Sarat Chandarlapaty, MD, PhD

 The potential roles for amcenestrant could be a replacement of every place we use antiestrogen therapy in breast cancer. There’s potential for replacement of aromatase inhibitors, in the neoadjuvant stage, in the adjuvant setting. There’s potential for replacement of other forms of hormone therapy, whether it’s fulvestrant, tamoxifen, or aromatase inhibitors in the metastatic setting as a single agent or as combinations with targeted agents. It has all the hallmarks of a hormone therapy that could inhibit ER [estrogen receptor] and is well tolerated enough to combine with other agents. All those are being tested. In terms of newer potential areas where the drug could synergize, there’s growing interest in looking at 

 [human epidermal growth factor receptor]–positive breast cancer where roughly 50% of patients also have estrogen receptor expression. When patients in that setting are going into a maintenance phase, they’re often given endocrine therapy together with HER2 therapy. That’s another setting in which the combination would be interesting to look at.

One of the questions that we’re faced with in the metastatic setting is, “How do we treat patients whose genomic profile comes back with an estrogen receptor mutation?” This tells us about a cancer that has a mutation that causes estrogen receptor to be constitutively active. This tells us that drugs like aromatase inhibitors won’t work, that drugs that sort of lower estrogen levels won’t work with a constitutively active estrogen receptor.

What we need are drugs that actually engage the mutant estrogen receptor. Amcenestrant and other oral SERDs [selective estrogen receptor degrader] have the potential to potently occupy the estrogen receptor when it’s mutated. Whether that’s as a single agent or in combination with CDK4 inhibitors or PI3 kinase inhibitors, when an estrogen receptor mutation is present on the genomic profiling, it favors the notion that you would treat with a SERD or a direct estrogen receptor antagonist like amcenestrant. In the AMEERA trials, we did observe that there was activity for amcenestrant regardless of whether the estrogen receptor was wild type or mutant. This is an increasingly prevalent phenomenon, where we’re profiling patients to see if they have, for instance, a PI3 kinase mutation to allow them to be treated with alpelisib. If we also find that patient has an estrogen receptor mutation, that becomes an important consideration in the endocrine therapy partner that’s chosen.

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Sarat Chandarlapaty, MD, offers his opinion on the potential roles amcenestrant could have in the treatment of ER+/HER2- metastatic breast cancer.

Amcenestrant’s Potential Role in ER+/HER2- Metastatic Breast Cancer

 The AMEERA-1 study comprised multiple arms looking at first the single agent and then combinations. Part A of the AMEERA-1 study was the first-in-human dose escalation looking at doses anywhere from 20 to 600 mg. The B component was an expansion of the study using 400 mg as a single agent. Part C was to look at the standard combination of antiestrogen with CDK4 inhibitor, in this case palbociclib, and part C, doses of 200 and 400 mg were looked at in combination with standard dosing of palbociclib. Then in part D, there was an expansion of that combination using the 200-mg dose of amcenestrant. There are subsequent arms that are enrolling, looking at other combinations such as with alpelisib, abemaciclib, and everolimus.

The main findings of the studies, part A and B, were designed to look at the safety of the single agent, showing it to be a very pure antiestrogen with adverse effects such as hot flashes in about 30%, 40% of patients and no grade 3 adverse events. In that study in patients who at least got to be what we consider to be an efficacious dose at 150 mg and above, clinical benefit was seen in about 35% of patients. That number goes up further if you look at the patients who hadn’t received as much prior therapy like targeted therapy. A very effective hormone therapy in this patient population.

Then part C and D looked at the combination with palbociclib. When you looked at the safety signal for that combination, what you saw was essentially the adverse-effect profile of the 2 single agents added together. You’ve got the adverse effects of Ibrance [palbociclib], and you’ve got the adverse effects of amcenestrant. But there were no synergistic or unique toxicities from the combination.

In that study in the patients who were evaluable, 74% of patients had clinical benefit. That strongly supported the opening of the AMEERA-5 clinical trial, which was looking at a randomized study in the first-line setting, in which all patients get palbociclib or patients are randomized to get standard-of-care letrozole as their hormone therapy or amcenestrant as their hormone therapy.

Right now, amcenestrant is not a clinically approved agent. What we’ve seen in terms of the adverse-effect profile, in terms of the potency of the agent and inhibiting the estrogen receptor, strongly support the growing program of AMEERA trials that are widely available in larger phase 3 trials looking at amcenestrant in the advanced setting in combination with a CDK4 inhibitor. Looking at amcenestrant in the early-stage setting, a trial that’s soon to open looking in the adjuvant setting. The data really point to us needing to, as an oncology community, evaluate this agent in large phase 3 studies.

Dr Chandarlapaty discusses the AMEERA-1 trial and its impact on the ER+/HER2- metastatic breast cancer landscape.

AMEERA-1 and ER+/HER2- Metastatic Breast Cancer

 Amcenestrant is a form of hormone therapy. It’s what’s called a selective estrogen receptor degrader. That means it’s a drug that binds to the estrogen receptor or an estrogen receptor antagonist. It does so in a way that causes the receptor to be degraded as part of its effects. This class of agents, these selective estrogen receptor degraders, includes an already approved drug, fulvestrant. Amcenestrant was designed to improve on existing estrogen receptor inhibitors, like fulvestrant or even tamoxifen, by overcoming some of those limitations those drugs have.

What are those limitations? Some of the limitations of those drugs are pharmacological. They don’t get to very high consistent levels in patients. That is, they’re not highly bioavailable. Fulvestrant particularly has to be given as an intramuscular injection every month, and it doesn’t achieve high consistent levels over time. That lack of bioavailability ultimately limits the efficacy of those drugs. The other limitations may be in their potency, particularly tamoxifen. What we’ve learned in the last few years is that estrogen receptors are subject to genetic mutations that lead to a constitutively active form, and those constitutively active forms will require even more potent ER [estrogen receptor] antagonists to inhibit. Amcenestrant is designed to be a more potent and more bioavailable estrogen receptor inhibitor.

The AMEERA trials have been the platform for the first-in-human all the way to up to phase 3 studies of amcenestrant in advanced breast cancer. The first-in-human study, the AMEERA-1 study, really evaluated amcenestrant as a single agent and demonstrated in dose escalation, as well as in the recommended dose, that amcenestrant is a very selective and safe molecule. The adverse-effect profile was very consistent with a pure antiestrogen. There were no grade 3 treatment-related adverse events with the drug. The adverse-effect profile was the typical antiestrogen adverse effect, with the No. 1 adverse effect being hot flashes, then low-grade joint aches or arthralgias, and constipation. Importantly, what was not seen was ophthalmologic or cardiac adverse effects.

An expert introduces amcenestrant as a potential new therapy for ER+/HER2- metastatic breast cancer and addresses how it differs from current treatment options.

Amcenestrant and Its Effects on ER+/HER2- Metastatic Breast Cancer

 The challenges associated with systemic therapies is that first, we don’t know up front which is more likely to work longer. Second, the adverse effects associated with them. For the most part, these therapies work in the majority of patients, whether you choose to give endocrine therapy or chemotherapy. Most patients will derive some benefit and the cancer will eventually evolve and develop resistance. We don’t have a way of saying cancer A is most likely to benefit from CDK4 hormone combination, and cancer B is most likely to benefit from chemotherapy up front. That’s work that’s ongoing to develop biomarkers to separate those groups. In terms of chemotherapy, the other challenge is that it has more significant adverse effects associated with it, particularly myelosuppression, fatigue, and neuropathy. We have therefore largely relegated chemotherapies to later lines of therapy, mostly because of adverse effects because we can’t distinguish between chemotherapy and endocrine therapy for many patients in terms of antitumor effects.

The major problem we have is that patients do succumb to their disease in the advanced setting. We have patients who benefit for years on therapy, but their cancer evolves and develops resistance, and ultimately we can’t treat it anymore. We need agents in that setting. We need new therapies that can overcome those resistance mechanisms and even prevent the cancers from evolving. Second, as I said, most patients who develop advanced breast cancer present as a relapse of their primary breast cancer. If we had better therapies to prevent that relapse, then we could also improve our overall outcomes. Those are 2 major areas in which we need new therapies and better therapies.

Dr Chandarlapaty elaborates on the challenges and unmet needs seen when treating ER+/HER2- metastatic breast cancer.

Challenges and Unmet Needs in ER+/HER2- Metastatic Breast Cancer

 For advanced breast cancer, there are a couple of treatment modalities. The mainstay of treatment is systemic therapy, drug therapy that goes to all locations where metastatic disease may be located. There are 2 classes of therapy. There are what we call endocrine therapies and chemotherapies. By 

, we’re referring to antiestrogens as a backbone often given in combination with additional targeted therapies. Those targeted therapies are CDK4/6 inhibitors or drugs targeting the PI3 kinase pathway: a PI3 kinase inhibitor or an mTOR inhibitor.

Most of these endocrine therapies have been developed to where they’re given together with those targeted therapies. The endocrine therapies can also be given as single-agent antiestrogens. That grouping of therapies, hormone therapies, and antiestrogens together with targeted agents or as single-agent hormone therapies. The other big class, of course, is chemotherapies that we’re very familiar with and drugs that are used for many types of cancers. In large measure, these are reserved for after failure of the endocrine-targeted therapies.

Historically it’s been a challenge to decide which systemic therapies to give when you have this menu of options. Endocrine therapies were given for patients with more limited symptomatic disease and chemotherapies were given up front for patients for patients who had visceral disease, liver metastases, or symptomatic disease where you needed a very fast response. That dichotomy still exists to some degree, but it’s largely been replaced by the combination of hormone therapies that, together with CDK4/6 inhibitors, work as effective as chemotherapies in inducing responses and alleviating symptoms of disease.

Based on overall survival data as well as that efficacy, the first treatment of choice is largely a hormone plus CDK4/6 inhibitor combination. Subsequent to that, patients may go on to chemotherapy or another targeted regimen. That choice is guided by clinical intuition of whether the endocrine therapy was somewhat effective or if it was completely ineffective. Often there’s a consideration for going next to chemotherapy.

A medical oncologist discusses the available treatment options for ER+/HER2- metastatic breast cancer.

ER+/HER2- Metastatic Breast Cancer and Available Treatment Options

I’m Sarat Chandarlapaty. I’m a medical oncologist at Memorial Sloan Kettering Cancer Center in New York.

As most oncologists know, estrogen receptor–positive breast cancer is the most common breast cancer that we encounter in the clinic. Roughly 65% to 70% of breast cancers are marked by the expression of the estrogen receptor. That’s the real hallmark: that these cancers express the estrogen receptor and are therefore subject to therapy with antiestrogens.

In terms of the diagnosis of advanced-stage breast cancer, the prevalence is roughly 5% of patients present with advanced-stage disease. A larger subset present with early stage and then relapsed later with advanced disease. Regardless of whether at presentation or at relapse, advanced-stage disease carries a significantly worse prognosis, as with most other cancers. The prognosis is that most patients who have advanced disease will die of their disease, but most of these cancers can be treated for many years with systemic therapies. Patients can have good quality of life on those systemic therapies.

Sarat Chandarlapaty, MD, gives an overview of ER+/HER2- metastatic breast cancer, including characteristics, diagnosis, and prognosis.

Sarat Chandarlapaty, MD, PhD | Authors

Articles

Amcenestrant’s Potential Role in ER+/HER2- Metastatic Breast Cancer

AMEERA-1 and ER+/HER2- Metastatic Breast Cancer

Amcenestrant and Its Effects on ER+/HER2- Metastatic Breast Cancer

Challenges and Unmet Needs in ER+/HER2- Metastatic Breast Cancer

ER+/HER2- Metastatic Breast Cancer and Available Treatment Options

A Breakdown of ER+/HER2- Metastatic Breast Cancer