Sara Hurvitz, MD

 In summary, the treatment for hormone receptor-positive HER2-negative [human epidermal growth factor receptor 2] advanced breast cancer continues to rapidly evolve. When I look back only 15, 20 years ago now, the most common agent that we were using for this type of breast cancer in the advanced setting was tamoxifen as we were just beginning to learn about the use of aromatase inhibitors. Fast-forward, now we have an IM administered SERD, [intramuscular selective estrogen receptor degrader or downregulator] fulvestrant, which has shown very good efficacy, maybe even better than aromatase inhibitors, although patients have to undergo IM injections which is not comfortable. We have the availability of PI3 kinase pathway inhibitors, including everolimus and more recently, alpelisib, in combination with endocrine therapy. And now we also have cyclin-dependent kinase[CDK] 4/6 inhibitors or CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, which have shown remarkable improvements in objective response rates, clinical benefit rates, progression-free survival for patients [receiving a diagnosis of] this disease in both the first-line and second-line settings.

It’s going to be interesting to see how the field evolves going forward. We do know that mutations can be accumulated in metastatic breast cancer causing resistance to therapy. For example, the accumulation of 

[estrogen receptor-1] mutations, the gene for estrogen receptor, can lead to resistance to treatments such as aromatase inhibitors and sometimes even fulvestrant. Finding new therapies, such as oral SERDs that may be able to work on tumors that have these types of mutations, is going to be an important discovery and move forward in this field.

My hope is that we will continue to increase our armamentarium of agents available for patients with ER [estrogen receptor-positive]-positive breast cancer, delaying the time that a patient can wait before needing to go on to chemotherapy which is more toxic. And my hope is also that as data continue to emerge and mature from registry trials, that we begin to see we are pushing the boundary of the envelope now and seeing longer median overall survivals for patients whose disease is diagnosed today. Thank you.

Videos

Sara Hurvitz, MD, provides insight on the potential role of amcenestrant in the treatment of HR+ breast cancer in the future.

Potential Role for Amcenestrant in the Treatment of ER+/HER2- Advanced Breast Cancer

 The AMEERA-5 clinical trial is an ongoing prospective, multinational, randomized, double-blind, double placebo-controlled clinical trial , which is phase 3, that is comparing the efficacy and safety of the amcenestrant plus palbociclib compared to letrozole plus palbociclib in patients who have advanced or locally recurrent unresectable metastatic breast cancer that’s ER positive [estrogen receptor]- and HER2 [human epidermal growth factor receptor 2] -negative. The study is enrolling patients who have not received prior therapy for metastatic disease. Patients who are excluded include those who’ve received another SERD [selective estrogen receptor down-regulator] for the treatment of early-stage disease or disease recurrence on or within 12 months of completion of adjuvant endocrine therapy. Patients who are eligible are randomly assigned 1:1 to each of the treatment arms, and the treatment cycles are 28 days each. The stratification criteria for randomization include de novo metastatic disease, yes or no, menopausal status, pre or postmenopausal, as well as visceral metastases.

The planned enrollment for this clinical trial is nearly 1100 patients. This study is going to be open widely internationally at over 350 sites in over 30 countries. It’s a large study with ongoing accrual occurring now. The endpoints. The primary endpoint is progression-free survival. The secondary end point is overall survival. And there are a number of other more exploratory endpoints including objective response rate, duration of response, clinical benefit rate, quality of life metrics, pharmacokinetics, safety, time to chemotherapy, and [progression-free survival].

If AMEERA-5 shows a clinically meaningful and significant improvement in progression-free survival associated with amcenestrant compared to letrozole in the frontline setting, it may end up becoming a new standard of care for the frontline treatment of ER-positive advanced breast cancer. These data would be exciting because it would provide rationale for the use of an oral SERD. Currently we only have an IM SERD [intramuscular selective estrogen receptor down-regulator] available to use in patients with ER-positive metastatic disease. If these results are promising as well, it would pave the way for other clinical trials potentially in earlier line settings, such as the adjuvant clinical trial setting, and/or in combination with other targeted therapies, including other CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors, potentially PI3 kinase pathway inhibitors among others.

An expert in breast oncology shares her thoughts on the importance of the AMEERA-5 findings to the evolving treatment landscape for HR+ breast cancer.

AMEERA-5: Key Data and Implications for Practice

 Amcenestrant is a novel therapy that is similar in mechanism of action to that of fulvestrant. It is an estrogen receptor down regulator, and it has potent activity. In contrast to fulvestrant, which must be given by intramuscular injection monthly, 2 injections every month, amcenestrant is an oral SERD [selective estrogen receptor down-regulator]. It antagonizes and it degrades the estrogen receptor and inhibits the estrogen receptor signaling pathway potently. The dosing of amcenestrant currently being evaluated in large phase 3 clinical trials is 200 mg orally daily continuously without a break.

A multipart phase 1/2 first-in-human dose escalation trial has been conducted in women who are postmenopausal with hormone receptor-positive advanced breast cancer that’s been pretreated. This study known as AMEERA-1 is showing promising antitumor activity as well as encouraging safety data. Among those cohorts treated with monotherapy amcenestrant of doses of at least 150 mg daily, there were 5 partial responses out of a total of 59 patients, and there were 24 patients or 41% of patients who had stable disease.

The clinical benefit rate of the combination of amcenestrant at 200 mg daily plus palbociclib at 125 mg 3 weeks on, 1 week off in 35 patients who had response evaluable disease, who had not received a prior mTOR [mechanistic target of rapamycin] inhibitor or CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor, revealed an objective response rate of 34%, all of them were partial responses, and a clinical benefit rate of nearly 3/4. These data are quite encouraging. Also, there were no significant cardiac or ocular findings in either set of cohorts, either the monotherapy or in combination with palbociclib. And these data support the ongoing phase 3 evaluation of amcenestrant that are now accruing patients.

Sara Hurvitz, MD, reviews clinical trial data on amcenestrant, an orally administered endocrine therapy, in patients with ER+/HER2- breast cancer as shown in the AMEERA trials.

Safety and Efficacy of Amcenestrant in the AMEERA Trials

 Focusing on the available treatment options for advanced hormone receptor-positive breast cancer, we have a variety of agents that target the hormone pathway. First, we have tamoxifen or estrogen receptor modulators which block the estrogen receptor in breast cancer cells. Tamoxifen is a pill that’s been around for a long time, we know a lot about it and we do know that it is effective for a time for patients with hormone receptor-positive advanced breast cancer.

More recently, a class of drugs known as aromatase inhibitors, including anastrozole, letrozole, and exemestane have been developed. These drugs block the production of estrogen from peripheral sources or nonovarian sources. They are pills like tamoxifen and can be used in women who do not have functioning ovaries, for example, postmenopausal women or women who are on ovarian suppression agents such as leuprolide or goserelin. Aromatase inhibitors are more effective than tamoxifen at controlling disease that’s hormone receptor-positive stage IV breast cancer.

And then more recently a class of drugs known as estrogen receptor down regulators have been developed. The first of these to be clinical validated and made available for stage IV breast cancer is fulvestrant, initially developed the dose of 250 mg once monthly. It looked like it had similar efficacy compared to aromatase inhibitors in later-line advanced disease. However, when dosing trials were done demonstrating better efficacy with the 500-mg dosing regimen and a loading dose given in the middle of month 1, this drug showed superior efficacy when compared to an aromatase inhibitor for hormone receptor-positive advanced breast cancer.

In 2012, we had the development of a class of drugs called mammalian target of rapamycin inhibitors or mTOR inhibitors. Everolimus was an mTOR inhibitor evaluated, a pill that is given with endocrine therapy and blocks PI3 kinase AKT mTOR pathway. When added to endocrine therapy in patients whose disease had progressed on an aromatase inhibitor, this drug was shown to lengthen the progression-free survival and is available to women with advanced hormone receptor-positive breast cancer.

In 2015, we saw promising data supporting the use of a class of agents known as cyclin-dependent kinase 4/6 inhibitors. The first of these was palbociclib, receiving accelerated approval in 2015 in combination with an aromatase inhibitor for the first-line treatment of patients with metastatic hormone receptor-positive breast cancer. There are now 3 agents, palbociclib, ribociclib, and abemaciclib, that have shown consistent dramatic significant improvements in progression-free survival and as well as improvements in the objective response rate when added to endocrine therapy compared with endocrine therapy alone. These agents have become the standard of care in the frontline treatment of breast cancer.

Sometimes there are challenges with any therapy that we give, and you must consider that the adverse effect profile of the new agent. Palbociclib and ribociclib can cause neutropenia. Patients are generally not aware of it and it’s generally not dangerous, but it does require that those 2 drugs be given 3 weeks on and 1 week off. Abemaciclib has some neutropenia associated with it but less and it can be given continuously and dosed BID. However, it has more GI [gastrointestinal] adverse effects associated with it, mainly diarrhea. Other adverse effect profile differences and dosing differences can help us sort out which patients would benefit from which therapy. But it is important to note that the progression-free survival associated with each of these agents is somewhat similar in the frontline setting.

Sara Hurvitz, MD, discusses the therapeutic landscape for HR+ advanced breast cancer and considerations for treatment selection.

Treatment Options For Advanced ER+ Breast Cancer

 Hello, I’m Dr Sara Hurvitz, professor of medicine at the University of California Los Angeles, Johnson Comprehensive Cancer Center. I’m going to be discussing today the AMEERA-5 clinical trial which is a randomized double-blind phase 3 clinical trial evaluating amcenestrant with palbociclib vs letrozole plus palbociclib for previously untreated hormone receptor-positive HER2-negative [human epidermal growth factor receptor 2] advanced breast cancer.

When you look at the scope of breast cancer and the different subtypes of breast cancer, it is notable that hormone receptor-positive breast cancer comprises the largest proportion of all cancers diagnosed. Hormone receptor-positive breast cancer represents about two-thirds to three-fourths of all breast cancers diagnosed. In terms of stage of disease, most patients in the Western world [receive a diagnosis at] stage I, II, or III breast cancer, only about 10% of patients at their initial diagnosis are diagnosed with advanced disease, meaning incurable stage IV metastatic breast cancer.

However, approximately 90% of patients who are diagnosed with early-stage disease, they are at risk for the rest of their life of being diagnosed with metastatic breast cancer or stage IV breast cancer. The risk of developing advanced stage disease goes up by the stage at which a patient is diagnosed. If a patient [received a diagnosis of] stage I breast cancer, she has a lower risk of developing advanced disease than somebody who is diagnosed, for example, with stage III breast cancer.

The prognosis of breast cancer, just focusing on stage IV breast cancer, is evolving over time as we have the availability of new agents come up. We do know, from some recent studies that are registry clinical trials and follow how long patients are living who are diagnosed with advanced disease, that the median overall survival is roughly on the order of 40 months or so for hormone receptor-positive breast cancer, HER2-negative advanced breast cancer. These data come from a French registry trial called ESME-MBC in which all women diagnosed starting around 2008 with metastatic breast cancer with subtype known were followed and assessed for median overall. Although we now have cyclin-dependent kinase 4/6 inhibitors available for the treatment of this disease, the median overall survival over this time course has not increased. It’s possible that in the future we will see the median overall survival improve as more time has passed and the data mature.

Sara Hurvitz, MD, provides an overview of  HR+ breast cancer.

Understanding the  Scope of ER+ Breast Cancer

Sara Hurvitz, MD, medical oncologist, UCLA Medical Center, discusses the results of a study looking at pembrolizumab (Keytruda) in patients with triple-negative breast cancer (TNBC).

Inhibiting the PD-1 pathway showed activity in advanced TNBC in a previous phase I study.

In this study, a heavily pretreated population of patients with TNBC tolerated pembrolizumab well. Durable responses were observed.

There remains a need for breast cancer doctors to understand how to manage toxicities associated with immunotherapies.

Sara Hurvitz, MD | Authors

Articles

Potential Role for Amcenestrant in the Treatment of ER+/HER2- Advanced Breast Cancer

AMEERA-5: Key Data and Implications for Practice

Safety and Efficacy of Amcenestrant in the AMEERA Trials

Treatment Options For Advanced ER+ Breast Cancer

Understanding the Scope of ER+ Breast Cancer

Pembrolizumab for TNBC