Gary Lyman, MD, Fred Hutchinson Cancer Research Center, Seattle, Washington, discusses a project exploring the cost of tyrosine kinase inhibitors, particularly imatinib and generic imatinib, for the treatment of patients with chronic myeloid leukemia (CML). This podcast focuses on a paper recently published in the Journal of Clinical Pathways.
Transcript
This whole area of study that we undertook 2 years ago, jointly with some colleagues at the Fred Hutch with OptumLabs, that provided the data, funding from Stand Up To Cancer Dream Teams that's managed by the American Association of Cancer Research (AACR), so a lot of players involved. It was a big project.
I did a major presentation at ASH in December and these papers are spinoffs of that. The first one is the article we'll talk about today in the Journal of Clinical Pathways. There was another publication just recently in JCO Oncology Practice. These covered different aspects of this larger project that we're doing.
Then we have another one coming out in the next few weeks in JAMA Oncology, focusing on what's happened since we did the initial analysis and what's happened in terms of pricing on tyrosine kinase inhibitors for CML with the very most recent data. And then there’s one other paper in Leukemia & Lymphoma, which is just being revised now and it focuses more on comparing the costs across disease categories.
Again, the background for all of this has to do with the cost of healthcare. When I presented the data at the American Society of Hematology, it was basically the question, “have cost predictions for the use of imatinib—particularly, generic imatinib for the original Gleevec—have they met expectations?”
All this driven by the fact that healthcare costs, and particularly drug costs for cancer, have increased dramatically over the past few decades. Some would argue unsustainably. More and more, of course, of this cost is being passed onto patients.
In fact, for the last half a decade, the median cost of new cancer drugs in the US has exceeded the median monthly household income in the US. Now, it's 2-3 times higher than the median monthly household income. That's a huge burden on families, as well as society in general.
Why this is the case and why drug prices are much higher in the US has been a topic that we've addressed, many have addressed. Fundamentally, it comes down to the fact that Medicare is not allowed, by statute from Congress, from negotiating drug prices with industry.
The price of the drug at the time of approval is much higher in the US than it is in other countries, and that's just the starting point. Our experience is that those high launch prices of these drugs begin to rise, continue to rise after approval.
The idea of bringing competition to the marketplace, either with generics, as in this case, or with the more complex biologic agents, monoclonal antibodies, and so forth, with what we call biosimilars, these are all to bring competition and choices to clinical practice, with the hope of that will rein in, or at least level off, this rise in drug prices.
CML is kind of the poster child for looking at all this, because it is a clonal disorder arising from a mutation in the hematopoietic stem cell that's driven by a fusion protein, BCR-ABL, and that can be targeted, and has been targeted, with dramatic improvement in outcomes of patients with CML which used to be a death sentence, because patients would uniformly develop acute leukemia and go on to die of their disease.
While it's not the common cancer—there's a little under 10,000 cases of CML diagnosed each year—it historically was, again, likely to result in poor outcomes and death.
It is most commonly diagnosed with increasing age, so in patients particularly over 65 or in their 70s. As I mentioned, the introduction of tyrosine kinase inhibitors, imatinib, revolutionized the care of these patients.
In fact, recent data would suggest that the outcomes of these patients, in terms of their prognosis, their risk of transformation into acute leukemia, or death, is now very close to that of the non-diseased general population in the US.
To achieve that, though, patients need to continue on these drugs, at least for now, for the rest of their life. While there's studies being done to see if we can shorten that period or give patients a break, most patients remain on these drugs indefinitely in order to keep the disease from transforming into acute leukemia.
So, what used to be a very uncommon disease, with just, again, 8,000 to 10,000 new cases a year, because patients are living longer, the cumulative number of patients with CML who are on treatment now is in the range of 200,000 in the US.
What used to be an uncommon disease that had a short natural history of 2-3 years is now a very common, or much more common, disease requiring ongoing, continuing treatment.
The launch of Gleevec, the original imatinib, back in the early 2000s resulted in a dramatic reduction in mortality, which has been maintained. As I said, patients now likely to experience close to a normal life expectancy, despite the disease, if they remain on drugs, the tyrosine kinase inhibitors.
The challenge, of course, as I alluded to is that the imatinib, Gleevec, is a very expensive drug and if it's a lifetime of treatment with this drug, the cumulative cost is an enormous burden on society, on insurance, and for many patients, increasingly a burden on the family, bearing much more of the costs.
We've all been waiting for these generic versions to come along, which was approved in 2016. However, before that happened, in the decade before generic imatinib was available, new generations of tyrosine kinase inhibitors—dasatinib, nilotinib, bosutinib, more recently, ponatinib—these are all tyrosine kinase inhibitors with a somewhat different structures, different mechanism, to some extent, although all these target this BCR-ABL mutation.
The results are that many patients, and many clinicians have put their patients, on these, what I call, next-generation tyrosine kinase inhibitors.
That's a result of a number of factors. Of course, intense marketing by the new drug companies. There’s some evidence that maybe the duration of remission or the duration of molecular response is longer with the new agents than with the originator. In the end, no study has yet shown a survival advantage of the new drugs to the originator.
Nonetheless, these drugs, again, launched with very high prices. While we thought they might provide some competition, the price of the originator as well as the new drugs has continued to go up.
Then come, in 2016, the new generic version of imatinib. Generic meaning it's the same molecule structurally, because it can be replicated once the patent expired, and made available with the idea of bringing competition and hopefully improving access to patients who have difficulty or cannot afford these expensive drugs.
What happened then? Again, the generic was compared to these new generation, next-generation. Again, no difference in mortality. The generic, when it was launched in 2016, was priced almost as high as the originator, around $140,000 for a year of therapy.
The other drugs, even more so, in some cases. Very different than the experience in Canada and the rest of the world. In India, this drug costs about $400 a year, not $146,000. In Canada, it's more, but it's less than $10,000 for a year of therapy with generic imatinib.
Where in the US, until recently, well over $100,000 for a year course of therapy. Enormous hardship, and again, the challenge has been that the US does not negotiate drug prices and clinicians are often driven to use the latest therapies, which, again, come with a high price tag.
More and more, the copay, or the caps on insurability, so what's covered by a patient's coverage, has been borne by the patient themselves. This had led to challenges that we and others have identified in terms of early discontinuation of these drugs, non-adherence to the therapy.
In fact, non-adherence to imatinib or to the tyrosine kinase inhibitors is the strongest predictor of relapse for CML patients prone to develop acute leukemia.
All this led to this big project, again, with Stand Up To Cancer Dream Teams and administered by the American Association of Cancer Research. A great collaboration with OptumLabs and Joe Henk, who's their Chief Scientific Officer, to get us data so we could actually look at what is happening and the changes in the use of these agents, and costs over the last couple of decades, right up to almost the present time.
In the paper recently published in the Journal of Clinical Pathways, we look at the early results coming out of this. Lo and behold, not a big surprise, the second and third-generation tyrosine kinase inhibitors are now the most commonly used agents for the treatment of CML.
It's no longer the original Gleevec, or even though they're available, generic imatinib. The use of the originator has almost disappeared. The generic has gained some foothold, but these next-generation TKIs, which are very expensive, have captured much of the market.
As a result, up until now, there has not been much of a dent in the price or the cost of treating patients with CML with these agents. Even those that are started on the generic, as some are —sometimes, insurance companies insist on that—20-30% of patients eventually switch, even in the first year of therapy to one of the second or third-generation agents.
Not because the imatinib wasn't working, but because someone has become convinced that these second and third-generation agents are better, when, in fact, the data would suggest these newer generation agents, while they're probably as effective at controlling the CML, they come with greater toxicity.
They have side effects that the original imatinib did not have, but the lure of trying the latest and greatest new therapy has led to that.
The paper goes into all of these issues and what some of the drivers are of the use of the generic imatinib or the next-generation tyrosine kinase inhibitors and how that has changed over time.
The fact that total costs for care of these patients has continued to climb, right up through 2019, and I'm sure into 2020, and the out-of-pocket costs have continued to increase dramatically, because the total costs have increased and the share of that that's being borne by patients has continued to increase.
The bottom line for us, looking at this data, and, again, more of it will yet be published, is that generic imatinib price competition has not had an immediate effect. We do have an early indication it may now be coming down.
For the first 3, 4 years of available generic imatinib, there was essentially no change in the high exorbitant price for imatinib, either the originator or the generic, for the care of CML. While that may change, much of the use of TKIs essentially remains these next-generation agents, which are still on patent. There's no competition. No generic version of these newer agents, and there won't be yet for several years.
The result is that, as I said, we're finding more and more evidence that patients are non-compliant because of cost. They're stopping a treatment, stopping their prescriptions early, because they can't afford them, or they don't want to leave their family in dire financial straits.
As a result, their non-compliance or early discontinuation of the drugs is leading to a higher rate of recurrent CML and eventual mortality than we would like to see and hope to see as these prices eventually do come down and access to these agents increase.
We now have 11 generic imatinibs approved by FDA in the US. One would only hope that, with that level of competition in the marketplace, the price of all these agents would begin to come down. As I said, we do have some early indication that that's happening.
It's been very slow, very delayed here in the US. Whereas in the rest of the world, the price of treating and controlling CML is a fraction of what it here is in the US.
The problem here is a structural one of our healthcare delivery system in the financing of cancer care and other chronic illnesses.
Until we solve that problem, we're going to continue to see these examples of extraordinarily high costs of care having a direct impact on patients and their survival and financial well-being.
