CDK4/6 Inhibitors for HR+ Breast Cancer

Transcript: Joyce O’Shaughnessy, MD: Hello, and thank you for joining this OncLive Peer Exchange® discussion, “Advanced Breast Cancer: Key Updates in Clinical Care.” Today’s expert panel will discuss the practical implications of recent data surrounding the use of systemic therapy for breast cancer. I’m Dr Joyce O’Shaughnessy, chair of breast cancer research and Celebrating Women chair in breast cancer at Baylor University Medical Center, Texas Oncology, and US Oncology in Dallas, Texas.

And joining me today are Dr Kevin Kalinsky, assistant professor of medicine, Division of Hematology and Oncology, NewYork-Presbyterian Hospital/Columbia University Irving Medical Center in New York. Kevin?

Kevin Kalinsky, MD, MS: Hello.

Joyce O’Shaughnessy, MD: And we have Dr Elizabeth Mittendorf. She is the Rob and Karen Hale Distinguished Chair in Surgical Oncology at the Dana-Farber/Brigham and Women’s Cancer Center in Boston.

And we have Dr Ruth O’Regan, professor and division head of Hematology/Oncology, Department of Medicine; and associate director of faculty development in education at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin.

And lastly, we have Dr Hope S. Rugo, professor of medicine and director of Breast Cancer Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California.

We have a lot of exciting topics to cover today. There’s a lot of new information that has come out, so let’s get started on our first topic, which is treatment approaches to metastatic hormone receptor-positive/HER2 [human epidermal growth factor receptor 2]-negative breast cancer.

So we have a lot of options for these patients who are presenting either de novo metastatic or recurrent ER [estrogen receptor]-positive/HER2-negative disease. You know, all the way from endocrine therapy alone to combination chemotherapy. Ruth, how do you approach the treatment of these patients, in general? What kind of characteristics in patients do you think about?

Ruth O'Regan, MD: I think most of us now use CDK [cyclin-dependent kinase] inhibitors in combination with endocrine therapy for most of our patients. As far as patients I’d just give endocrine therapy to, I think they are few and far in between. But this may be an option for an older patient with de novo disease or very long disease-free interval, who perhaps has some comorbidities where maybe you want to avoid the CDK inhibitor in the first-line setting. As far as when I would use chemotherapy—people who have visceral crisis, but I kind think about that as somebody who, if the cancer doubles one more time, they’re going to get in trouble.

So the chemotherapy potentially might work earlier, or more quickly, but we don’t know that for sure. So for those patients I would consider chemotherapy. So somebody with elevated liver function tests [LFTs], something like that, I would consider in those patients. But I have to say that for the majority of patients I go with the CDK inhibitor and endocrine therapy.

Joyce O’Shaughnessy, MD: That’s interesting. That’s kind of a change I think over the last few years, Hope, what about you? How do you think about these patients?

Hope S. Rugo, MD: Yes, I think it is a change. I think it’s really taken us by storm in many ways, because the agents are generally well tolerated. We’ve gotten used to managing the toxicity of the CDK4/6 inhibitors. And then trying to keep somebody on a mainly oral-based regimen, regardless of your hormone partner, for as long as possible is very appealing to us to try and avoid the start of chemotherapy.

And so, we seem to be able to do that by giving a CDK4/6 inhibitor upfront. I also think that the fact that we’ve seen similar efficacy in patients who have visceral disease at presentation, albeit with a hormone-type phenotype—you know, not a liver full of tumor, but the liver, lung disease, soft tissue, bone that we see with hormone receptor-positive disease—the drugs seem to work very well to help hormone therapy to work longer and more effectively in those patients. So that’s also been very encouraging to me. And, of course, we have options if patients have difficulty with tolerance as well.

You know, I was reflecting on what Ruth said about who you might use single-agent endocrine therapy for, and I’ve actually only given it to 1 person who had a 32-year disease-free interval and a single lesion in bone and soft tissue and rib and is a little mentally unstable. I gave her fulvestrant alone, which I think was very reasonable, and she’s still on it 3 years later. But for most people, I think if you could stay on therapy even longer, it always seems to me that people who respond, respond even better with a targeted agent.

Joyce O’Shaughnessy, MD: Yes. And you know, it’s double clamping down on that ER-driven pathway to get both the ER and the CDK. So for ER-driven disease, which makes a great deal of sense, but, I think a lot of people are still a little queasy when it comes to liver metastasis or grade 3 disease. How about you, Kevin? When somebody has liver metastasis, how do you think through chemotherapy or a CDK?

Kevin Kalinsky, MD, MS: I think that we have a very similar approach. As Ruth had mentioned, for a patient who presents with de novo disease and bone-only disease, I think one of the notable things with these drugs is that we see significant response rates. Response rates can be up to 50% or so, and the median time to response can be around 2 months. And so, I think that our threshold for the utilization of chemotherapy really has changed just because we can see significant responses with these drugs.

Joyce O’Shaughnessy, MD: Yes, and we’ve all had to kind of get used to that. I think particularly liver disease, or even some symptomatic lung disease are where we all start getting a little concerned about things. But you’ve had success with some of those patients with liver metastasis, and even for some abnormal LFTs, you’ve had some successes?

Kevin Kalinsky, MD, MS: Yes. I think that if somebody has a liver that is full of metastases, for whom you really feel like you need to get a quick response … if somebody were to present like that, I would maybe consider chemotherapy. But the truth is, when you look at the waterfall plot and you look in all of these various studies at all the different factors, really the combination seems to benefit for all those concerning features, right? Grade, lacking PR [progesterone receptor] status, visceral disease—you really do see a benefit with these drugs.

Hope S. Rugo, MD: It’s an interesting question. Before we had the CDK4/6 inhibitors, if somebody presented, especially a young patient with de novo ER-positive disease to liver, maybe we would do induction chemotherapy. And I remember all these patients would come from multiple opinions. But now with the CDK4/6 inhibitors, I’ve treated a number of young women who presented with de novo metastatic disease to the liver who’ve had CRs [complete responses] in the liver, and these patients are now on for 2 and 3 years with no disease—like 1 little non-FDG [fluorodeoxyglucose] avid remaining lesion. It’s been very encouraging. In fact, so much so that we bring up the question of: Should we be doing something about their primary tumor now? That’s a big question that Elizabeth has a lot of experience with. But I’ve been really encouraged by this. I think that we can try, and you don’t lose much. I agree with Kevin: That somebody who has an abnormal liver function test where you need a quick response, if they’re short of breath, I’m going to give chemotherapy. But otherwise, you know, we’ve had amazing responses.

Ruth O'Regan, MD: And maybe sometimes those patients actually do better than they would with chemotherapy because, if they’re really like a luminal-A phenotype, chemotherapy is probably not going to benefit them very much. I will say I think it would be great if we had a biomarker to tell us who needed treatment in the first-line setting, especially since we don’t have survival data from the first-line trial, apart from PALOMA-1. But we’ve tried, so far, and we haven’t found anything conclusive apart from the estrogen receptor.

Joyce O’Shaughnessy, MD: Yes. And the PFS [progression-free survival] for the CDK4/6 inhibitors in the first line is 2-plus years right across the studies, which is getting close to triple what you’d see with PFS even with first-line chemotherapy, even with combinations. It’s just so much more durable if they respond. But the response rates are very similar. So I think this is actually a major sea change, and it sounds like we’re all coming to a similar conclusion in our practice. This is still evolving, but we are still coming to a similar conclusion.

Transcript Edited for Clarity