Options for Treatment-Naive Metastatic ER+ Breast Cancer

Komal Jhaveri, MD, FACP:New data from the phase III FALCON trial showed that when we utilized fulvestrant in the first-line setting compared [with an] aromatase inhibitor—in that case anastrozole for that particular trial—we saw that the progression-free survival (PFS) favored the treatment with fulvestrant, which was statistically significant in the order of about 16.6 months, compared [with] 30.8 months with anastrozole. Now, what is important to note about that trial was that those were treatment naive. These women had not seen any endocrine therapy in the early-stage setting. And so certainly that kind of dropped fulvestrant in the first-line realm for us.

The FALCON trial was actually designed after we had heard the results from a precedent trial, the phase II first trial, which had shown a statistically significant improvement favoring fulvestrant compared [with] anastrozole, and also showed the overall survival (OS) benefit for that approach. We are yet to hear about the overall survival from the FALCON study, but certainly it is a trial that actually helps us justify the use of fulvestrant in patients with, specifically with de nova metastatic disease or treatment-naive patients.

An interesting subgroup from the FALCON trial was those women with nonvisceral disease. They benefited with fulvestrant a lot more than patients who were treated with nonvisceral disease with anastrozole.

Now, I think that is a little hypothesis generating but an interesting one at that because one can certainly try to use fulvestrant for those with nonvisceral de novo metastatic disease, with the hope that upfront loading approach with a more effective endocrine PARP inhibitor, particularly subgroup, might improve the outcomes for [those] particular women even more.

So based on that and based on [new] data from the MONALEESA-3 trial, which also evaluated the combination of ribociclib with fulvestrant in treatment-naive first-line [estrogen receptor] (ER)-positive metastatic patients. I think we have data that [are] favoring the use of fulvestrant, not only in the second line but also in the first-line setting for our patients.

We really don’t have any data thus far that can justify what do we do necessarily for our patients who are now being treated with a CDK4/6 inhibitor, either in the first- or second-line setting. That is something that is evolving, and a lot of research trials are trying to answer this question as we speak. There was one particular trial that perhaps gave us a glimpse of that data. That was the TRINITY trial. It’s a phase I-II study that is evaluating ribociclib with exemestane and everolimus. And it did show a small cohort of patients [who] had progressed on a prior CDK4/6 inhibitor and showed that the clinical benefit rate for this triplet therapy in that cohort that had progressed on a CDK4/6 inhibitor was in the order of about 39%. But we have yet to hear the progression-free survival and the phase II data from that trial.

But outside of that we have other ongoing trials but no real data to actually make us understand what we do for a patient in clinic now. So what are we doing in clinic? We are doing what we used to do. We have data from the BOLERO-2 trial that justify the use of exemestane and everolimus in patients [who] have progressed on a nonsteroidal AI, up to 1 line of chemotherapy in the metastatic setting. In fact, in that study, a very small fraction of patients had also received fulvestrant trying to be enrolled for this regimen. And that regimen, when compared [with] exemestane and placebo, showed a statistically significant improvement in progression-free survival of about 7.8 months with a hazard ratio of 0.48. So one can certainly use a BOLERO-2-like regimen with exemestane and everolimus when patients progress on first-line CDK4/6 therapy.

We also have data for combining everolimus with tamoxifen based on the phase II TAMRAD trial, which also again showed that the combination led to a statistically significant improvement in time to progression compared [with] tamoxifen alone. And so certainly we can have different partners, endocrine therapy partners, to combine with everolimus, and use that in the second-line setting without really knowing, or without really having data from trials that are now evaluating, what do we do next after CDK4/6?

Transcript edited for clarity.

A 65-Year-Old Woman With Metastatic ER+/PR+ Breast Cancer

December 2013

• A 65-year-old woman was examined by her gynecologist after discovering a right-sided lump in her upper inner breast; she reported feeling exhausted lately, requiring frequent rest
• PE showed a grape-sized right palpable mass at 3 o’clock
• Diagnostic ultrasound showed a spiculated and hypoechoic mass measuring 26 x 23 x 21 mm; imaging in the left breast was unremarkable
• Core biopsy showed high-grade infiltrating ductal carcinoma
  • Hormone receptor status: ER+/ PR+
  • HER2,IHC 1+
• She underwent lumpectomy and axillary lymph node dissection that revealed a 2.3-cm infiltrating ductal carcinoma, 4 of 12 nodes were positive for disease
• CT of the chest, abdomen, and pelvis showed that the disease had spread to her bones and biopsy confirmed metastatic disease
• ECOG 1
• She was started on ribociclib + fulvestrant