COMMENTARY

Will pCR and Pembro Redefine Breast Cancer Treatment?

Kathy D. Miller, MD; Laura J. Esserman, MD, MBA

Disclosures

June 19, 2017

Kathy D. Miller, MD: Hi. I'm Dr Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis. Welcome to Medscape Oncology Insights and the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO).

In breast cancer, the neoadjuvant setting has been used to evaluate the potential activity of new drugs using pathologic complete response (pCR) as an early marker of activity. But how strongly does pCR correlate to overall survival, and how important has the neoadjuvant setting become as a drug development tool? My guest today is a leader in that field, and she will take us through some of those questions. I'm pleased to welcome Dr Laura Esserman. Laura is a professor of surgery and radiology at the University of California San Francisco (UCSF) School of Medicine and director of the Carol Franc Buck Breast Cancer Center at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California. Welcome, Laura.

Laura J. Esserman, MD, MBA: Thank you. It's so nice to be here, Kathy.

Reducing the Knowledge Turn: Genesis of I-SPY

Dr Miller: Take us back to the beginning of the I-SPY platform. Where did this idea come from?

Dr Esserman: Actually, the idea came from the semi-conductor industry. Everyone is used to having new technology and being able to have the latest phone every year. The reason why you have that incredibly quick knowledge turn is because in that industry, they used early endpoints—in that case, chip failure—as their indicator of response. They could design new ideas and try them out. They would constantly test ideas.

Andy Grove, one of the founders of and CEO of Intel, wrote a very scathing article about medicine.[1] I recommend it to everyone. It's something I had talked about for a long time. If you take a development cycle and say, "I have a drug. I'm going to look for safety in phase 1, then do phase 2 studies, and then phase 3 studies in the metastatic setting," that is about 5-7 years. Then you say, "I'm going to do adjuvant therapy. I'm going to give someone surgery, take away their tumor, and give them chemotherapy, plus or minus something else." It will take 5 years to recruit because you need thousands of patients, and then you have to wait 5 years to get an answer. There is no way to get that knowledge turn in less than 17 years.

I'd like to see a complete change in the way breast cancer is treated in my lifetime, not three lifetimes from now.

When you think about the people you take care of—a 40-year-old woman with three little kids—they do not have 17 years for you to get your act together. You have to look at the process. With the whole argument of whether pCR is good enough, perfection is the enemy of good. It's a whole lot better than nothing. I'd like to see a complete change in the way breast cancer is treated in my lifetime, not three lifetimes from now.

The idea is to get safety data for a promising agent. You start before you take away the tumor, before you take away your incredible early indicator. Even if it's not perfect, the whole idea is to get an idea of what else can work. In 1996, when I first got the idea, I said, "We'll create a whole platform. We'll get everyone working. We'll standardize the way we do the imaging and the way we do the biopsy. We'll show that people can work together and create an engine or a platform to cycle through." Then I wondered: Where is all the time wasted? Where is all the white space that you could compress? This idea of writing a new protocol and starting all over every time we want to try a new drug is the same drill.

Dr Miller: It takes a lot of time. Each protocol takes time to write and time to approve. All of that takes time.

Dr Esserman: All of that should be standardized. That is the whole idea, right? It's a platform, a pre-competitive consortium. Set up your group and get it organized. Do it that way. Don't start all over. Get some standards around the things that don't matter so that you can test things that do matter. Originally, I wanted to figure out how to adapt within patients. At the beginning, Don Berry said to me, "You don't have any other drugs." You also have to take a step back and say, "Is what we are doing so great?" Last I checked, our patients don't love what we have to offer. Our therapies are toxic. They don't always work, and they are far from great. Can we do better? Absolutely.

For I-SPY 1, it took me 4 years just to get through the investigational review board (IRB). After getting it through the IRB once, I was going to do everything else by an amendment. The platform was set for I-SPY 2. We were going to just cycle drugs through. We are actually putting drugs 14 and 15 into the drug [cycle]—and that's in 7 years. We have graduated around six agents. This last one, pembrolizumab, triples the response [in breast cancer].[2]

You know that people who get a pCR do a whole lot better than people who do not. You are trying to find out who are the great responders and who are the people who are still in trouble. The differences in survival in those two groups are big. It tells you where to start. Now that we have gotten a bunch of drugs through that can graduate, we can start to say, "How can we start thinking about combinations that give a response without Taxol® (paclitaxel)?" You can assign to the next drug, and then you only give AC (doxorubicin/cyclophosphamide) in the setting of a last resort if they still have residual disease.

I-SPY Platform and Its Graduates

Dr Miller: Let me take you through some of the specific I-SPY studies and what has happened with them. The most recent one looks the most exciting. Which one graduated first?

Dr Esserman: Veliparib and carboplatin graduated first.[3,4] It's interesting because we have the BrighTNess study, which absolutely confirmed our results.[5] The only problem is, it happens to be carboplatin that is making the difference, but that is okay. This shows that a trial four times bigger gave the exact same result as a smaller trial. The whole idea is, how fast can you learn?

I did my training at Stanford, and I spent a couple of years in management science and engineering. That whole group was steeped in Bayesian design. It's the heuristic of where you have an impression, and each person you treat updates that probability. That is how our brains think. It's just not very intuitive. This idea of cycling and learning as you go is an important concept. It's designed especially for decision-making under uncertainty.

One of the most important things I learned at this particular meeting was that the veliparib-carboplatin combination nearly doubled the pCR rate.[6] That is exactly what the larger BrighTNess trial showed. We did not separate it out; we did not think that carboplatin would be that effective in that particular subgroup. But when they separated it out, it was.

Dr Miller: I'm interested to see if that's one of the things that you learned from that experience, because you mentioned a next plan for the I-SPY platform, looking at combinations. Did what you learn tell you that you need to look at them as single agents first because every drug adds some toxicity? While the combination might be fantastic, if it's all one drug, then the other one is only along to add toxicity cost.

Dr Esserman: Correct. Now that we have a whole stable of drugs that change response rates, and now that response rates are bigger, the trial is set up so that we adapt within the trial. What that means is: Each person going through the trial informs the trial and the next person that comes in is given a regimen that is more likely to work based on her particular subtype. But that does not mean that each individual person can achieve a pCR.

Optimizing Response Using pCR

Dr Esserman: One of the things we are trying to do, and it's something I'm really excited about, is figure out how we can optimize response in each patient and still inform and learn within a scientific trial. That is the way we would like to practice. We just got a big program/project grant to do that. We have this fantastic opportunity with over 1000 patients who have been through the trial. We have the capacity to say that we are just getting our 3-year follow-up data in the next month or two. We will be able to ask, under any circumstance, is pCR the right outcome? I presume it's true, but data are data...we will find out. If it's true, then the goal is to get everyone to pCR.

We will to be able to ask, under any circumstance, is pCR the right outcome?

You know as well as I know that there are some people who are super-responders. Even with Herceptin® (trastuzumab), there are some people, maybe 10%-15%, who would respond to Herceptin alone. Why should they get all of the other stuff? If pCR, whatever way you get there, is the endpoint (the early indicator), then that should be okay. You start with less. If that does not work, you add more, and then you add Taxol. You start and you can layer in more. If that does not work, then you try something else. That gives us yet a whole other way of learning.

Dr Miller: That seems like a better way to use pCR for patients. One question is using pCR to inform drug development. But just giving more and more to everybody is not feasible. If pCR for an individual patient is a good predictor, then we could use that better by doing less initially, and only adding if you do not get there. When you get to pCR, you are done.

Dr Esserman: When we started in 2009-2010, there were not a lot of choices. You have to have something that you know. Now, I have a whole stable of regimens. I hope people all over the country are much more accepting of the idea of neoadjuvant therapy. We started with people saying, "What?" I said, "I'm the surgeon. I should know better." If you have high-risk disease, I am not going to cure you. You do not die because of the tumors on the breast. You die because it gets someplace else. If I can get you a good response, and I know I have the response, I might as well learn that right now.

The order of therapy does not matter. I can approve your surgical options, your adjuvant therapy choices, and know whether I'm on the right track. It's a better thing. That was a hard sell for many years. Now it's more common. Now I can say, "Let's try something less. Don't worry. If it does not work, I've got something really good to give you that is more specific for your tumor." That is something that people will try. If you say, "I'm going to try something out there," you may or may not get something that is better. Now we have things that are better than what the standard of care has been. How exciting.

I-SPY: Pembrolizumab Results

Dr Miller: Take us to the pembrolizumab data, because I know this has you tremendously excited.

Dr Esserman: I'm so excited. Pembrolizumab, which is a programmed death (PD)-1 inhibitor, as you know, triples the response in the HER2-negative subset.[2] Importantly, not only does it triple the response of triple-negative disease, it triples the response in hormone receptor–positive HER2-negative breast cancer. Again, these are the high-risk, high-grade, hormone receptor–positive tumors.

Dr Miller: These are the hormone receptor–positive tumors that we would agree need chemotherapy.

This is the beginning of the end of treatment for breast cancer as we know it.

Dr Esserman: Correct. They are MammaPrint® (Agendia; Irvine, California)-high to start with. This is the first drug we have seen move the needle. This is really exciting because it tells me that this is the beginning of the end of treatment for breast cancer as we know it. I am really tremendously excited because now we can start to build on that. We will be able to look at all the complexity, such as the T-cell infiltrates, and learn what to combine that with. We can start to say that we have things. What does a combination like AC add? You could say, "It's an active drug combination, but your complete response rate is about 10%. It's nowhere near what this drug is." That is so much better. I'm so excited about it. I can see the end. I can imagine the different ways in which we can combine agents and learn. What I see is a better future for people. With I-SPY 2 plus, this new design that we are taking on, we have set a goal: getting 90% of patients to pCR, all without traditional chemotherapy, in 5 years. I do not know if we will make it, but it's a great aspirational goal.

Dr Miller: It's a goal that many of our patients would share.

Dr Esserman: The thing is, if you don't try something new, you absolutely cannot get a different answer. If you're willing to have a little courage and try something new, I think we'll find much less toxic treatments for patients and find out who needs less and can get a great response, and then serially who needs more and how different it should be. That, to me, would be a great contribution.

Dr Miller: We will get you back in 5 years to see how the goal is coming.

Dr Esserman: Let's try 3.

Dr Miller: We'll try 3. Thank you for joining us. To you, our listeners, thank you for joining us today as well. This is Kathy Miller, reporting from ASCO 2017.

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