive breast cancer. Elacestrant is a targeted inhibitor of ESR1 mutations, and it is oral. In addition to being evaluated in the context of ESR1 mutations as a selective estrogen receptor degrader [SERD], it has been compared directly with fulvestrant. In patients who have [ESR1] mutations, [elacestrant] may have some evidence of increasing response rates. We are now starting to get more familiar with the use of these drugs, and we will be evaluating a lot more about which patients have these ESR1 mutations, at what point patients acquire them, and at what point we can detect them in circulating tumor DNA.

It will be exciting to see [if elacestrant] ends up moving into the adjuvant setting and whether there is any value to earlier approaches for targeting the emergence of ESR1 mutations. At least right now, our use [of elacestrant] is in the metastatic setting.

We also talked about emerging therapeutics, such as targeting the ATP pathway. This is a very active pathway in breast cancer, and some of the emerging therapeutics [include] our current use of alpelisib [Piqray] and other [agents targeting] the mTOR or PIK3CA pathway. The entire field will certainly be under active investigation for new targets in breast cancer.

Your presentation focused on the management of patients with TNBC. How has the emergence of HER2-low as a breast cancer subtype affected the TNBC space?

[One of] the major clinical changes over the past couple of years [in TNBC] has been the [phase 3] KEYNOTE-522 trial [NCT03036488] and the emerging recognition and use of neoadjuvant pembrolizumab [Keytruda] for patients high-risk TNBC who are receiving neoadjuvant chemotherapy. The addition of pembrolizumab to chemotherapy improves pathologic complete response rate.

What has also affected TNBC is the identification of patients with HER2-low tumors, and that subset of patients with HER2-low tumors who may be eligible to receive trastuzumab deruxtecan. The relative use of sacituzumab govitecan vs trastuzumab deruxtecan in this patient population is still an active area of clinical discussion.

What questions still need to be addressed regarding the use of ADCs in breast cancer?

There is still a lot of discussion around the relative sequencing of ADCs, particularly in [patients with] HR-positive breast cancer. Trastuzumab deruxtecan has been a well-tolerated drug by and large, but it still has issues with pulmonary toxicity. Identifying who is at risk for that toxicity was one of the comments that came up in the panel discussion, [along with] understanding how to sequence these different ADCs.

Is there any ongoing or planned research at Mayo Clinic that you would like to highlight?

One of the things that I’m excited about that has been emerging not just at the Mayo Clinic but at a number of sites around the country, is the role of adjuvant immune therapy, in particular vaccine therapy, targeting tumor-specific antigens, proteins, and alterations.

Some of the data in melanoma and other tumor types that have [emerged] recently [have raised] the questions about the role of targeting immune activation in the adjuvant setting to help reduce recurrence rates. Mayo Clinic has been conducting [a phase 2 trial (NCT03012100)] in the adjuvant [setting for patients with] TNBC [using a] vaccine targeting folate receptor alpha, [which is] an antigen of relevance in TNBC. We will hopefully be able to see some of that data soon. That is one of the early vaccine studies, and there are many that are going to be coming forward. We do not know whether there is going to be a role for [vaccines] in breast cancer. However, I am excited to see where these studies from around the country will end up landing.