In ER+ Advanced Breast Cancer, Yet Another Option

Nick Mulcahy

December 07, 2016

SAN ANTONIO — Clinicians who care for postmenopausal patients with advanced, hormone receptor (HR)–positive breast cancer may now have another treatment option when resistance to endocrine-based therapy inevitably emerges.

New data show that, in this setting, the combination of everolimus (Afinitor, Novartis) and fulvestrant (Faslodex, AstraZeneca) more than doubled median progression-free survival (PFS) compared with fulvestrant alone (10.4 vs 5.1 months; hazard ratio, 0.60; P = .02).

All 130 patients in the randomized phase 2 trial were also negative for human epidermal growth factor receptor 2 (HER2) and had locally advanced or metastatic disease.

"In my opinion, this is likely to become a good treatment option for women," lead author Noah Kornblum, MD, a medical oncologist at the Albert Einstein College of Medicine in the Bronx, New York, said today at a press conference here at the 2016 San Antonio Breast Cancer Symposium (SABCS), where the study debuted.

This is likely to become a good treatment option for women. Dr Noah Kornblum

The new results were not unexpected.

"We were not surprised to find that the combination of everolimus and fulvestrant improved progression-free survival," said Dr Kornblum in a meeting press statement about the study's primary endpoint.

Both agents in the combination are approved by the US Food and Drug Administration (FDA) for use in this setting of advanced HR-positive, HER2-negative postmenopausal breast cancer that is endocrine treatment resistant.

The mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) has been approved to be used with the aromatase inhibitor exemestane (Aromasin, Pfizer) to treat patients who progress on first-line endocrine therapy. Also, the selective estrogen receptor downregulator fulvestrant (Faslodex) has been approved for use when disease progresses, both as a single agent and in combination with the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer).

Steven Vogl, MD, a medical oncologist in private practice in New York City, said that "it's not surprising that this works since the first everolimus study in people was of everolimus and tamoxifen and it doubled PFS there — and fulvestrant is just a super-tamoxifen."

"The reason that it matters that everolimus works with fulvestrant is some patients somehow get through exemestane, anastrozole, and tamoxifen, and never got everolimus," Dr Vogl told Medscape Medical News. "There is no evidence that, if you give them the same drug again [ie, an antiestrogen including fulvestrant] everolimus makes it work. Here you have data that everolimus works with fulvestrant."

In part, the data are important for insurance company reimbursement, said Dr Vogl. "You know why they call it everolimus? Because it's ever-oh-so-expensive."

Virginia Kaklamani, MD, a medical oncologist at the University of Texas Health Science Center, San Antonio, who moderated the press briefing, agreed that the study data will facilitate clinical use.

"What is important for clinicians who use combinations with their patients, is that there is some sort of clinical trial that has validated that combination," she also commented.

"What this clinical trial tells us is that we can use fulvestrant with everolimus clinically when a patient has been on an aromatase inhibitor and we don't want to use another aromatase inhibitor right after that," Dr Kaklamani further commented.

No phase 3 trial is planned or underway for this combination, said Dr Kornblum.

He acknowledged that the combination has some annoying side effects. "It is not uncommon to experience to low-grade stomatitis, mucositis, and fatigue," he said.

This was a reference to the findings that grade 3 adverse events occurred in 48% of patients receiving the combination vs 14% receiving fulvestrant alone and that the most common (>5% of patients) grade 3 adverse events included stomatitis (9%) and fatigue (5%).

But the study did not use prophylactic corticosteroid mouthwash, which has been shown to reduce the risk for grade 1/2 stomatitis from about 65% to 20%, he also said, citing a recent study (J Clin Oncol. 2016;34 suppl: abstract 525).

The mouthwash "minimizes" troublesome stomatitis, agreed Dr Kaklamani.

Much needs to be learned about the array of treatments in this setting, said Dr Kornblum.

The new study is limited by the fact that it was designed and started before FDA approval of palbociclib as a treatment for metastatic HR-positive breast cancer.

CDK4/6 inhibition has been called a new standard of care because of the unprecedented magnitude of the PFS benefit seen in phase 3 trials of these agents.

Dr Kornblum told reporters that only two patients enrolled in the current trial had been treated with a CDK4/6 inhibitor. He also said that it will be important to determine whether combination treatments that include everolimus will be active in such patients.

"How we're going to learn to sequence these drugs and which should come first" is not currently known, said Dr Kornblum.

The study participants had Eastern Cooperative Oncology performance status of 0 to 1 and had received at least one prior chemotherapy regimen for metastases.

In the study's induction phase, all patients received fulvestrant 500 mg intramuscular injection on day 1 and day 15 of cycle 1 and then day 1 of cycles 2 to 12 (28-day cycles; 48 weeks total). Half of the patients received oral everolimus (10 mg) daily and the other half, placebo (1:1 randomization).

Patients who had no disease progression or no unacceptable toxicity at 48 weeks continued treatment in a continuation phase. Treatment continued until progressive disease by RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria.

This study was funded by Novartis Pharmaceuticals. Dr Kornblum, Dr Vogl, and Dr Kaklamani have disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium (SABCS) 2016. Abstract S1-02.

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