HER2+ Therapy: Getting Less Toxic All the Time

Kathy D. Miller, MD; Clifford A. Hudis, MD


December 22, 2014

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You Say You Saw a Revolution?

Kathy D. Miller, MD: I am Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis, Indiana. Welcome to this edition of Medscape Oncology Insights, from the 2014 San Antonio Breast Cancer Symposium. At this meeting and over the past several years, there has been a real revolution in the treatment of patients with HER2-positive disease. Joining me today to sort out what has changed in HER2 and to look forward to where we might be headed in this subtype is Dr Clifford Hudis, chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center in New York.

The past couple of years have seen several new agents approved in the treatment of HER2-positive breast cancer and a lot of investigation about how to best use those agents. First, remind us about the CLEOPATRA trial[1] and the amazing overall survival data.

Clifford A. Hudis, MD: You are absolutely right. We have witnessed a revolution. When I trained, we didn't even identify HER2-positive breast cancer, and in retrospect, some of those unfortunate patients I saw early in my career who showed up, got sick, and died quickly, probably had HER2-positive disease. Once we began to test for it, we identified it as a poor prognostic subgroup. Then trastuzumab came along,[2] and relatively efficiently that drug was developed, tested, and proven in the metastatic setting.[3,4,5] It changed the standard of care in the first-line setting for metastatic breast cancer. In 2005, it was advanced to the adjuvant setting,[6,7] and I have seen some estimates of about a one third approximate reduction in the incidence of HER2-positive metastatic disease in the years after that.

I say all that to give a sense that we are living in a new era. Against that backdrop, the goal of CLEOPATRA was to notch up a further gain. And CLEOPATRA adds a second antibody: pertuzumab. This antibody binds to a different and distinct domain from trastuzumab, so you can give two antibodies to HER2-positive patients at the same time. They don't conflict. Its mechanism of action may be a bit different from and complementary to that of trastuzumab, but the key is that in CLEOPATRA, in the first-line setting, compared with placebo, in patients receiving a taxane and trastuzumab, adding the second antibody was associated with a significant prolongation in the primary endpoint, which was progression-free survival. This past year at the European meetings, this was updated[8] to a fairly remarkable improvement in overall survival. It has become the case now that when I go to clinic and give this three-drug regimen in first-line for metastatic disease, I have seen patients at 18 and 24 months without disease progression. It is no longer extraordinary.

Let It Be...HER2 Positive

Dr Miller: The shift is extraordinary. I remember early in my career, before trastuzumab, when HER2 had been identified as a poor prognostic feature. But we didn't have anything we could do about it. If I saw someone with locally advanced or newly metastatic disease and was waiting for the HER2 test, I would literally find myself praying, "Please, let it not be HER2 positive." Now it is exactly the opposite. I find myself rooting, “Please, God, let this be HER2 positive." There is so much more that I can do about it.

Dr Hudis: Right, and it's not just that the treatment is effective. In the long term, the quality of life is better than ever because we typically give a taxane in first-line for about 6 months and stop. For many of these patients—I am not saying everybody—there is a large tail on that survival curve where people just hang out with stable disease for a long time. That is what CLEOPATRA rightly taught us. Where the drugs are available, the study led to an immediate shift in standard first-line treatment.

Now, there are some nuances to point out. In CLEOPATRA, patients had not received previous adjuvant trastuzumab, whereas, of course, in the United States, most of our patients do so when they relapse. It doesn't seem that this is having a big impact in practice, and the phase 2 studies support this. But more of our patients have had previous taxane and trastuzumab therapy, so that is reassuring. The other part of it is, when they are off therapy after 6 months, the quality of life is better than what we used to offer with sequential chemotherapy. This has been important, and truly—I won't say universal—I think this is probably a pretty common pattern now for most of us.

Pertuzumab: Don't Pass Me By

Dr Miller: Certainly it is common [to give the drug combination] for those patients who reached the first-line setting since the pertuzumab approval. Thankfully, at least in my area, it has become easier to get approval for pertuzumab for patients who may have passed through the first-line setting before pertuzumab was available. We don't have phase 3 data in that setting, but we do have some phase 2 data suggesting that there is still a potential benefit from that agent.[9]

Dr Hudis: That is what brought the drug forward. As a single agent, like many of these antibodies, there was a glimmer of activity—not enough to say that this is a breakthrough, but it suggested activity. What was interesting in the Spanish studies[10] was that when pertuzumab was given with trastuzumab in patients who were refractory (or so we thought) to trastuzumab, the response rate was already up to about 25%. That was in the salvage type of setting, down the line. It was that observation that you are alluding to, and that informed a nuance in the National Comprehensive Cancer Network (NCCN) guidance, which basically amounts to saying that a patient can have a trial of pertuzumab, if not in first-line, per the label because you missed it, or because her physician didn't make the right choice, you can—within the NCCN guidance—get it later.

Dr Miller: The other agent approved in the past year or so is a HER2-targeted antibody-drug conjugate. Going back to the first thought about antibodies, one of my earliest grants was denied because it was widely known that antibodies would not be therapeutic. The first thought was that antibodies would just be an address label. Take this toxin, take this radionucleotide to where you want it to go. We have come full circle to that with T-DM1.

Dr Hudis: It's also interesting that the immunologic effects of trastuzumab were something we began to speculate about when we saw the activity-beyond-progression part of this story, because our mechanistic thinking didn't quite jive with a targeted signal transduction inhibitor working beyond progression. It still could be that there is some of that, but that is one part on the trastuzumab side. I agree with you. Early in my career, we all thought that this was the Buck Rogers future, right? We were going to give targeted drugs and the antibodies would target them.

Dr Miller: They would fly right to where you wanted them to go, leave the rest of you alone, and all would be well.

It's Getting Less Toxic All the Time

Dr. Hudis: Right, so T-DM1 takes advantage of an important, if hidden, biology breakthrough, which was the development of these dissolvable linker molecules, which bound three, four, or five molecules of cytotoxic chemotherapy as a payload to trastuzumab. It's worth pointing out that although no other drug conjugate in HER2-positive breast cancer is yet approved, there are other drugs of this design across oncology and a number are in development in HER2-positive breast cancer as well, now that the idea is proven. It's interesting, because one can take a drug that might be too toxic to give at full dose systemically, but you are leveraging the risk-to-benefit ratio if you deliver it just to the cancer. So T-DM1, which is what we are alluding to here, is exactly that. It is basically trastuzumab and an otherwise unavailable chemotherapy agent. The molecule and the chemotherapy we think are internalized, and the link is broken. The chemotherapy is delivered either intracellularly or possibly right at the cell surface. There are two versions of that story. But either way, it's clearly active.

It isn't transformative, in my opinion, the way that the first anti-HER2 therapy was. It doesn't move the ball to the 50-yard line from the end zone. It adds an important new option with unique but generally lesser toxicities than the alternatives. We have very good palliative therapy for metastatic disease after pertuzumab/trastuzumab with T-DMI. The interesting thing about pushing this drug to the adjuvant setting, which is what is happening now, is this may be a case of making a swap for lesser toxicity more than it is a swap from greater efficacy over current treatments. We are going to have to see.

Dr Miller: It is interesting that you mentioned lesser toxicity, because I have started to see a shift in our conversations from adding HER2-targeted therapy to a backbone of chemotherapy, to starting to think about a backbone of HER2-targeted therapy. Do we really need to add chemotherapy to those patients?

Dr Hudis: You're right.

You're Going to Lose That Chemo

Dr Miller: Do you see a day where you will treat patients in the adjuvant or metastatic setting only with HER2-targeted therapy and reserve chemotherapy for those at particularly high risk?

Dr Hudis: We are getting there already in baby steps. Backing up for just a moment, when we were talking about CLEOPATRA, one of the big points is, after a few months of therapy, a good number of those patients are able to back down to maintenance, if you will, with just antibody therapy. So that is a sort of preview.

Then we have this Dana-Farber–led, roughly 400-patient trial,[11] which should be in press soon, looking at a selected group of low-risk patients treated with just paclitaxel and trastuzumab. They still got chemotherapy toxicity but it's less than that of our conventional anthracycline-based therapy. It challenges some of our notions about how to establish standards, because this backs down from a good outcomes perspective and says, "How many recurrences will we have to see to make us think that this is undertreatment?" Right now, as you remember from their presentation, it was less than a handful of recurrences, with 3.5 years of follow-up, more or less.

Although that is not perfection, it's pretty hard to design a prospective study that would be better than that. With that as a framework, there is now a randomized phase 2 trial that is taking low-risk, node-negative, early-stage patients and randomly assigned them to T-DM1 or a "conventional" regimen of paclitaxel and trastuzumab.[12] That gets to your question. If there is something like equivalence and very low event rates, and a toxicity profile that favors it, I could see turning to those data in a few years and saying, "With a 9-mm HER2-positive node-negative breast cancer, I don't know whether T-DM1 for a year is necessary." But we don't see recurrences with it.

Dr Miller: Then the next step, further ratcheting it down, could be trying to shorten the duration. But at least we are starting to see trials looking at less rather than more and shifting the framework, where the HER2-targeted therapy is the primary treatment.

Dr Hudis: I agree, and it’s from a completely separate domain. But as you know, at the San Antonio meeting this year, in a separate disease type—estrogen receptor (ER)-positive disease— the SOFT trial was reported[13] and published in the New England Journal of Medicine.[14] What nobody should avoid noticing is that there was a cohort of ER-positive breast cancer patients with very low event rates. I think HER2 patients, some of them, are going to fit into a category like that, defined by biology but also, perhaps, node negativity and small tumor size.

The Long and Winding Road of Multinode Pathways

Dr Miller: Lest our readers think that everything that is done in the HER2-positive world works and turns out swimmingly, that is not always the case. In this case, we thought that we understood some of the biology, that the activation of the mTOR pathway would lead to resistance, and, therefore, dual blockade of HER2 and mTOR would be more successful. That was tested in the BOLERO-1 trial,[15] and we saw the results of BOLERO-1 at this meeting.

Dr Hudis: We are touching on a pretty challenging topic now because we have a multinode pathway with AKT and mTOR, as well as PI3K. We understand a good bit about it and we know very well that it's the most commonly mutated pathway in breast cancer, especially ER-positive, but it also has an important role in HER2-positive disease. It is very appropriate to believe that by dual targeting—if you will, parallel and communicating pathways— we will amplify the activity of active drugs. But at the same time, what this is teaching us is that sometimes there is more to the story. Some have shown—for example, Neal Rosen and Sarat Chandarlapaty—that inhibiting a pathway can lead to an unfortunate rebound upregulation of compensatory bypass pathways. That leads to very complex questions about dose, schedule, and duration.

With respect to everolimus, we are seeing some of those challenges.[15] We know the drug is active. We have a really big signal in the metastatic ER-positive setting from earlier work.[16] Yet, we are getting some results that challenge the simple notion that we just need to give the drug and hammer down on the pathway. By the way, we are seeing it a little more broadly. Some of the early work with PI3K inhibitors—and, for that matter, some of the AKT work—shows that it's not all simple. But I'm optimistic that if we figure out how to optimally use these drugs, we will be able to get some utility out of them. To your point, it isn't as simple as giving a continuous exposure and continuous dosing schedule with these drugs, and crossing our fingers and hoping it works. Unfortunately, that is not yielding fruit.

Dr Miller: Thank you, Cliff, for coming in and reviewing these changes. We will look forward to more. To our audience, thank you for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller, from San Antonio.


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