Treatment and Cost Implications of Pertuzumab

Pertuzumab, a new HER2-positive breast cancer drug, is being launched at a 31% premium to the price of trastuzumab. This is an aggressive strategy that will substantially increase the cost of treating patients with metastatic HER2-positive breast cancer, while also aiming to deliver the best outcomes for patients.

Pertuzumab will be used as an add-on to trastuzumab to treat patients. Progression- free survival was boosted by 6.1 months when the drugs were used in combination in the CLEOPATRA study.

With payers already anxious about the rising costs in oncology, an 18-month course of the combination treatment is estimated to reach more than $180,000. This cost sets the bar high for the future, as expensive targeted drugs are expected to be used increasingly in combination to deliver the best outcomes.

To examine these treatment benefits, cost concerns, and potential insurance coverage strategies, AJMC’s co-editor-in-chief, Michael E. Chernew, PhD, professor, department of healthcare policy, Harvard Medical School, moderated a panel discussion with Lee Newcomer, MD, MHA, senior vice president, oncology, UnitedHealthcare, and Sandra M. Swain, MD, medical director, Washington Cancer Institute, Medstar Washington Hospital Center.

Dr Chernew:Dr Swain, I am interested in the current treatment landscape for patients with breast cancer. If you have any thoughts on how physicians choose breast cancer treatments for their patients, it would be interesting to hear them.

Dr Swain:

There are a lot of different treatment paradigms for breast cancer and it really depends on if you are talking about early stage disease or metastatic disease. Let’s start with metastatic disease. Unfortunately, even with some of our very effective treatments, we really don’t affect survival in a lot of cases of metastatic breast cancer. However, breast cancer has really been categorized now into different kinds of breast cancer—ER-positive breast cancer, triple negative breast cancer [meaning there is no estrogen receptor or HER2], and HER2-positive breast cancer [in which patients have the HER2 oncogene that is overexpressed]. So, it’s very complex; you can’t just answer that with 1 answer. The way an oncologist would choose is to look at the biology of the tumor [to see] if it has the receptors or not. For example, if the tumor had the HER receptor with metastatic disease and it was first line you would choose trastuzumab. And, with the recent data in the CLEOPATRA study showing that the addition of pertuzumab to trastuzumab plus docetaxel actually has a large benefit, oncologists would consider this also at this point.

Dr Chernew: So, can you provide a brief overview of the CLEOPATRA trial?

Dr Swain:

The CLEOPATRA trial was a prospective, phase 3, randomized study in patients who had not received any chemotherapy for metastatic HER2-positive breast cancer. The study included 808 patients and they were randomized to either receive placebo plus trastuzumab plus docetaxel [control group] or pertuzumab plus trastuzumab plus docetaxel [pertuzumab group]. It was first-line treatment, and the end point of the study was to look at an independently assessed progression-free survival. It really had a spectacular result in my opinion. It was a progressionfree survival advantage of 6 months. This was actually a placebo-controlled study, so even though progression-free survival can be a difficult end point, it was clear in this study that there really was a benefit to the addition of the drug pertuzumab. The interim analysis of survival showed a trend in favor of pertuzumab in the initial report that we released at the San Antonio Breast Cancer Symposium and published in the New England Journal of Medicine in December 2011, but most recently we’ve reanalyzed the survival and, actually, a press release came out this past June showing that there was a survival benefit also with the addition of pertuzumab. This top-line data was submitted to a major meeting, so hopefully it will be presented in the next few months.

Dr Chernew:As a first-line treatment, how many breast cancer patients would be eligible? Just the patients who would have the correct target—the HER2 target?

Dr Swain:

The patients with HER2-positive overexpression are approximately 15% to 20% of breast cancer. And, the indication is only for patients who have not had previous chemotherapy. It wouldn’t be for someone who’s had trastuzumab or other drugs or second-, third-, or fourth-line treatments. It’s only for first-line treatment.

Dr Chernew: OK, and that would be approximately 15% or less because of the exclusions?

Dr Swain:

Maybe a little less than [the general population of patients with breast cancer]. Per year, it would be 15%, but of the patients now, it’s certainly going

to be less because a lot of patients now would have had other treatments.

Dr Newcomer:

The manufacturers are estimating that there would be approximately 8000 women who would have HER2-positive metastatic breast cancer, per year, in the country. That’s a fair estimate.

Dr Chernew: One of the biggest challenges— because it sounds, clinically, like there are a lot of optimistic results— is how we might finance access to this treatment. The cost of the pertuzumab and trastuzumab combination is approximately $187,000 for a course of treatment over the entire duration. So, Dr Newcomer, how do you think plans might respond, how do you think oncologists might respond, and what general strategies will be utilized to provide access to this drug?

Dr Newcomer:

Well, I am in complete agreement with Dr Swain in that pertuzumab is a good drug. The trial showed a clear benefit and the benefit was probably one of the larger ones we’ve seen in a long time. Therefore, I would be quite surprised if there wasn’t ready access to pertuzumab from any payer for the indication for which it’s approved. So, as first-line therapy in combination with trastuzumab and docetaxel, I can’t imagine that anyone wouldn’t cover that. That said, it’s expensive, there’s no question. From a total expense though, it’s a very small population compared with all of the women with breast cancer. And, the way that we deal with that, as does every payer in the country, is we simply build it into the premium, and the premium for the next quarter goes up. So, there isn’t a way to pay for this other than simply passing the costs on in the premium, which means everyone who buys health insurance will see a slight increase.

Dr Chernew: Do you do modeling—because the population is so small—to show how big that increase might be? Is the premium increase small because of the small number of women, despite the per treatment sticker price?

Dr Newcomer:

Yes, we actually do model all new technologies. We generally model them approximately 6 to 12 months prior to their emergence into the market and start building that into the premium in anticipation of the new technology coming on board. I don’t know the exact amount for pertuzumab and wouldn’t be able to release it anyway, but that is a process that we do routinely, looking for the new drugs coming out or other new technologies, estimating their costs and how many people would be using it, and building that into the premium.

Dr Chernew: In certain cases, and you were very clear in your earlier answer, there’s utilization of drugs or, more broadly, new technologies beyond the populations that were originally studied or for whom it was originally approved. Do you think that’s a bigissue in this particular case and, if so, how do you think your plan and other plans might deal with that issue?

Dr Newcomer:

I think it clearly is an issue to consider. Every drug that comes to the market eventually finds new uses as further clinical trials are undertaken and they may be reflected on the FDA label. What we’ve done at UnitedHealthcare is turned to the National Comprehensive Cancer Network (NCCN) recommendations to decide when there is enough evidence for coverage. If the NCCN recommends it in their guidelines, then we provide coverage. Other insurers are examining the evidence, whether using their own staff or other sources, but we are going to see people testing this drug in other indications. They may use it as an adjuvant with trastuzumab. They may try using it in second- and third-line treatments. If the evidence shows there is still a benefit, then I do think you will see a use expand.

Dr Chernew: Do you think there will be that type of experimentation prior to rigorous studies in those other populations?

Dr. Newcomer:

There already are other people attempting to use it that way, and as I was discussing with Dr Swain prior to the call, almost 90% of our requests for this drug in the first week were for indications other than what the CLEOPATRA trial showed. And, we don’t cover in that circumstance until there is proper evidence.

Dr Chernew: When you say other indications than what the CLEOPATRA trial showed, do you mean indications that were studied and there wasn’t an effect or do you mean indications that simply weren’t studied in the CLEOPATRA trial?

Dr Newcomer:

In clinical situations that simply weren’t examined in the CLEOPATRA trial; for example, patients on their fourth or fifth line of therapy.

Dr Chernew: More broadly, what drives the cost of drugs in cancer care?

Dr Swain:

Well, I think what the companies say is that it’s very expensive to develop these drugs, such as the clinical trials. The CLEOPATRA study was 808 patients—I don’t know how many millions of dollars it cost, but it cost a huge amount of money. Sometimes the number you see is a billion dollars to develop a drug. And, many of the drugs that they start developing don’t go to market, so then they don’t recoup any of those costs for developing those drugs. However, I think that the pricing is as high as the market can bear. And, so there’s really no link right now between the pricing and effectiveness of drugs. For example, many of these other drugs that are chemotherapy drugs used for second-, third-, fourth-line treatment in breast cancer don’t have survival benefit and are expensive, and yet that really isn’t taken into consideration. I think we need to do that, certainly in the future. One of the things that I am very interested in doing is not getting incremental benefits with our drugs. I think what’s happened in the past is that a lot of drugs have been approved when it’s later-line treatment because there’s not a lot of treatment for the patient—the bar is lower. In other words, the benefit is not as great. In addition, the patient may have a lot of toxicity and may not have the benefit, so there’s a high cost there, too.

Dr Chernew: In this case, it seems pertuzumab provides a lot of value at a very high cost and, if I understand Dr Newcomer’s earlier answer, the benefit seems great in this case and the overall population seems relatively small. So, the overall premium impact isn’t enormous and he [Dr Newcomer] would expect that there would not be restrictions on access to pertuzumab. Is that generally your sense, Dr Newcomer?

Dr Newcomer:

The restrictions that will be placed will involve ensuring that the HER2 gene is actually overexpressed, so that the drug isn’t used on HER2 underexpressed patients. This was a problem when trastuzumab initially came out. I would expect the same thing here. But, within the same criteria that the trial used, I do think there will be readily available coverage.

Dr Chernew: I think that breakthroughs such as this lead to a lot of excitement. However, it does lead to a general dilemma about financing access to expensive, although I think in this case considered valuable, care.

Dr Newcomer:

First, I would love to hear Dr Swain’s opinion and others on whether the CLEOPATRA trial should have had a third arm. That arm would have compared the control regimen used until progression followed by the addition of pertuzumab until the second progression. The study would then compare overall survival between the groups. One way to reduce the total cost of therapy is to use the drugs sequentially rather than as an initial combination. This would reduce the time required to use the more expensive medication if the results were comparable. Yet manufacturers, for obvious reasons, don’t ever do that trial. If sequential therapy obtained the same type of responses, it would significantly reduce the amount of drug necessary to treat them.

Dr Swain:

I think that’s a really good design and that’s my criticism of a lot of trials and a lot of combinations. However, with pertuzumab, for example, when it was used as monotherapy, it had a very low response rate. Therefore, in this situation it would be unlikely to have had a benefit. If you use the sequential design, you still end up having the cost, though, because you would end up having both drugs over the lifetime, so I’m not sure it would decrease the cost that much.

Dr Newcomer:

Yes, unless you could treat the patient for just 6 months instead of 18 months. So, if the patient got 12 months out of trastuzumab plus docetaxel, then the oncologist was able to add the pertuzumab to those 2 drugs at the time of relapse and get another 6 or 7 months of progressionfree survival—that’s the kind of scenario I was thinking about. That would mean patients would be treated for only 6 months with pertuzumab instead of 18 months.

Dr Chernew: Do you think some plans, or I think more relevantly some healthcare providers, would try such a strategy? Or, do you think because of the way the CLEOPATRA trial was designed that it’s unlikely?

Dr Newcomer:

I think given the trial design they are almost required to use the 3-drug combination. What I just described needs testing because we don’t know if it would work. However, if it did, it would be one way to get the total cost of therapy down.

Dr Swain:

And, the problem is that there’s a survival benefit now with the 3-drug combination. You don’t know if there will be a survival benefit if you’re dropping out the newer drug. You may not have the survival benefit. So, I think that providers will go with the indication that’s in the trial right now.

Dr Chernew: So, it’s much more likely that the drug’s use will be expanded by testing other indications in clinical trial rather than trying to economize by attempting indications that might not be as good?

Dr Swain:

Well, I think that people do need to economize, but definitely expansion is already being tested in the adjuvant setting and in the neo-adjuvant setting. The other issue that we kind of touched on is the length of treatment in these targeted drugs, especially in the adjuvant setting. There are several trials ongoing in the world looking at the length of treatment for trastuzumab, for example, to see if you really need to give a 1-year adjuvant treatment; there are trials looking at 9 weeks. I think those trials are going to be extremely informative, certainly for the adjuvant setting, and may even also help us in the metastatic setting.

Dr Newcomer:

I’m in complete agreement. I just want to make very clear, though, that the suggestion I had about the 6 months of therapy after failure could only be done in the context of a clinical trial. I’m not recommending that anyone would do that in the clinic today.

Dr Chernew: Thank you for clarifying. I did not mean to imply anything otherwise.

Dr. Chernew: There have been many advances recently, as the CLEOPATRA trial illustrates, and we welcome those advances for a whole number of reasons, but it does place some burden on financing. It might be the case that any particular product, such as pertuzumab, doesn’t add a lot to the overall premium; however, in combination with technologies, illnesses, and so on, premiums have been rising to rates that people consider difficult to finance. Therefore, how can we support the innovation that we all desire in our healthcare system without having a price tag that we can’t afford?

Dr Swain:

We really need to have a high bar for what we consider effective treatment. I think that’s where we’ve gone wrong in the past. We’ve had statistically significant benefits for some of these drugs that may be a month-to-month [or] a couple weeks’ benefit if you look at the randomized study, but what does it mean to the patient? It probably doesn’t mean a whole lot. I really feel strongly about this issue. We’re looking at some of these things in my role as president at the American Society of Clinical Oncology (ASCO) to ensure we set a higher bar and don’t have incremental benefits. I think that’s where you get into very high costs, is when you are using these drugs that are marginally effective. We also need to be looking at toxicity issues, which we are doing. For example, in the CLEOPATRA trial, pertuzumab really didn’t add a lot of toxicity per se. A few patients developed febrile neutropenia and diarrhea, but not significant toxicity in most cases. We really need to be looking at cost-effectiveness and we really haven’t done that well in most of our randomized studies in the past.

Dr Newcomer:

I’m in complete agreement with Dr Swain. We have to do something to reduce the consumptionof both drugs and other technologies that aren’t really making a big difference. And, that’s going to be a very painful thing to do, but there’s a reason we have to do it. There are 3 reports recently on the ASCO News website where economists took a look at current trends in medical costs and current trends in US salaries, and what they found is that in 15 years you will have to use your entire US average salary to pay your average US healthcare premium. So, that doesn’t leave anything for food, clothing, and shelter. Obviously, we can’t do that. And, the only way we are going to be able to bring our healthcare costs down is to eliminate those things of very marginal value. It means we have to say no. And, that’s a tough thing for us to do politically in the United States.

Dr Swain:

It’s very tough and it’s also tough for patients in the United States— the American patients expect to be treated. They expect to come into the physician’s office and get a drug, antibiotics, or whatever in all aspects of healthcare. We just have to change that culture and educate the population that just because we have a drug doesn’t mean it’s the right thing to do at that point. And, it is very hard, as I do it in my practice all the time. People don’t want to hear “This drug is going to cause you a lot of side effects and it’s not going to help you a whole lot.”

Dr Chernew: How will utilization responses to innovation be affected by changes in payment models (eg, payfor- performance, new bundled payments systems)? In general, how will oncology respond as many of these new drugs coming out are applied to cancer?

Dr Newcomer:

There’s no question that, as we move forward in the United States, we’ll see more financing approaches that use budgets. The accountable care organizations are an example and bundled payments may be another. In those systems, a budget would require physicians to separate out those things that are really important from those that either don’t have an effect or don’t have enough of an effect to be important. I really believe those decisions are best made at the professional level. So, I’m hoping that as we evolve new financing systems that it will be doctors involved in making the decisions. But, I can’t emphasize enough, as we both said before, that it’s going to be hard. Looking at a patient and saying we aren’t going to do some of these things because they just don’t have value, even if the patient might want them, is a difficult thing to do.

Dr Swain:

I think we are also in an era in which we are looking at quality improvement. One of the things we are doing at ASCO also is the Quality Oncology Practice Initiative program in which we are observing approximately 700 practices, and we have done this at the Washington Cancer Institute, to study different measures and how these different measures can improve the quality. We need to link that now to outcomes, and I think that’s really one of the basic areas of research that’s being done. If you make these changes, will the outcomes actually be better?

Dr Newcomer:

An important part to add to that is that drugs are only onethird of the cost of caring for a patient with cancer. So, if you can anticipate problems, deal with them early, and keep the patient out of a hospital, there will be significant savings in terms of caring for that patient. This isn’t all about drugs; it’s about how we can improve the whole care process.

Dr Chernew: Some of these other payment models might enable the decisions to reflect these other savings?

Dr Newcomer:

Yes, I think that is true as well.

Dr Swain:

Something we’ve done at ASCO is the Choosing Wisely campaign. I know several other organizations have done something similar. We chose 5 common, costly procedures in oncology that are not supported by evidence and that should be questioned; for example, performing surveillance with PET scans or CTs for early breast cancer and prostate cancer, using growth factors when the likelihood of febrile neutropenia is low, or giving drugs in the last days of life when it’s really not effective. So, we have rewhere ally taken this issue on and we are trying to do something as an organization of physicians to try to decrease healthcare costs. I think it’s going to take all of us working on this issue—the payers’, physicians’, and patients’ understanding and education of it— to really solve the problem.

Dr Newcomer:

I was on the committee that developed the 5 choices and I’m finding, in my current role, people coming back and saying “OK, is it time for us to stop paying for PET scans? We’re getting a lot of pushback.” Even though ASCO has done a beautiful job of laying out the reasons for why it shouldn’t be performed, as we try to put some of that in the field, a lot of providers are pushing back on us and saying it’s unfair. And, it just helps illustrate how difficult this is going to be.

Dr Chernew: Do you think there’s any role in patient incentives to get patients with cancer more engaged, or isn’t it realistic to expect these patients to be engaged in the process, at least in weighing any of the financial ramifications of the decisions?

Dr Swain:

Well, I think they are doing that now. They have to do that with some of the copays—they have to look at whether they can afford it. However, we as physicians have to be honest and clear with the patientsas to what the benefits are with the treatment being recommended. And, that’s why I again get back to having a very high bar. If you administer a treatment, it needs to have really good efficacy for the patient, especially if they are going to be paying some money out of pocket, which happens many times now, especially for oral drugs.

Dr Newcomer:

The actual amount of out-of-pocket money for these folks— typically the ceiling is around $5000—is fairly high. It’s enough that some patients are forgoing treatment. So, I agree; patients get involved in the economics of some of these decisions pretty early.

Dr Chernew: In a case where the evidence of effectiveness is as strong as it is for pertuzumab, you might think that some different copay structure would be reasonable to avoid placing financial access barriers to very good medications. Do you see that type of differentiation going on now?

Dr Newcomer:

Well, what you are describing is called a value-based copayment or value-based coinsurance and the concept is wonderful; putting it into action is really hard, particularly for drugs that have more than 1 cancer where they’re active. So, you might give a drug a good rating for effectiveness in 1 cancer, but a very low rating in a second cancer. Trying to keep that simple enough for a patient or consumer to understand and a business office to bill correctly gets to be pretty complex. It’s a great idea, but we haven’t learned how to simplify it enough to make it work.

Dr Chernew: Drs Newcomer and Swain, do you have any other comments or something you would like to add?

Dr Swain:

I think one thing that we didn’t really talk about today is the importance of approving companion diagnostics with the newer drugs in oncology. This sets a higher bar for the new drugs that are coming out, plus it decreases the population of patients in which the drug is being tested. Therefore, clinical trials in the future should cost less and, hopefully, the drugs will cost less. So, that’s something where research is really important to try to decrease some of these costs.

Dr Chernew: I assume UnitedHealthcare supports the relevant companion diagnostics to assess, for example, whether HER2 is over- or under-expressed in order to get access?

Dr Newcomer:

Absolutely, for all the reasons that Dr Swain just mentioned. They make perfect sense. We also didn’t address that the pharmaceutical industry is going to have to find a way to lower the costs of drug development. They’re a very innovative group and they are finding great drugs. They’ve got to find a way, then, to make the cost of developing those drugs less as well. So, some of that innovation needs to be turned inward to see if we can reduce the price of those medicines.Participant Affiliations:From the Department of Healthcare Policy, Harvard Medical School (MEC), Boston, MA; UnitedHealthcare (LN), Minneapolis, MN; Washington Cancer Institute, Medstar Washington Hospital Center (SMS), Washington, DC.

Funding Source:None.

Participant Disclosures:Dr Newcomer reports being an employee of United- Healthcare and owning stock in UnitedHealth Group. Dr Swain reports uncompensated participation in advisory boards with Genentech/Roche and receiving grants from Genentech. Dr Chernew reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Treatment and Cost Implications of Pertuzumab