Cost Problem Only Getting Worse With IO Combos, Adjuvant Use

Jeffrey S. Weber, MD, PhD: Hello. I'm Dr Jeffrey Weber, deputy director of the Perlmutter Cancer Center at New York University Langone Health and co-director of its melanoma research program. Welcome to Medscape Oncology Insights. Joining me today is Dr Omid Hamid, chief of translational research and immunotherapy, and director of the Melanoma Center at the Angeles Clinic and Research Institute in Los Angeles. Welcome, Omid.

Omid Hamid, MD: Hey, Jeff.

Pharmacoeconomics of Cancer Drugs

Weber: We are going to talk about the cost of oncology drug development and some pharmacoeconomic issues. What do you think are the key pharmacoeconomic issues surrounding cancer drug development today?

Hamid: I think it's the oncoming train of costs. As [cancer drugs have become] more successful for patients, we have increased the number of patients who are benefiting and the indications of these drugs. These drugs are not inexpensive. When we increase exponentially the number of patients we are giving these drugs to, we will be faced with a problem.

Weber: One thing that I don't understand is that we had sort of an arithmetic increase in benefit from the drugs. There is no question that patients are doing better; that is certainly the case in my business of melanoma. It maybe is not quite as clear, but it's still present in other cancers with the new immunotherapy drugs. But there seems to be a geometric increase in the costs. I guess I'm not quite understanding how this works. It does raise some concerns because we had single agents and now we have double agents. As I remember, don't you have triple combination trials?

Hamid: We have triplets. There are going to be trials that begin with two drugs and move on to three drugs. I can even see a time where we add more. Again, these single agents and combinations are being approved more frequently. And the paradigm in oncology is, when you show survival benefit, as we are showing in the metastatic setting, then you look at the adjuvant setting. The number of patients [in the adjuvant setting] is exponentially greater. The amount of dose that you would give to these patients who will have longer survivals is going to be greater. You may say that it's 1 year of therapy. But in our metastatic setting, few patients get to the end of 1 year of therapy.

Weber: It's an interesting paradox. Now that we are developing adjuvant therapies with immunotherapies, which are approved as several melanoma adjuvant therapies and benefit patients in terms of recurrence-free survival, you had better bet that it's going to happen in other cancers. It's going to happen in lung, renal cell, head and neck, and maybe other cancers. More patients have resected disease than metastatic disease in most cancers. They stay on [therapy] for longer, so the costs will go higher and higher.

Hamid: And the adjuvant benefit will push us to look solely at combinations in the metastatic setting. When you have a patient who has seen single-agent programmed cell death–1 therapies and then has a recurrence, there is an indication that you may need to do more than just restart them on that single-agent therapy.

Paradox in the Adjuvant Setting

Weber: I see this as the biggest problem. In the adjuvant mode, let's say you have a great hazard ratio (HR) of 0.5. I was educated that an HR of 0.5, which is a 50% decrease in the risk for the event (ie, relapse/recurrence), is great. The problem is, some patients are going to be cured anyway, unless you choose the worst-acting patients. So let's say that half the patients are cured and your HR for relapse, or even survival, is 0.5. That means you have treated four patients to benefit one. You are treating a huge number of patients to benefit a small number. Is there any other benefit on the backend?

Hamid: Right. It's very easy to say that you are going to exponentially increase costs. But it's a shortsighted view because these patients who we cure are going to have extended lives. They are going to go back to the workforce and give back to the community in ways that are financial. For relapse, there are the costs of diagnosis and surgical resection. There is the possibility of metastatic recurrence and morbidity that comes with hospitalizations. There are the costs of second- and third-line therapies. All of these factors need to be taken into consideration. And when this happens, it's exponentially greater than if you are curing one person.

Weber: That's true. Say you have a patient who has metastatic disease who is really debilitated and in bad shape. You treat them—say, for the sake of argument—with dabrafenib/trametinib or ipilimumab/nivolumab or whatever. They go into remission. They go back to work and pay taxes. They are having a good life with good quality of life. I get a lot of pleasure from this. While you can argue that you are treating four patients to benefit one, having that one back in the workforce may overcome the increased cost of treating those four. You need to think about both pros and cons of these drugs.

Hamid: These long-term financial issues are very important. In melanoma trials, we have gone from single agents to combinations. In the near future, we may have combinatorial immunotherapeutics in the adjuvant setting. Those have shown higher response rates. In the metastatic setting, you may argue that that high response rate may not translate into survival, but in the adjuvant setting, there may be a greater ability for it to affect long-term survival.

There is clearly now a dichotomy of helping our patients in the short term, which may hurt our patients in the long term.

Weber: The increasing cost of drugs, interestingly, is going to raise the bar for whether docs are willing to utilize drugs, government authorities are willing to pay for them, and insurers are willing to pay for them. In the United States, we are very lucky in that we can do a lot of off-label use of drugs. I'm hard-pressed to think that, in 10 years, I'll be able to use multiple relatively expensive drugs off-label the way we do today.

Hamid: I agree with you, and this is a great time to say that those patients need to go into clinical trials. We need to do a better job of understanding who those patients are and how they benefit. But now, even in the adjuvant setting, there is no pushback. I foresee there being greater pushback and ultimately [to the point where it] affects our ability to help our patients.

'The Problem Is Only Going to Get Worse'

Weber: What if you have a quadruple drug regimen? In lymphoma, for example, they are using the five-drug regimen R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone). Many of those chemotherapeutic drugs are way off patent. They are extremely cheap and not expensive to give, although rituximab is a relatively recent drug. But all of these new drugs in the immuno-oncology world are going to be on patent. They are all very expensive. I think the problem is only going to get worse. The logical thing is to give multiple drugs to try to boost the effect of existing drugs. There is only so much money in the world. I don't see how we can keep going with an exponential increase in cost for drugs without an impasse being reached. You mentioned a train. The train is going to crash unless we do something about it. I'm concerned.

Hamid: Me too, and it's just the beginning. In meetings, we are seeing more regimens giving greater benefit. Those will all come to the adjuvant setting and they will hit a greater group of metastatic patients. The cost train is coming. We need to begin the dialogue that will help us come to a solution. For me, the primary objective is to help our patients. There is clearly now a dichotomy of helping our patients in the short term, which may hurt our patients in the long term.

Weber: Cost has risen to the attention of governmental agencies in this country—and certainly in Europe, Canada, Japan, and other countries—insurance companies, physician organizations, and physicians as individuals. All of a sudden, cost is on the radar, which is why we are having this discussion. This is a big deal. Like I said, there is only so much money in the world. We need to do a better job of deciding how to spend it rather than the profligate way we have expended money in the past on trials (where the chance of a phase 3 trial working was less than 50%) and drugs (where sometimes the benefit is marginal and sometimes it is considerable). There are just more patients in the adjuvant mode. What are we going to do? We need some solutions, and we will talk about that in a later discussion.

Omid, thank you for joining me.

Hamid: Thank you.

Weber: This has been a fantastic discussion. And thank you, the audience, for joining us. This is Dr Jeffrey Weber for Medscape.

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