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Evidence-Based Oncology February 2014

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.

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, 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.

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