Immunotherapy in Cancer Care: Understanding the Impact of Shifting Treatment Paradigms in the Managed Care Setting

The American Journal of Managed Care convened an expert panel to address the impact of increased use of immunotherapy in treating cancer in a managed care setting. According to the American Cancer Society, immunotherapy is a treatment that wards off disease either by boosting the immune system in general or by training it to attack specific cancer cells. Immunotherapy may be used alone or in combination with standard chemotherapy regimens.

Panelists discussed the positive and negative aspects of using immunotherapy, traditional chemotherapy, and combination regimens. They addressed the importance of promoting both patient and provider understanding of immunotherapy. Finally, panelists discussed the cost associated with immunotherapy in cancer care.

Peter Salgo, MD

The discussion was moderated by , a professor of medicine and anesthesiology at Columbia University and an associate director of surgical intensive care at NewYork-Presbyterian Hospital, New York City. The panelists included:

• Jeffrey Weber, MD, PhD,

senior member of the H. Lee Moffitt Cancer Center and director, Donald A. Adam Comprehensive Melanoma Research Center, Tampa, Florida.

• Michael A. Kolodziej, MD,

national medical director, Oncology Solutions, Aetna, Inc.

• Daniel J. George, MD,

Duke Cancer Institute.

Peter Salgo, MD, initiated the discussion by stating that immunotherapy markets were expected to exceed $14 billion this year; of the 12 FDA (US Food and Drug Administration)-approved drugs in 2012, 11 cost more than $100,000 a year. He said this points to a trend toward increasing costs for everyone. Dr Salgo then specifically asked Daniel George, MD, to comment on the previously unmet medical needs that are now being met by cancer immunotherapies.

Daniel J. George, MD:

Cancer immunotherapy, and immunotherapy in general, has a long history of almost 100 years or more of recognizing the importance of the immune system in monitoring, preventing, and controlling cancer. We probably have not used this to our best advantage, but recently there’s been a breakthrough in a number of agents and strategies that have harnessed this access of therapy, an endogenous approach to managing this disease and taking advantage of our own immune system and the way it fights cancer.

Dr Salgo:

The way I’ve looked at it, if I may, is in the past when you gave chemotherapy, you just killed all the cells and hoped that the rapidly dividing cells went first and then salvaged patients back. That’s not what’s going on.

Dr George:

This is a really different paradigm. The immune system is present and we are trying to manipulate it in a way to reactivate it against cancer. There’s a concept called tolerance where, by multiple different strategies, cancer cells can evade recognition by the imanothermune system; there’s a way of reharnessing the immune system by overcoming that tolerance. Unlike chemotherapy or radiation therapy, where the treatment stops when you stop the drug, these are therapies that potentially could keep going and keep working following reactivation. We’re actually sort of vaccinating, if you permit me to use an umbrella term that may be imprecise, against cancer such that you are sensitizing an immune system against a particular tumor. You don’t have to re-vaccinate every 3 days. You give it once and the immune system keeps working.

Jeffrey Weber, MD, PhD:

Well, the Holy Grail of cancer immunology is to create a cancer vaccine. Provenge was the first and only cancer vaccine that was ever approved. But that is truly the mantra, that is, the immune system is the ultimate way to perform targeted therapy. So immunotherapy is targeted therapy, and its hallmark is memory.

Michael A. Kolodziej, MD:

I was a practicing oncologist until just recently, and there’s an unmet need because what we were doing wasn’t working very well. So now we have the emergence of immunotherapy as an approach. We have the emergence of targeted therapy and even to the point of precision medicine as an approach, and we’ll see what wins. It’s very exciting because the science has advanced quite rapidly, but what we did earlier wasn’t very effective in most patients.

Dr Salgo continued the discussion by asking the panelists to clarify his understanding of the mechanism by which immune therapy works. His understanding was that we continually develop malignant cells every day that are consumed by the immune system to prevent tumor development, and the immunotherapy drugs seem to target the failure of immune recognition and immune response.

Dr Weber:

There are certainly data to suggest that this idea of immune surveillance is indeed valid. On the other hand, people on immunosuppressants don’t always present with 30 different types of solid tumors. Transplant patients often develop squamous skin cancers, especially virally related squamous skin cancers. So there are data to suggest that we always have immune surveillance to prevent cancer from developing.

In response, Dr Salgo queried the panelists on the different types of immunotherapy drugs that are now available and the types of cancers they treat. In their expert opinion, which of the available treatments could be considered clinical successes with a meaningful impact on patient outcomes?

Dr Weber:

You can divide immunotherapies into 4 or 5 categories: these include chemicals like cytokines; antibodies…cells, which are not really well developed; vaccines, which is always the Holy Grail to try to vaccinate someone against his or her own cancer. You’ve got 1 approved vaccine. One of the antibodies, which are the most exciting and promising, is approved. That’s ipilimumab, the anti-CTLA4 antibody. In terms of the cytokines, in 1996 and 1998 IL-2, interleukin-2, was approved for kidney cancer and for melanoma. The cell therapy is immature, and you will hear a lot more about the antibodies coming up in the next couple of years.

Dr George:

I know we’re all very excited about the newest approvals and directions of immunotherapy, but just to take a look back, we’ve made tremendous progress with immunotherapy over the last 30 years. Bladder cancer is the tumor we use immunotherapy in the most on a regular basis, with bacillus Calmette-Guerin (BCG) in instillations for superficial bladder cancer, which has changed the natural history of superficial bladder cancer. How does IL-2, which has been around a long time, recognize that this is a mechanism that, although rare, does result in complete responses? These are durable complete responses in some tumors, some advanced metastatic solid tumors, and in renal cell and melanoma, in particular?

With some of the newer approaches, however, we’re seeing even a broader range of tumors that are susceptible to these strategies and we’ll talk about some of those examples as we get into the drugs. But to me, this is one of the most exciting areas right now and the validation is that we’re seeing this not in the niche of one tumor or another but beginning to branch out into a whole host of different tumors in stages.

Dr Weber:

Immunotherapy never got respect because it was always that drug which worked in 1 or 2 cancers like melanoma or kidney cancer, which were the immunotherapeutically sensitive histologies. But now, PD-1 has definite activity against non-small cell lung cancer. So, now, for the first time, the common epithelial malignancies will have immunotherapeutic options and that’s great.

To follow up, Dr Salgo asked Dr Kolodziej and Dr George to comment on the restrictions if any that are placed on reimbursement for these agents.

Dr Kolodziej:

I think from a payer perspective, the science aside, there’s not a great distinction around mechanism of action or promising early results. It’s all about results. And I think managed care has a historical way of dealing with new therapies that are expensive, and the most typical is prior authorization or precertification. If you look at the new drugs, and you mentioned it in your prologue, they’re all very expensive. And then we have a lot of discussion about how we should add expensive drug A to expensive drug B. You don’t see a new drug that didn’t come out at $10,000 a month, but I don’t really know how that number is arrived at.

However, there is an established way of dealing with the process, and that continues to be the way of dealing with it, and that is prior authorization or precertification. And I will say that the prior authorization and precertification clearly reflects the FDA label. If you’re going to get Provenge, you have to be minimally symptomatic. And, if you call us to get it approved, we will ask you that question.

Dr George:

I think this is a good point on the FDA labels. This will gain increasing importance; you are seeing real trends for our immunotherapies now that are expensive, and people really are following these labels. These really do matter. In years past, they were just sort of an entree into the field and then people did a lot of off-label use of treatment. We see much, much less of that because of the expense, which in some ways is appropriate; we should be a data-driven field.

Dr Weber:

Although, to tell you the truth, the data that we have access to are not always what is reflected in the package insert or the label. An example would be, reinduction therapy was part of the original trial that led to the registration of ipilimumab. Admittedly, a modest number of patients on those registration trials were reinduced. Over time, the reinduction rate, if you get ipilimumab, if you’re stable and respond over 24 weeks, maintain it for some modest period of time, and then relapse later, which is most patients, that you can be reinduced and have about a 40% response rate, which is very respectable by anybody’s standards. That’s not in the label, those of us who know would want to reinduce, but that doesn’t mean we’ll always get to be able to do it. I mean, I can argue my way pretty well with most insurers to get it done, but most community doctors won’t.

Dr Salgo steered the conversation to talk about the guidelines published by the NCCN and CMS. Dr Salgo sought the panelists views on the increased paperwork and requirements, whether they thought it a good thing or simply bureaucratic obstructions.

Dr Kolodziej:

I think you will find fairly consistently that most payers, national payers, largely respect what the NCCN has to say almost completely. Most payers realize they do not have the expertise in-house to try to adjudicate the quality of the evidence, and they look to a panel of experts to help them negotiate those waters, which is fair. The radiation therapists are not all happy with NCCN. They think that protons guidelines are not upto- date. Maybe the immunotherapists aren’t happy with the immunotherapy, although they do say you can give ipilimumab a second time in the NCCN guideline.

Dr Salgo:

What I’m really trying to get at here is, guidelines are fine. And what I hear you saying is guidelines are guidelines and they do make sense, and experts have approved them and signed off on them. But on top of these guidelines, there’s more paperwork, and more sign-offs, and more gatekeepers. Is this rational or is it simply a way for payers not to pay?

Dr Kolodziej:

I personally believe the answer is we’re going to get to a point in healthcare reform, this is not Aetna’s view, this is my view, where we go from a point where the payers are the gatekeepers to where providers become gatekeepers. And so I think that the burden of adjudication of appropriateness of evidence is going to shift. That locus of control is going to shift to providers. Now, providers may or may not like that. help, which is why pathways and other ways of treating patients are going to become paramount for oncologists, which means it will take away our autonomy.

Dr Salgo specifically wanted to know whether the increased bureaucracy and paperwork, over and above the scientific, CMS, and NCCN guidelines, would force the providers into giving up.

Dr Kolodziej:

No, I don’t think so. When I started (at Aetna), I reviewed every single prior authorization policy we had at Aetna. And if you can’t finish that form in 1 minute, you’ve got a problem. I get administrative burden. I was in practice for a long time, and I worked for US Oncology so I know a lot about administrative burden, and the burden is small. The truth of the matter is: give me a solution. Tell me what else we ought to do, and the answer is, we trust the providers. The idea that they’re motivated by profit, I don’t buy into that.

Dr George:

And I would agree with Dr Kolodziej on this one. I don’t see this as a burden. Filling out the form is not the problem, but when we get the largely inappropriate peer-to-peer, that’s an annoying burden that we sometimes have to carry. ... If a request for coverage gets denied, then we have to request a peerto- peer, doctor-to-doctor, or healthcareprofessional- to-healthcare-professional review of the case. We take time to set that up and then review the case. It’s frequently because some of the records were either not available or there was a misinterpretation of the case. It’s usually clarified, but it just takes time. This makes us stop and think whether this really is appropriate use of therapy, and very expensive therapy at that. Going forward, we may need to pause and think about cost as well.

Dr Salgo:

From a payer perspective then, which has more value? You can define value any way you like. Is it immunotherapy or genomic precision therapy?

Dr Kolodziej:

I’ve actually been thinking about it a long time. And I don’t mean to trivialize this, but there are different ways to get at the problem. They’re both intellectually satisfying. I’m not sure there’s a huge cost differential between them. We will find out. The data will tell us what the right approach is.

Dr George:

Are they mutually exclusive?

Dr Kolodziej:

I think not.

Dr Salgo:

However, they had the cost additive?

Dr Kolodziej:

Maybe yes and maybe no. So I think it’s a mistake, and I felt this way for a very long time, to focus solely on what the cost of the infusion is. I think we need to think about other things when we think about the cost of care of a cancer patient. If you look at the cost of an episode of care for a cancer patient, about 25% is the chemotherapy, but another 20% is imaging, another 30% is hospitalization. All I’m saying to you is this, if the Institute of Medicine is right, 30% of healthcare is wasteful.

As we get into a world of precision therapy, the opportunities for improving care and controlling cost is not keeping the right drug from the right patient, keeping the patient out of the hospital, keeping them out of the ED, dealing with their symptoms at home, knowing when to say when. And I can’t stress that last point enough. This is again my opinion, not Aetna’s, but the greatest return of investment (ROI), and this is from work we did with US Oncology, is really on end-of-life care and doing the right things at end of life.

Dr Salgo brought up the encapsualization of care. The cost of immunotherapy is known up front, because it keeps working with a single administration. Whereas, with traditional chemotherapy, you’re going to be paying out of pocket.

Dr Kolodziej:

No one is saying this is curative therapy yet. Let’s just recognize that there’s an episode of immunotherapy treatment and we don’t know how long that episode is going to (require coverage).

Dr Weber:

But let’s hold that thought for a second because as data develop with the use of ipilimumab, at least in melanoma, there has been or there is a plateau of survival in patients who are out 3, 4, or 5 years. So, if 18% of your patients are alive at year 3, 18 or 19 at 4 and 5, some of those patients are probably cured. And the best data from the longest follow-up at 7 and 8 years suggested if you have a complete response (CR) or a near complete response, made CR by surgery with ipilimumab in melanoma, you’re going to be alive continuously in remission at least 90% of the time, out at 7 or 8 years. So maybe those patients are cured.

Dr Salgo:

I want to put this on the table without comment. One of the very few times I’ve heard the word “cure” in this context, whether or not we can use it reliably, the fact that we’re even discussing it is remarkable.

Dr Weber:

The fact that in current targeted trials, for example, with BRAF, BRAF/MEK drugs in melanoma, we’re seeing patients on protocol and they come in and you look at the chart. It’s week 140, week 170, week 180, which is phenomenal.

The ultimate outcome is survival. If I were a cancer patient and I had treatments pitched to me by my oncologist, my first question would be, ‘How long am I going to live compared with not having treatment or compared with the control treatment and how am I going to feel?’ So it would essentially be the quality adjusted years of life prolonged, which is not a trivial calculation. The problem is in the medical oncology business, at least until recently, we haven’t been able to quantitatively assess what that benefit would be. Now we have more data, and I would agree with what Dr Kolodziej said, about 30% of everything we do is wasted. I’ve been saying that since I became an oncologist 25 years ago, and I was absolutely convinced that at least a third of what I did was a complete waste of time. That’s got to change.

Dr George:

I think the new healthcare reforms should give us more opportunity to have a say in that. I think the challenge is that now we’re going to own that more and that’s going to come back to us in terms of a reimbursement model. And that’s something we are inexperienced in.

Dr Kolodziej:

I think the interesting thing is that we have been stuck for a very long time in a paradigm of designing clinical trials with a view toward what registration for that drug should look like. That is going to change because now there’s going to be a burden on the innovators to look at meaningful outcomes that will allow them to position their product, immunotherapy product, or targeted agent, to position it in a global treatment for that patient. So it shifts the burden of identifying value, and as a healthcare consumer I’m all for that.

Dr Salgo then asked Dr George to comment on the newly approved mover-and-shaker drugs in literature.

Dr George:

I’ll simply walk through the clinical data and the mechanism of action of these drugs. Provenge is an autologous cellular immunotherapy from the patient’s own cells. It’s really the ultimate in personalized therapy. The drug is made from the person’s own cells through a process called leukapheresis; the cells are then shipped to a centralized laboratory and activated ex vivo against antigens that are relevant to prostate cancer, in this case, a fusion protein, a prostatic acid phosphatase in GMCSF (granulocyte macrophage colony-stimulating factor), an immunostimulant. That creates, within that peripheral blood mononuclear cell compartment, some activated cells against those proteins, which are then reinfused back in 3 days later, almost like a blood transfusion for the patient, an autologous blood transfusion. It’s repeated every 2 weeks for 3 doses. So it’s a 0-, 2-, and 4-week regimen.

Of 2 independent clinical trials, a relatively small randomized study demonstrated an overall survival advantage of about 4 months and a second pivotal trial, 512 patients randomized, demonstrated about a 4.1 month improvement in overall median survival with a hazard ratio of about 0.77. And interestingly, as alluded to by Dr Weber, the patients that live longer derive a greater benefit. So a landmark analysis at 1 year demonstrates about a 12% improvement in survival, about a 24% improvement in overall survival by 2 years, while patients that are out to 3 years, there’s a 32% improvement in overall survival for that population, showing an absolute benefit that’s much greater. Bottom line, identifying the patients who are destined to live 3 years is ideal to treating with Provenge.

Dr Salgo:

And, again, with just 3 doses, you know up front what it’s going to cost.

Dr George:

But the benefit is extended over the lifetime of that patient. It’s not $100,000 for 1 month. It’s an investment in a patient that we believe is going to live 3 years or more. If you annualize that out, it’s $30,000 a year.

I don’t want to make it sound like it’s a black and white thing. This is against 1 antigen that may or may not be relevant, and some or many of these patients may not necessarily fully respond to that. I view this more like a platform. Because it has very low toxicity, there really isn’t a longterm residual toxicity from this treatment, in addition to the opportunity to building on this with subsequent therapies, whether targeted, immunologic, or otherwise. We’d now like to build and improve on this therapy.

Dr Salgo:

Where does ipilimumab fit in this whole group of pharmaceuticals?

Dr Weber:

Well, ipilimumab is a very different drug. Provenge is a vaccine, again, the first cancer vaccine ever approved by the FDA. But ipilimumab is a checkpoint protein inhibitor. The immune cell has multiple brakes and accelerators. If you had a drug that bound the accelerators, you would push the immune system. It turns out that in the cancer bearing state in chronic infection, the immune system is suppressed and you have high levels of substances that are essentially the brakes like CTLA4, PD-1, TIMP-3, LAG-3. CTLA-4 plays a predominant role in the cancer bearing state; you have lots of CTLA4 on your immune cells, which means they don’t work very well. What ipilimumab does is that it blocks the braking mechanism. About 15% of the patients will have traditional anti-tumor responses and there will be a clear increment in survival over time. But the survival benefit plateaus out, meaning you have the same proportion of patients alive at 3, 4, 5, 6 years. So some of those patients may well be cured, which is unique.

Dr Salgo then asked the panelists to compare the safety profiles of Provenge and ipilimumab relative to traditional chemotherapies.

Dr George:

With Provenge, because we’re activating ex vivo, an infusion reaction occurs following reinfusion, likely due to the induction of cytokines within that cellular mix. It results in a very acute, short-term, generally mild inflammatory profile: fever, chills, and back pain. Less than 3% incidence of grade 3, or what we consider serious adverse events, for any one of these toxicities is observed, which is short-lived, and completely resolves within 24 to 48 hours in the vast majority of cases. So cumulative toxicity, residual toxicity, or end organ damage that are typical of chemotherapy or targeted therapy, in some circumstances, are not observed.

Dr Weber:

The beauty of a vaccine against cancer is it will not be toxic. Ipilimumab and PD-1 antibodies are a different scenario because here you’re breaking tolerance. If you break the self tolerance of the immune system, it indirectly increases the ability to recognize the cancer, but there will be some collateral damage. About 10% or less of the patients who get ipilimumab will have grade 3 and 4 clinically meaningful serious adverse events that we call IRAEs, or immune-related adverse events, including colitis, inflammation of the pituitary or hypophycitis, low thyroid, rashes, rarely pancreatitis, or hepatitis, all manageable. And I probably spent 8 or 9 years figuring out how to manage these things, and I’ve written on it extensively. But there will be a cost in side effects.

Dr Salgo then asked the panelists to discuss the associated costs. How can such expensive treatments, sometimes in the range of $90,000 to $100,000, be remunerated?

Dr Weber:

Overall survival is the goal. That’s what we’re judging these drugs by. So, the cost estimate should not be in terms of the cost for that month, but rather in terms of the course of that life.

Dr Kolodziej:

However, an unspoken fact is that it doesn’t work in everybody. I don’t know why it doesn’t work in everybody. But as an interested party and not as a payer, I’d love to know who it works in and why.

Dr Weber:

Well, the FDA would agree because, as you’re probably well aware, biomarker development for patient selection is a huge priority at the FDA. It certainly is a huge priority in our field. In fact, my laboratory works on identifying predictive biomarkers for ipilimumab and PD-1 antibodies. With a predictive biomarker, by selecting out patients that won’t benefit, the treatment is significantly more effective.

Dr Kolodziej:

Patients who do not respond bear that expense, and then the expense of the next therapy down the line, and perhaps have a different clinical course that uses all kinds of other resources. So the real question is who does it work in and why? With precision medicine, you chart patients down a certain course, although those aren’t curative therapies.

Dr Weber:

But that’s why Aetna should be supporting the research into the biomarkers.

Dr Kolodziej:

I’ve been told many times that we’re not a research institute, and so I’ve stopped trying to fight that battle.

Dr Weber:

It’s not just research. It’s a way to make things have a greater value and, essentially, over time, save money.

Dr Salgo then referred back to the question of guidelines. Could the treatment guidelines be changed to incorporate the immunotherapies, and how would it differ from what payers reimburse for and have been reimbursing for?

Dr Weber:

The NCCN guidelines now incorporate ipilimumab or a clinical trial for melanoma as your front-line choice or a targeted therapy if BRAF is mutated. So we have a predictive marker now for our BRAF drugs. A genetic change in the tumor is a predictive biomarker, and in its absence the drug is not going to work and might hurt you. So we think the NCCN guidelines, which most of the payers are following, are fair and reasonable. The unspoken issue with immunotherapies is most of them are investigational, and some payers will cover research-related costs and some will not.

Dr Kolodziej:

So let’s be very clear. It’s not Aetna’s money that Aetna is spending. Aetna is the administrator for employers who have self-insured plans. They’re the payers, while Aetna administers the plan. That’s two-thirds of Aetna’s business. The other third is people who pay premiums out of their pocket. So you are paying for ineffective therapy today and the responsibility of that is to try to decide whether evidence supports all of us bearing that cost burden or supports the self-insured plans bearing that cost burden. And so we have a fiduciary responsibility to you, if we’re your insurer, or it’s the responsibility of the self-insured plan. The insurance industry isn’t a methodology to answer a research question, but most payers and most national payers agree to pay for research that meets certain criteria.

Dr Salgo:

Despite some clinical guidelines which are really very clear, how do you account for some payers that are not paying and are forcing providers not to offer guideline-related therapies?

Dr Kolodziej:

I am occasionally asked to review the evidence base for our coverage policy regarding therapies. Aetna has an evidence shop that does just that, and if it’s a cancer-specific issue, the person there will come to me for content and I think he tries to be fair.

Dr Weber:

But the NCCN guidelines for melanoma say first choice front-line, a clinical trial would be up there with immunotherapy or a targeted therapy for BRAF mutated. Yet, as Dr Kolodziej himself pointed out, the coverage of decisions for going on a phase II or phase III clinical trial can be very inconsistent.

Dr Kolodziej:

People who pay the bills can make the decision on what they’re going to pay for. So CMS has decided that they’ll pay for usual and customary in research and it was a big deal when that finally got approved. All I’m saying is you have that discussion with every single plan....

As a follow-up, Dr Salgo asked the panelists’ opinion on the requirement for additional paperwork and hoops to jump through to keep the system functional.

Dr Kolodziej:

I personally think it is, yes.

Dr George:

Ideally we wouldn’t need that but we’re recognizing that we’re in a dynamic state right now. And what Dr Kolodziej points out is that it’s a very heterogeneous state, and I don’t think there’s going to be a simple solution to get away from paperwork. We’re inundated with paperwork in every aspect of our lives, including our professional lives, and payers are just one other aspect of it. But there are ways to streamline it. There are policies, but these are such individual cases. When it comes down to an individual patient in a clinical trial, their eligibility, the appropriateness, the alternative options, etc, there’s no way to really have a set policy without being able to have sort of individual review of those cases.

On future directions in cancer immunotherapy:

Dr George:

EBO

I think this is the most exciting area in cancer research right now. As Dr Weber alluded to, there’s a lot of targets we haven’t hit yet. We’ve just started hitting some of these checkpoint inhibitors.…Although only in the early years of immunotherapy, what’s critical is the credibility that has been established by these therapies in terms of overall survival benefits and long-term disease-free survival benefits with the checkpoint inhibitors. Precision, recognizing for individual patients what those checkpoints might be or what those antigens might be, recognizing newer clinical settings, and how we build on all these findings, is going to be critical. Currently, we’re developing these drugs in the most metastatic refractory settings, but where we envision immunotherapy working best is probably in the more curative settings of adjuvant settings or minimal disease state settings. I hope there’s a change in the population of patients we can treat as well as the armamentarium we have to treat them with in a precise and directed way that will make it rational, effective, and hopefully real value.