Emerging ESR1-Targeted Therapy Added to Abemaciclib to Treat Metastatic ER+/HER2– Breast Cancer

Senthil Damodaran, MD, PhD

In the backbone of modern therapies for patients with metastatic breast cancer who express hormone receptors lies endocrine therapy. Prior research suggests that the efficacy of endocrine therapy is improved with the addition of CDK4/6 inhibition, but resistance does develop in these patients and is commonly due to the presence of ESR1 mutations.

Currently, the landscape has no available agents to address resistance to endocrine therapy with a CDK4/6 inhibitor nor to target ESR1 mutations. Fortunately, one selective estrogen receptor modulator (SERM) called lasofoxifene, which has demonstrated promise preclinically, is being investigated in the ELANE and ELAINE 2 clinical trials (NCT03781063 and NCT04432454), both as a single agent and in combination with the CDK4/6 inhibitor abemaciclib (Verzenio), to fill these areas of unmet need.

The open-label, randomized, multicenter phase 2 ELAINE trial is evaluating lasofoxifene versus fulvestrant in up to 100 postmenopausal women with locally advanced or metastatic endocrine receptor (ER)–positive, HER2-negative breast cancer with an acquired ESR1 mutation, as detected by a cell-free circulating-tumor DNA liquid biopsy test, who have progressed on an aromatase inhibitor in combination with a CDK4/6 inhibitor. Based on the Breakthrough Therapy designation granted by the FDA for lasofoxifene, a positive report from this trial may result in FDA approval later down the road.

In an interview with Targeted Oncology, Senthil Damodaran, MD, PhD, assistant professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the need for an ESR1-targeted agent for the postmenopausal women with ESR1-positive, locally advanced or metastatic ER-positive/HER2-negative breast cancer. He also explained the design and protocol of the ELAINE 2 study.

TARGETED ONCOLOGY: Can you explain the rationale behind examining lasofoxifene in combination with abemaciclib in this patient population?

Damodaran: We know that 1 of the secondary mechanisms of resistance that happens in patients with ER-positive breast cancers who are treated with endocrine therapy in the metastatic setting, [is the development of] ESR1 mutations. These mutations are thought to mediate resistance, leading to poor outcomes and poor prognosis, in general. We typically see these mutations in about 30% to 35% of patients with metastatic breast cancer that are hormone receptor positive. Unfortunately, we don't have a therapy that is designated or approved for ESR1 mutations.

Preclinical studies and some [later] studies have shown that fulvestrant might be active in some ESR1 mutations. Lasofoxifene has an FDA breakthrough designation especially for ESR1 mutations because of preclinical work showing that SERM is active against this mutation. The ELAINE trial is looking at lasofoxifene versus single-agent fulvestrant in patients who are ESR1 mutation carriers. The [ELAINE 2] study is looking at the addition of abemaciclib to lasofoxifene. The idea [behind this combination is] that these days, we go for combination therapies, and a CDK4/6 inhibitor could likely be one of the partners [for lasofoxifene]. ELAINE 2 is going to be done primarily as a safety study because this combination has not been studied before. The initial goal is to make sure the combination is safe, and then we plan to expand it further to look at efficacy.

TARGETED ONCOLOGY: What can you tell us about the mechanism of action behind lasofoxifene?

Damodaran: Lasofoxifene is a third-generation SERM. In essence, it [represents] the evolution of tamoxifen (Soltamox) and raloxifene (Evista). It does have some activity similar to the tamoxifen, but it also has activity against the mutant ESR1 molecule so unlike drugs like fulvestrant, which in part, is almost like a target receptor for destruction or indignation. These are supposed to kind of reverse, and they're agonistic too, in some ways. That’s where lasofoxifene is unique because most of the studies that are being done right now are looking at other SERM products.

The drug has actually been studied in patients with osteoporosis in the past. The study looked at lasofoxifene for the treatment of patients with bone loss, and as a byproduct, it showed that there was a decreased incidence of breast cancer. That's how the development of this agent in the breast cancer space evolved. Eventually, as preclinical studies showed that this drug had activity against ESR1 mutations, the next step was to look at that specific population.

TARGETED ONCOLOGY: Can you explain the preclinical research obtained for lasofoxifene that support use of the drug in this patient population?

Damodaran: There have been preclinical cell lines and PVX models that have actually shown activity of the SERM compared with fulvestrant. Even with fulvestrant, there's been this belief that fulvestrant could be active against some ERS1 mutations. For example, ESR mutations in general tend to be polyclonal. The 2 major residues are 538 and 537. In fact, in the PALOMA studies (NCT00721409, NCT01740427, and NCT01942135), 537 was actually enriched in patients treated with fulvestrant. The laso vaccine seems to have activity in both wildtype as well as ESR1 mutations, and it's not just restricted to the 528 residue. It seems it's also active against the 537 residue in preclinical and clinical models. The ELAINE trial has not been reported yet and that’s looking at comparison in the clinical setting. I think that study will add more clinical data in terms of how activity is withlasofoxifene compared with fulvestrant.

TARGETED ONCOLOGY: Can you discuss the design of the ELAINE 2 study?

Damodaran: The design itself is very simple because it is a safety study for which the plan is to enroll 24 patients. The primary goal is to look at safety and tolerability of abemaciclib and lasofoxifene. The analysis in some sense is largely descriptive, just looking at toxicity. There aren’t any efficacy end points built into the primary analysis. But again, once we get the initial safety data, the expectation is that it will expand to look at other efficacy-related questions.

In terms of dosing itself, lasofoxifene will be given 5 mg daily, and abemaciclib will be given 150 mg twice daily.

TARGETED ONCOLOGY: With the Breakthrough Therapy designations granted to lasofoxifene, what is your prediction on the implications of a lasofoxifene FDA approval in postmenopausal women with ESR1-positive, locally advanced or metastatic ER-positive/HER2-negative breast cancer?

Damodaran: Determination cannot be made based on data from ELAINE 2. It will likely be based on data from ELAINE. If that study shows promising activity, then there’s a good

chancethat lasofoxifene would be a choice agent for patients with ESR1 mutations. Again, the hope with ELAINE 2 is to build on what is likely to happen with ELAINE because combination therapy is considered more pragmatic or likely to be used in clinical practice as opposed to a single-agent therapy.

TARGETED ONCOLOGY: What do you think future research needs to focus on in order to move the needle forward for patients with ESR1-positive disease?

Damodaran: I think we need an understanding of which drugs work in this space, and more importantly, how safe they are to use in clinical practice. That’s been one of the challenges with some of the initial agents that were introduced. We want drugs that are very effective, but also safe for patients.

The other part of it is that ESR1 mutations are more evolutionary compared to PIK3CA mutations, which are more chronical. It is possible that we might have agents that are active against one form of ESR1, but not necessarily as active against other forms.

There's definitely a role for using something like circulating tumor DNA, in terms of identifying and tracking these patients to assess early response. But it does pose a challenge, because some of these mutations can be subclonal. We don't quite know how clinically significant they are, or what to make of it in terms of allele fraction tracking. I think once we have agents that show a specific activity in the ESR1 space, we would have agents in that space that would specifically target these mutations, either as a single agent, or in combination with something else. It's very likely these mutations are not going to exist by themselves, because it's possible, that they will coexist with PIK3CA mutations or FGFR amplifications.

_Reference:

_{Plourde PV, Schwartzberg LS, Greene G, et al. An open-label, randomized, multi-center phase 2 study evaluating the activity of lasofoxifene relative to fulvestrant for the treatment of postmenopausal women with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract 112.}