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The cost of living: Financial constraints put benefits of revolutionary treatments at risk
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In early March, long-term follow up results of the IRIS trial appeared in The New England Journal of Medicine.
This study, opened in 2000, compared the use of first-line imatinib (Gleevec, Novartis) with interferon alfa and cytarabine for patients with newly diagnosed chronic myeloid leukemia in chronic phase. More than 1,100 patients participated in this landmark study, which included a crossover design for patients who progressed on the control arm.
Results of this study — with very mature follow-up — remain truly remarkable. With median follow-up of 10.9 years, the 10-year OS rate is 83.3%. No major new toxicities have emerged.
‘Seismic’ impact
The impact of imatinib on our framework for cancer treatment has been seismic.
As Dan L. Longo, MD, pointed out in the excellent editorial that accompanied this study, tyrosine kinase inhibitors have caused a paradigm shift in our concept of cancer treatment, with imatinib as the prototype molecule.
A disease for which the only curative option had been allogeneic bone marrow transplant can now be controlled — if not cured — long term by a highly specific targeted and orally available agent, returning most patients to a normal quality of life for many years.
The introduction of this drug validated the concept that targeting a specific aberrant gene product could change the clinical course of a malignant neoplasm.
However, it also provided proof of the concept that cure is not the only meaningful endpoint in treatment, and achieving very low levels of residual disease in the long term is compatible with excellent survival and quality of life. In many patients, this state of minimal residual disease is maintained for long periods, even after treatment cessation.
Of course, subsequent studies have investigated the phenomenon of imatinib resistance and the development of second- and third-generation TKIs.
Many studies — some of which were presented in December at the ASH Annual Meeting and Exposition — have explored the feasibility of stopping TKI therapy after varying periods on treatment. These are important data for practicing oncologists who may need to advise patients on long-term therapy, when they may be experiencing significant financial burden from the use of these drugs for many years.
Cost and adherence
Although no one can question the extraordinary impact of TKIs in this disease, how do the data from the IRIS study relate to real-world practice in the United States?
A study of initiation and adherence to TKI therapy among Medicare beneficiaries with CML revealed some disturbing data on the impact of out-of-pocket costs on the use of these drugs.
Winn and colleagues used SEER–Medicare data to identify 393 patients aged 66 or older who were enrolled in a Medicare Part D plan and who were alive at least 180 days after CML diagnosis. Researchers investigated time from diagnosis to initiation of TKI therapy, and the adherence to therapy during the first 6 months from initiation.
To place this study in context, it is important to remember that the price of newly approved anticancer drugs is typically more than $10,000 per month.
Although prescription drug coverage reduces out-of-pocket costs for most patients, the complexities of Medicare Part D coverage mean that many patients will have to pay as much as 30% of the total cost, and those rates can be even higher until a threshold level is reached. However, for those patients who qualify for low-income subsidies, out-of-pocket costs can be much lower — often by orders of magnitude.
The study showed that only 68% of patients initiated their prescribed TKI therapy within 180 days of diagnosis. Because there are several studies that show delayed initiation of therapy is associated with inferior outcome, this is a disturbing statistic.
Those patients who qualified for a cost-sharing subsidy started TKI therapy at a median 58 days from diagnosis, compared with a median 108 days for those who did not (P = .04). This emphasizes the presence of a coverage gap for those who do not qualify for a subsidy and may wait, for example, for a new calendar year before they start treatment.
The analysis also revealed potential disparities. For example, age older than 80 years or living in an urban vs. large metropolitan area appeared associated with later TKI initiation. The number of patients from rural communities was too small to analyze, but there is at least a suggestion that those outside major metropolitan areas may be at a disadvantage.
Overall adherence to TKI therapy at 6 months was 61% and, again, appeared lower among patients aged 80 years or older. The reduced initiation and adherence to therapy were not associated with lower survival rates, but because the eligibility for the study required patients to be alive 180 days from diagnosis — and given the relatively short term over which adherence was measured — this is maybe not surprising.
Consequences of high costs
Because of the actual out-of-pocket costs for some of these new agents, many patients hesitate before starting or continuing expensive therapies.
Studies have estimated that about half the elderly population has less than $14,000 per year in available funds. If they lack any subsidies for cost sharing, they will start with $3,000 in out-of-pocket costs, which will fall to a little more than $500 per month until they reach their annual threshold.
Even when generic imatinib becomes available, out-of-pocket costs are expected to be more than $100 per month — still a lot of money for those with limited means.
In addition to the potential and pervasive disparities that are a consequence of the high cost of these drugs and the complexities of Medicare reimbursement, these data also raise questions about the value proposition for many new anticancer agents.
Imatinib and its second- and third-generation successors are blockbuster drugs, targeting a single gene product that is the primary driver of malignant transformation in CML.
Even in this situation, in which the benefits of therapy are clear and the risks for delayed treatment are concerning, out-of-pocket costs are a significant obstacle for treatment adherence for a high proportion of patients. They are trading off the potential for many years of good-quality survival against high short-term cost.
The situation is murkier for patients with other more complex cancers, with more genetic abnormalities that may evolve over time, and for which targeted agents — although undoubtedly changing the natural history of their disease — have lower long-term benefit. In these diseases, it is not clear whether high out-of-pocket costs will affect treatment initiation or compliance, but it is certainly a major concern.
Orally available TKIs and other targeted agents are revolutionizing cancer care, but financial constraints put the societal benefits of these drugs at risk.
As one of my former mentors told his patients, “The pills only work if you take them.” It seems as though, even in the best clinical situation, a sizable percentage of our patients choose not to take potentially life-extending and health-extending cancer therapies. For many, especially the elderly, the cost of living is simply too high.
Attention to drug costs is part of the solution. As I mentioned in my last editorial in the March 10 issue of HemOnc Today, I believe we have our part to play by limiting the use of these drugs to situations in which we are confident of meaningful benefit.
Another positive move would be to extend the cost-sharing subsidies across a higher proportion of Medicare beneficiaries to reduce their financial burden. Is this something that the new administration could consider as it thinks about changes to the Affordable Care Act?
References:
Hochhaus A, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1609324.
Longo D. N Engl J Med. 2017;doi:10.1056/NEJMe1700833.
Winn AN, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.67.4184.
For more information:
John Sweetenham, MD, FRCP, FACP, is HemOnc Today’s Chief Medical Editor for Hematology. He also is senior director of clinical affairs and executive medical director of Huntsman Cancer Institute at University of Utah. He can be reached at john.sweetenham@hci.utah.edu.
Disclosure: Sweetenham reports no relevant financial disclosures.