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Evidence-Based Oncology March 2014

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

Part Two
The previous issue of Evidence-Based Oncology (EBO) featured the first part of a condensed edition of a peer exchange on the future of immunotherapy in cancer care, which was convened by The American Journal of Managed Care. This edition of EBO features the rest of that exchange.
The previous issue of Evidence-Based Oncology (EBO) featured the first part of a condensed edition of a peer exchange on the future of immunotherapy in cancer care, which was convened by The American Journal of Managed Care. This edition of EBO features the rest of that exchange. Immunotherapy, according to the American Cancer Society, is treatment that uses the immune system to ward-off diseases such as cancer by either boosting the body’s immune system in general or by training the immune system to attack some specific cancer cells, and may be used alone or in combination with other 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.

The discussion was moderated by Peter Salgo, MD, 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

• Daniel J. George, MD, Duke Cancer Institute.

Peter Salgo, MD, continued the discussion by asking the panelists to comment on the excitement surrounding the use of novel cancer therapies such as immunotherapy. Dr Salgo asked whether the thought process for funding the associated costs of the new treatments would be similar to traditional treatments.

Michael A. Kolodziej, MD, warned that excitement is tempered by a need to wait for evidence. Immunotherapy, he said, is not treated differently from other therapies from an insurance standpoint.

Michael A. Kolodziej, MD: I’m not an immunotherapist, so I’m waiting to see the results. I mean, I still remember when the IL-2 paper was published and we were going to cure renal cell cancer with IL-2. So I’m waiting to see what the results are. Do we distinguish? No, I don’t think so… We’re interested in what it’s going to mean to our members. Are our members going to get better?

Daniel George, MD: I think skepticism is healthy. We still give IL-2 in limited circumstances, but we’re frustrated by the limitations of the therapy. What we’re excited about are the advances which seem to be moving us faster beyond those limitations….This is the opportunity to move those therapies that are doing some remarkable things, granted maybe not in everybody, but in a subset of patients with advanced metastatic disease, to earlier settings.

However, we have to meet a bar, and we have to pass the standards set by both skeptics and our regulatory agency. We owe that to all the future patients out there that those bars are met. However, what we are frustrated by is when we have met those bars and when people are still skeptical because this doesn’t fit the paradigm of traditional chemotherapy and shrink the cancer 20%, and therefore, I know it’s working in those circumstances.

Dr Salgo asked for comment about the fact that, compared to traditional chemotherapy, immunotherapy is subtle and quite well-tolerated.

Jeffrey Weber, MD, PhD: The effects depend on the situation. You might see tumor responses with PD-1 or PD-1 plus ipilimumab that are almost as impressive as you would see with  chemotherapy or targeted drugs. You can see responses that happen rapidly and steeply. So we’re in a different realm, and as we expand the repertoire of drugs available to us, you’re going to

find that we will be able to overcome the skepticism.

Dr Salgo nudged the panelists to discuss the safety profile of immunotherapies. Traditional chemotherapies shrink the tumor burden but are associated with a lot of side effects. On the other hand, immunotherapy has a good safety reputation.

Dr George: A cancer patient wants to live as long as possible, and he wants the quality of life, with not much concern for reduced tumor burden or slow progression. We have patients with a tumor burden that have a fantastic quality of life and they’re going along just fine. As long as that quality of life is going along and we’re not seeing any detriment in terms of either the disease progression or their cumulative toxicities, we’re achieving their goals.

So, to me, tumor regression is probably the least valuable of all the surrogates that we tend to use in our practice….

Dr Salgo continued the discussion by commenting that although it made sense that living with a tumor burden may not affect survival and wellbeing, he had never heard an oncologist endorse the concept.

Dr George: Well, let me qualify this that I’m a prostate cancer doctor. For the longest time, we’ve had bone scans that don’t meet RECIST (Response Evaluation Criteria in Solid Tumors) criteria.

They don’t even represent the cancer, they represent a reaction around the cancer, the calcium deposition around the cancer. And we’ve had (PSA) prostate specific antigen as a biomarker. We really haven’t had measures of tumor burden, and it’s actually been the biggest hindrance to drug development in prostate cancer over the last 30 years, and we’ve just finally gotten over that in the last 10 years. So, I’m probably a little bit of a different oncologist than maybe what you’ve heard before.

Dr Weber: Although, to be honest, reduction of tumor burden is usually not regarded as an end in and of itself; it is a surrogate or a substitute for the greater variable, which is obviously survival and progression-free survival. … On the other hand, there are plenty of patients who present a significant decrease in morbidity and improvement in their symptoms and increased quality of life when they get some tumor reduction. So it can be a desirable endpoint, and the FDA (US Food and Drug Administration) does recognize, in single arm studies, that tumor reduction is an acceptable end point. They much prefer the ultimate end point, as they’ll always tell you when you meet them, of survival in a well-controlled, well-conducted randomized trial. So I agree with

Dr George in principle; response is not the ultimate end point but it can be a useful end point.

Dr Salgo continued the discussion by asking how payments are made; questions such as is it a single payer, is there a committee that decides, is it practice-driven? He also asked the panelists to discuss the influence of the 12-month review by the Centers for Medicare & Medicaid Services (CMS) on Provenge and other immunotherapies on managed care.

Dr Kolodziej: The situation varies by payer. We have an evidence shop that adjudicates the evidence. We do pay attention to bodies like the NCCN (National Comprehensive Cancer Network) as we make our determination. It’s interesting because that particular committee is actually firewalled off from the coverage policy committee and the pay committee. So the evidence shop is all about evidence, but they do respect what other people say….As for the CMS review, I wasn’t at Aetna then, but I don’t think the review had much influence.

CMS had already decided they were going to pay for it, and then they opened the national coverage decisions. Additionally, the FDA had approved the drug and there was already a coverage policy in place. I don’t think that it didn’t make people feel that they got it right.

Dr Kolodziej pointed to the example of bevacizumab in breast cancer treatment. The FDA withdrew approval, but CMS still pays for it and NCCN still recommends it.

Dr Salgo continued the discussion on decisions made on the cost of treatment. One treatment may cost $100,000, while another may cost less initially but must be taken over several years, with possible hospital admissions and treatment for side effects....

He asked whether the actual cost of treatment had been estimated for Provenge, ipilimumab, tumor-infiltrating lymphocytes (TIL) for melanoma, transduced T-cell therapy, and other high-attention agents.

Dr Weber: Well, they’re going to be very different with TIL, which is essentially a 1-time treatment. The approved regimen for ipilimumab is 4 doses over 12 weeks. Maybe you’ll get reinduced somewhere in the future but usually not. Some targeted drugs are taken every day forever until you progress, and if the BRAF/MEK combination has a 2-year median survival, that means

half the patients will be on for a year or more. So that could get even more expensive because if it’s $100,000 a year and you’re on for 3 years, now it’s $300,000.

Dr Kolodziej: Leave cost out of this for a second, okay? How many drugs are available for renal cell cancer? Six?

Dr George: Seven.

Dr Kolodziej: Seven oral agents? I suspect, and I did a lot of genitourinary medicine when I was in practice, if you start with drug A and then give drug B, that may be different than starting with drug B and then giving drug A. However, if you talk to people who do renal cell, they will come to you and say, I intend to use every drug, every single one, as long as the patient can tolerate it….

Now, is that the right thing to do? I don’t know. In some cases it’s futile. But we actually don’t know the answer to that question.

Dr Weber: It’s a testable question. All the more reason why Aetna should be supporting that kind of research.

Dr Kolodzieij: It is a testable question. The data that are required to do that is, it may sound simple, but it’s not so simple. So this is the heart of comparative effectiveness. And we will come to a point where those questions are going to get answered.

Dr Kolodziej said comorbidities make such answers complex, and costs may be spread in many places. But he agreed with Dr George that the real questions are: how much does it cost to take care of a patient with cancer, and what is the timeline? Patients who respond live longer and live better. Dr George said these questions affect how patients are selected for clinical trials.

Dr Salgo then specifically asked Dr Weber to explain some of the factors that would determine a product’s cost versus benefit.

Dr Weber: Well, the cost is obviously set by the pharmaceutical company; as Dr Kolodziei said, the process is ambiguous. Although, my gut, by the way, is it’s whatever the market will bear, and we do live in a capitalist economy. The FDA explores this extensively because they’re always thinking risk-benefit. That’s the charge of the FDA and the Code of Federal Regulations.…However, we think about this as oncologists. Can I take an 85-year-old and give him ipilimumab if he’s got Crohn’s disease? Well, that’s probably not going to happen. So I have to always make the assessment, as all of us do as physicians, of will a patient be able to tolerate a drug, does the drug have more than marginal benefit, and what’s the likelihood it’s going to prolong survival with a decent quality of life?

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