Adam M. Brufsky, MD, PhD: Hello, and thank you for joining us today for this OncLive^® Peer Exchange^® panel discussion entitled “Global Insight on Advanced Breast Cancer Management.” As research in the field of breast cancer continues to flourish, we are advancing at an unprecedented pace toward a more personalized approach to treatment. Today, I am joined by a distinguished panel of internationally known experts in breast oncology. We will focus our discussion on refining the use of targeted therapies for treatment of advanced disease and improving outcomes after progression. We’ll provide perspective on the latest research findings from ESMO 2017 and their application to clinical practice.

I am Dr. Adam Brufsky and I am a professor of medicine at the University of Pittsburgh, and associate director for Clinical Investigation at the University of Pittsburgh Cancer Institute. Participating today on our distinguished panel are Dr. Michael Gnant, professor of surgery and director of the Department of Surgery at the Medical University of Vienna, Austria; Dr. Joyce O’Shaughnessy, chair of Breast Cancer Research at Baylor University Medical Center, Texas Oncology and US Oncology in Dallas, Texas; Dr. Hope S. Rugo, professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center; and Dr. Michael Untch, professor of medicine at the Clinic for Gynecologic Oncology and Obstetrics, and head of the Interdisciplinary Breast Cancer Center of the Helios Klinikum Berlin-Buch in Berlin Germany. Thank you so much for joining us, let’s begin.

So, the first thing we want to talk about I think is something that really has taken at least an ER-positive part of the metastatic breast cancer world by storm on the CDK4/6 inhibitors. Joyce, how are you now using CDK4/6 inhibitors in your practice right now?

Joyce A. O’Shaughnessy, MD: I am pretty much recommending either palbociclib or ribociclib now in the first-line metastatic disease setting with letrozole. Initially, I wasn’t really sure that some patients with de novo metastatic disease or small volume asymptomatic bone only disease really required it. But the reason I’m doing it now pretty much across the board as I’ve gotten more experience is that every single subset you look at, including the de novo metastatic, for example, in the MONALEESA-2, there are Kaplan-Meier curves looking at letrozole plus/minus ribociclib, and the curves are very, very much a part in favor of the ribociclib and for the de novo metastatic disease setting. So, I don’t have any data not to give these patients every single subset benefit, so that’s what I’m doing in practice now.

Adam M. Brufsky, MD, PhD: The question I have now is, even before we can go into that, the FDA in the United States did something that was highly unusual, and that is, they approved these drugs, palbociclib in particular, on the basis of a 160-patient phase II trial. Hope, do you want to comment on that, on PALOMA-1?

Hope S. Rugo, MD: It’s very interesting because we were busy preparing to go to ODAC to discuss this, which seemed a reasonable approach for a randomized phase II trial. And then the FDA gave it accelerated approval. I actually think that in this situation, it was quite reasonable. It gave people access to the drug. It’s similar to pertuzumab in that a randomized phase III trial had been completed. So, the accrual had already been completed so they didn’t have to worry about not getting the final results. They didn’t have safety concerns that hadn’t been well described, and the safety concerns had already been added to from the randomized phase III trial, PALOMA-2. And then there was evidence of a significant prolongation of progression-free survival. So, I think in many ways, it just gave people the option to use the drug while we waited for the final information without a big risk other than financial.

Adam M. Brufsky, MD, PhD: So, we have PALOMA-1. Let me ask my European colleagues. Michael, the European EMA did not accept that data, correct? They would not accept the initial PALOMA-1 data for approval?

Michael Untch, MD: Well, the European agency approved the drug and it is approved like in Germany, since November 2016. But we have a second institution in Germany, which we call G-BA (Federal Joint Committee). It’s similar to NICE (National Institute for Health and Care Excellence) in the United Kingdom. And this institution said, “Well, progression-free survival as an endpoint does not convince us enough.” And now the pharmaceutical company has to negotiate with the insurance company about the price. So, it’s not about approving the drug, the drug is approved. And the sales, to be very honest, in the last 7 months went up and up and up because we use a lot of this drug. And now with the approval of ribociclib in Germany, or in Europe—since this week—we have a second player on the market, which is good for the patients. Again, we have to start then the next talk with the G-BA about, is it enough to have progression-free survival as an endpoint? And my opinion is, yes, it is enough.

And we were waiting, to be very honest, for this kind of drug for more than 10 years because in the area of endocrine treatment of breast cancer patients, the last innovation has been aromatase inhibition, and that was it. So, actually, I’m very happy to have these drugs now on the market. And we have to continue discussing this topic of endpoints, and that is not the last time we are going to discuss this because probably with FDA, this is also going to be a discussion about the endpoints of randomized clinical trials in oncology.

Adam M. Brufsky, MD, PhD: What do you think, the Austrian perspective?

Michael Gnant, MD: As always, our good luck here with our German colleagues, we have had rapid reimbursement for palbociclib and we expect it for ribociclib as well. However, I think that Michael has said that we were waiting in this; after all, this is the most common subtype of breast cancer. For the past decade, we were giving talks on personalized treatment, on the breaks, losing targeted, but essentially it was HER2 and maybe sometimes HER2-negative. And with the exception of mTOR inhibition, we have been waiting almost for 2 decades. So, I think part of that rapid move of the FDA may also reflect the clinical need in patients with hormone receptor-positive HER2-negative breast cancer.

Having said this—and I think we see extremely consistent data in the PALOMA set of trials, obviously in the MONALEESA trials, and also with abemaciclib, with a little delay—I believe, as a scientific community, we have so far failed to identify a biomarker that would help us to apply these interesting, but also very expensive, agents in a very rational way. So, I started the same way as Joyce has reported: I said there must be patients out there who respond well with that smoldering bone-only indolent disease. And, yes, we have them all—3 years of perfect response to letrozole alone and we saw this in the past.

But then when you look into the subgroups and you see that bone-only, for example, in PALOMA-2, is actually the hazard ratio is 0.3, and then you get down to the crash question, what would you do if this is mother and she has bone-only disease? And are you now saying, well you are the patient for fulvestrant only? So this is really very difficult.

On the other hand, and that may not be as limiting in clinical practice in the United States, for now, but in many European environments cost is really an issue. And I think that it is very important that we keep trying to do these translation studies to collect tissues and biomaterials throughout all these clinical trials in order to eventually be able to find a better rationale for the algorithm of multi-line treatment.

Transcript Edited for Clarity